Knee osteoarthritis (KOA) seriously reduces quality of life and is a major threat to the health of the middle-aged and elderly. This study aimed to assess the efficacy of Miao crossbow needle therapy vs. acupuncture for KOA therapy.This multicenter, randomized controlled trial was performed at three hospitals between April 2016 and December 2016. The patients were randomized to receive crossbow needle (CN) or acupuncture (AT). All treatments were completed within 46 days. Evaluation of treatment was conducted on the 46th, 62nd, and 77th days. The primary endpoint was change of Western Ontario and McMaster Osteoarthritis Index (WOMAC) score on the 46th day. The secondary endpoints included WOMAC score, the Lysholm knee score, the Japanese Orthopedic Association (JOA) knee score, visual analog scale (VAS), and the MOS 36-item short-form health survey (SF-36), on the 46th, 62nd, and 77th day.P < 0.001]. In the CN group, the WOMAC score was lower at all three time points , while the Lysholm knee score (P = 0.03) and JOA score (P = 0.013) were higher and the VAS score (P = 0.011) was lower on the 77th day.Finally, data of 301 participants were analyzed for the efficacy of treatment. Compared with AT, there was a larger change of WOMAC score in the CN group after treatment [− 25.0  vs. − 18.8 , Both Miao crossbow needle therapy and acupuncture reduced the WOMAC score. Miao crossbow needle therapy can be an alternative method for treating patients with knee osteoarthritis.ChiCTR-INR-16008032. Registered on 12 March 2016.ChiCTR,  Knee osteoarthritis (KOA) is a common chronic progressive disease, mainly involving articular cartilage retrogression and secondary hyperostosis. Its onset is associated with multiple factors like age, body mass index (BMI), sex, inflammation, long-term irrational exercise, and genetics. The main clinical manifestations include joint swelling, stiffness, and dysfunction. KOA and obesity are considered to be the most common chronic diseases affecting the health of Americans aged 50 to 84 . More thThe repair capacity of articular cartilage appears to be extremely limited, and damage is often irreversible. All existing medical measures  fail to reverse the pathological changes of damaged articular cartilage. Therefore, the treatment of KOA to a great extent aims to relieve or eliminate pain, reduce inflammation, improve or restore joint function, delay disease progression, and improve patients’ quality of life . To thisKnee pain belongs to the category of chronic pain of the motor system. As early as 1996, during a conference in Milan , it was recognized as one of the indications for acupuncture . Furtherleng gu feng”, and “mao tou feng”  and the AT group [− 18.8 ]  reported adverse reactions in the two groups during the trial: six 3.9%) in the CN group and 10 (6.5%) in the AT group. The adverse reactions in the CN group were all redness and slight itching of the knee joint skin at the procedure site. The patients were advised not to scratch, and the symptoms disappeared the next day without treatment. In the AT group, adverse events included four (2.6%) cases of subcutaneous hematoma , three cases (2.0%) of bending of the needle (caused by patients’ voluntary changes of body position during acupuncture without doctor’s permission), two cases (1.3%) of sticking of needle (caused by hypertension as the patients received acupuncture for the first time), and one case (0.7%) of dizziness during acupuncture treatment  (Table .9% in thThis study shows that the efficacy of Miao crossbow needle therapy is no worse than that of acupuncture therapy. The WOMAC score was lower after treatment in the CN group on the 46th, 62nd, and 77th day. In addition, the VAS score was lower and the Lysholm knee score and JOA score were higher in CN group. The adverse events of crossbow needle therapy and acupuncture therapy were not significantly different.This study used acupuncture as the comparison. A randomized controlled trial in 570 patients with KOA during the course of 26 weeks concluded that acupuncture could provide significant improvement in joint function and pain relief compared with sham acupuncture for the treatment of KOA . By carrChinese studies on acupuncture indicated that early KOA belongs to the grade II evidence-based acupuncture disease spectrum and patients may receive an overall improvement with acupuncture-based therapy or acupuncture therapy alone . AdvanceA needle roller is usually used to replace the traditional crossbow medicinal needle in modern clinical practice , where tGaultheria yunnanensis, Periploca forrestii Schltr., and Chinese alangium root, feature anti-inflammatory, analgesic, and sedative effects [As a combination therapy, the efficacy of crossbow needle therapy might be associated with two factors: needles and drugs. First, the repeated mechanical stimulation of the needle roller on the skin surface can convert mechanical energy to thermal energy, which will dilate the small local vessels and accelerate blood circulation, thus strengthening the nutritional supply and metabolism at the lesion site and thereby promoting recovery from disease. Secondly, some components in the crossbow medicinal liquid, such as raw kusnezoff monkshood root,  effects –34, whicStudies have previously shown that Miao crossbow needle therapy could reduce the WOMAC score of patients after treatment, reduce the pain and stiffness symptoms of patients with KOA, and improve their joint function , 35. OneSince the extraction of knee joint fluid would cause trauma, which would then hinder the following rolling acupuncture treatment on the knee surface using the needle roller, detection of the changes in knee joint fluid of participants was not designed in our protocol. The insufficient objective indicators required to illustrate the clinical efficacy of Miao crossbow needle therapy will be optimized in future research designed to explore the mechanism of crossbow therapy. Another limitation is that no blank control group was set. In addition, the efficacy of crossbow acupuncture in the treatment of KOA was not based on objective measures, but on subjective measures of the patient on a scale. Finally, no cost analysis was performed.Both Miao crossbow needle therapy and acupuncture reduced the WOMAC score. The results of the WOMAC, JOA, Lysholm knee score, and VAS scales on the 77th day suggested that the longer-term effect of crossbow acupuncture might be better than that of acupuncture. This therapy can be used as an alternative therapy for KOA.


This study aimed to develop and validate the Food and Nutrition Literacy Questionnaire for Chinese School-age Children (FNLQ-SC).A comprehensive literature review and qualitative study were initially performed to identify the dimensions and core components of food and nutrition literacy. A cross-sectional survey of 4359 school-age children was conducted, and junior middle school students were used to analyze the reliability and validity of the questionnaire (n = 2452). The reliability of the questionnaire was determined by internal consistency, the construct validity was assessed by exploratory factor analysis (EFA) and confirmatory factor analysis (CFA), and the content validity was assessed by the Pearson correlation coefficient.2 = 0.226, F = 81.401, P<0.05).From the literature review and qualitative methods, 19 core components of the FNLQ-SC were developed, including one dimension of food and nutrition knowledge and understanding, and four skill dimensions . The overall FNLQ-SC questionnaire had acceptable internal consistency (Cronbach’s α = 0.698). The EFA of skill components extracted 5 factors that were included in the conceptual framework in a slightly different model, and the cumulative contribution of variance accounted for 50.60% of the overall variance. The CFA of skill components showed an acceptable fit in general and the root mean square error of approximation (RMSEA) was 0.070 (between 0.50 to 0.80). The communality was greater than 0.20 for all components. The Pearson correlation coefficients between each dimension and the overall questionnaire ranged from 0.370 to 0.877. The average FNLQ-SC score of all 4395 participants was 61.91 ± 9.22, and the score for the knowledge and understanding dimension was higher than that for the skill dimensions. Multiple linear regression analysis indicated that not only social demographic characteristics  but also the home food environment were predictors of food and nutrition literacy in school-age children (RThe Food and Nutrition Literacy Questionnaire (FNLQ-SC) developed here had good reliability, and it can potentially be a useful instrument for assessing food and nutrition literacy among Chinese school-age children. The Global Burden of Disease Study 2017 indicated that dietary risks were responsible for 22% of all deaths and 15% of all disability adjusted of life years (DALYs) among adults globally, and these numbers were even higher in China  [Improving the dietary habits of children is a multifaceted societal task that demands an understanding of the social context and individual food-related skills and abilities . At indiThere are several instruments for measuring food and nutrition literacy, such as the Nutrition Literacy Assessment Instrument (NLAI) , the NutOverall, food choices and dietary quality in childhood can affect the lifelong risk of nutrition-related diseases , 15. AccIn China the health literacy among residents has been monitored nationwide from 2008. While the health literacy assessment instrument can reliably identify individuals with health literacy skills, it is not specific to nutrition. This distinction is important because literacy is situation specific, and someone’s capacity may be perfectly adequate in one setting and marginal or inadequate in another. Functional literacy is situation specific, and the instruments for measuring Chinese health literacy are likely inadequate to measure food and nutrition literacy.Our study aimed to develop and validate the Food and Nutrition Literacy Questionnaire for Chinese School-age Children (FNLQ-SC) to assess the food and nutrition capacity of children and provide targets for further nutrition education and intervention.The development of the Food and Nutrition Literacy Questionnaire for Chinese School-age Children (FNLQ-SC) mainly comprised two stages:First, the conceptual framework and dimensions of food and nutrition literacy in school-age children were preliminarily constructed based on a literature review and expert interview, considering the cognitive level and dietary behavior problems of school-age children. A systematic retrieval of the literature was performed using the key words of “food literacy, nutrition literacy” from the earliest data to June 2018, in the English and Chinese databases of PubMed, Web of Science, ScienceDirect, CNKI and WanFang. And additional publications were identified by conducting a hand search of references in included publications. Then an expert panel meeting was convened in August 2018, to discuss face to face and develop a provisional framework of food and nutrition literacy of school-age children. The experts were qualified with adequate experience in nutrition, health education and primary education, who would participate in the following Delph consultation, in which their detailed information would be presented.In this study, food and nutrition literacy is defined as a collection of interrelated knowledge, skills and behaviors required to plan, manage, select, prepare and eat foods to meet needs and determine food intake . AccordiSecond, a qualitative consensus study was conducted to determine the dimensions and core components of the FNLQ-SC. A two-stage electronically distributed Delphi consultation was held with 15 food and education experts, based on the following criteria: 1) experts with adequate experience in nutrition, health education and primary education; 2) representatives of Chinese nutrition society. The Delphi study was conducted from September 2018 to December 2018, which consisted of two rounds. In the first-round survey a Delphi questionnaire with the outline of a provisional food and nutrition literacy core components was mailed to each expert. Each member was asked to rate the appropriateness of each statement using a five-point Likert-type scale . A consensus in this study was defined a priori when agreement (4–5) was provided by a minimum of 75% of the experts. A summary of the first-round survey was discussed by our research team and the FNL components was revised. Then we implemented a second-round survey using the same method as well as the revised components, until a compromise was reached.Based on the conceptual framework identified at stage one, a pool of 51 questions was generated to measure the core components of food and nutrition literacy. The questions included 5-point Likert-type questions , choice questions , and fill-in-the-blank questions (“Fill in your height and weight.”). Because the questionnaire was developed with the children’s real-life situation in mind, sometimes one question assessed more than one component of food and nutrition literacy. Therefore, the reliability and validity were analyzed based on the components, not the questions.The appropriateness of the questionnaire was evaluated by food and nutrition experts in the study steering group, and the readability and difficulty of the questionnaire were evaluated and adjusted by two senior teachers in primary and junior middle schools. After redundant items were eliminated, the final questionnaire included 50 questions.From Baoding district, Hebei Province of China, five intermediate level schools (three primary and two middle schools) were selected as investigation sites, according to regional socioeconomic and student’s population density.The participant students were voluntarily recruited in June 2019. The inclusion criteria of participant students were as follows: being apparently healthy without severe acute or chronic physical and mental diseases, being able to fill out the self-administrated questionnaire. And the students who did not meet the inclusion criteria were excluded. Based on this, the investigators explained the investigation protocol to all 4520 students from grade 3 to 8 and their parents or guardians while parent-teacher conference. Finally, written informed consent was obtained from 4359 children and their guardians, the response rate was 96.4%. Even though there was not formula calculating, the sample size was sufficient to draw conclusion referring to literatures .For all participants, food and nutrition literacy was assessed using the FNLQ-SC, and social demographic characteristics , home food environment, and school nutrition education were investigated by a self-reported questionnaire. Family affluence status was assessed using the adjusted Family Affluence Scale (FAS), which is a six-item scale that was used in a WHO collaborative cross-national study of the Health Behavior in School-aged Children (HBSC) . ConsideThe study protocol was approved by the Peking University Institutional Review Board , and conducted according to the Declaration of Helsinki and ethical guidelines. The privacy of participant students and the confidentiality of their personal information would be protected.Several psychometric properties of the FNLQ-SC were assessed. To reduce the effects of cognition difference, only the junior middle school student samples were used to analyze the reliability and validity of the questionnaire (n = 2452).The internal consistency reliability was measured by calculating the Cronbach’s alpha coefficient of the overall questionnaire as well as of each dimension and each component. For the overall questionnaire, a coefficient greater than 0.7 indicated acceptable reliability –22.The floor and ceiling effects were assessed by the proportion of respondents who had the lowest or highest score .P<0.05) and total variance explained were used for the evaluation of factor analysis. Oblique rotation and principal axis factoring (PAF) extraction were used to explore the existing factorial pattern. The number of factors was determined through eigenvalues above 1, the percent of explained variance by each factor, scree plot and interpretability criteria. Confirmatory factor analysis (CFA) was also conducted for the skill domain, and the root mean square error of approximation (RMSEA) being equal or smaller to 0.08 was considered an acceptable fit (≤0.05 as a good fit). Two incremental fit indexes were selected, the goodness of fit index (GFI) and adjusted goodness of fit index (AGFI), which values at or above 0.90 were considered a good fit.To assess the construct validity of the scale, exploratory factor analysis (EFA) was used to explore whether the statements in the questionnaire reflected the conceptual framework of the FNLQ-SC. Considering that the knowledge and skill dimensions were based on different logical frameworks and there was only one dimension in cognitive domain, we analyzed only the components of the skill domain by EFA. The Kaiser-Meyer-Olkin (KMO) measure (>0.7) was used to determine the sampling adequacy. Bartlett’s test of sphericity . Finally, 19 core components of the FNLQ-SC were determined, including one dimension of food and nutrition knowledge and understanding, and four skill dimensions , as well as three levels of functional, interactive and critical literacy, as shown in A total of 25 core components of food and nutrition literacy in school-age children were originally proposed. An electronically distributed two-round Delphi consultation was conducted. The response rates of both rounds were 100%, and the average authority degree of the experts was 0.8767. The mean of the total scores (4.60) for all components in the second round was better than that in the first round (4.38), and the total coordination coefficient was 0.22 in the first round and 0.18 in the second round  and 2105 girls (48.29%). Among those, the junior middle school student samples (n = 2452) were used to analyze the reliability and validity of the questionnaire, and the total samples (n = 4359) were used for the final study. The sociodemographic characteristics of the two study samples are shown in The overall FNLQ-SC questionnaire had acceptable internal consistency (Cronbach’s α = 0.698). The Cronbach’s α coefficients for the five dimensions , were 0.452, 0.300, 0.244, 0.148, and 0.436, respectively.An additional alpha test that deleted components one at a time showed that removing components did not result in an increase in the Cronbach’s alpha, showing that each component had acceptable internal consistency with the overall questionnaire, as seen in CFA indicators of the skill domain showed an acceptable fit in general. The RMSEA was 0.070 (between 0.50 to 0.80), and GFI and AGFI were close to 0.90, being 0.838 and 0.813 respectively.P<0.001). Finally, EFA extracted 5 factors with eigenvalues greater than 1, and the cumulative contribution of variance accounted for 50.60% of the overall variance. The model identified five factors as “Factor 1, selecting and eating”, “Factor 2, access and preparation”, “Factor 3, food labels and measurements”, “Factor 4, picky eating”, and “Factor 5, eating snacks”. The communality was more than 0.20 for all components, as shown in Only 14 components of the skill dimensions were analyzed by EFA. The KMO test showed sampling adequacy (KMO = 0.738), and Bartlett’s test confirmed that factor analysis was appropriate  was higher than the score for skill dimensions, and the score for eating was the lowest (60.45±11.00).P<0.05).As shown in 2 = 0.226, F = 81.401, P<0.05), as shown in Multiple linear regression analysis indicated that not only individual and family demographic characteristics but also the home food environment were predictors of food and nutrition literacy in school-age children . For the skill domain, the exploratory factor analysis (EFA) extracted 5 factors that were included in the conceptual framework but in a slightly different model, and the confirmatory factor analysis (CFA) showed an acceptable fit in general. The communality was more than 0.20 for all components. The Pearson correlation coefficients between the dimensions  and the overall questionnaire were more than 0.6, which indicated a strong correlation. Using the questionnaire to assess food and nutrition literacy and its related factors in school-age children, the results showed that literacy was low; both social demographic characteristics and the home food environment were predictors of food and nutrition literacy in school-age children.Improving dietary habits demands that individuals have food-related skills and abilities and requires an understanding of the social context. In this regard, nutritional science and education researchers are currently discussing the concepts of nutrition literacy and food literacy. A systematic review 2018)  revealed  revealeWe used the Cronbach’s α coefficient to analyze the internal consistency. The total Cronbach’s α was 0.698, which indicated that the overall questionnaire had acceptable internal consistency. However, the Cronbach’s α coefficient of various dimensions was low, ranging from 0.148 to 0.452. One possible explanation for the low internal consistency values of the dimensions is that internal consistency reliability values depend on the number of items in the scale . Since tConsidering that the knowledge and skill dimensions are based on different logical frameworks, some studies have independently analyzed the variables of cognitive and skills domains by exploratory factor analysis (EFA) . On the P>0.05). Additionally, our results showed that the home food environment was significantly correlated with children's food and nutrition literacy. The total score of food and nutrition literacy was higher for the children who often had fruit at home, rarely ate out, did not eat in front of a screen, and frequently communicated about food and nutrition information with their families (P<0.05). Overall, these results are a general reminder to schools of the different learning needs of children from different family backgrounds: children in rural areas, younger children, children from large families, and children from families with a poor economic status and food environment should be the main target of nutrition education and nutrition improvement. The study highlights the need for continuous improvement in the nutrition education curriculum of schools in China, particularly highlighting the need for placing greater attention on the development of practical food and nutrition skills alongside more traditional food and nutrition knowledge. Additional studies are needed to more fully assess and understand the prediction capability of the FNLQ-SC.Using the FNLQ-SC, we assessed the food and nutrition literacy level of 4359 school-age children in grades 3–8. The results were similar to those of other studies. The FNLIT assessment of 803 students aged 10–12 years from elementary schools in Tehran, Iran, showed that more than half of the children (69%) had high levels in the cognitive domain of the FNLIT, but in the skills domain, very few (3%) scored highly . Always Overall, the FNLQ-SC has good reliability to some extent, and it could potentially be a useful instrument for assessing food and nutrition literacy in Chinese school-age children, despite the choice of convenience sampling and the risk of self-reported bias. It should be revised furtherly. The development and validation of an appropriate instrument is an essential step for food and nutrition literacy research in children. To our knowledge, this is the first reported food and nutrition literacy questionnaire for school-age children in China. The questionnaire can potentially be used with other Chinese populations. Of course, because the investigation sites and sample couldn’t represent Chinese school-age children, a nationwide survey of FNL was necessary to identify the target population for further nutrition education, to develop targeted interventions to improve the food and nutrition literacy and dietary quality of school-age children, thus further improving their health.S1 Table(DOCX)Click here for additional data file.S1 Dataset(XLSX)Click here for additional data file.S1 File(PDF)Click here for additional data file.S2 File(PDF)Click here for additional data file.


The World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) introduced in 2007, and updated in 2018, nutrition-related recommendations for cancer prevention. Previous studies generally reported inverse associations of breast cancer with the 2007 recommendations, while no study has yet evaluated the association with the 2018 guidelines. We investigated the association between adherence to the 2018 WCRF/AICR recommendations and breast cancer risk in a case–control study from Italy and Switzerland (1991–2008) including 3034 incident histologically-confirmed breast cancer cases and 3392 hospital controls. Adherence to the 2018 guidelines was summarized through a score incorporating eight recommendations , with higher scores indicating higher adherence. Odds ratios (OR) were estimated using multiple logistic regression models. We also conducted a meta-analysis including 15 additional studies using random-effects models. In our case–control study, adherence to the 2018 WCRF/AICR guidelines was inversely associated with breast cancer, with ORs of 0.60 , 0.51–0.70) for a score ≥5.5 vs. ≤4.25, and of 0.83  for a 1-point increment. In our study, 25% of breast cancers were attributable to low-to-moderate guideline adherence. In the meta-analysis, the pooled relative risks (RRs) were 0.73  for the highest vs. the lowest WCRF/AICR score category, and 0.91  for a 1-point increment. This work provides quantitative evidence that higher adherence to the WCRF/AICR recommendations reduces the risk of breast cancer, thus opening perspectives for prevention. After lung, breast cancer is the second most common neoplasm worldwide. In women, it accounts for almost 1 in 4 cancer cases and is the first cause of cancer death in most countries . PrimaryThus far, only very few modifiable risk factors for breast cancer have been recognized, including overweight/obesity, menopausal hormone replacement therapy (HRT), low physical activity and sedentary behavior, with possible differential associations in the life course of women ,5. DespiIn 2007, the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) published the Second Expert Report, in which defined a set of evidence-based public health recommendations on body fatness, physical activity and diet with the aim of reducing the burden of cancer . In the Previous studies showed that higher adherence to the 2007 WCRF/AICR nutrition-related recommendations reduced the risk of total cancer and of specific cancers . An inveIn the current report, we assessed the relation between adherence to the WCRF/AICR nutrition-related recommendations for cancer prevention and breast cancer risk in a large Mediterranean population, and conducted a meta-analysis of available studies on the topic.Data came from a multicentric case–control study carried out between 1991 and 1994 in 6 Italian areas  and between 1992 and 2008 in the Canton of Vaud, Switzerland ,26. Over2). The interviewers measured the waist circumference (2 cm above the umbilicus). We collected information on occupational/household and leisure time physical activity at different ages . Cases and controls defined their level of occupational/household physical activity as very heavy, heavy, intermediate, standing or sedentary, depending on their occupation/household activity. Leisure time physical activity was based on the total number of hours of physical activity  per week . Women were asked for menopausal status at the time of cancer diagnosis. Information on dietary habits during the two years before diagnosis (for cases) or hospital admission (for controls) was assessed through a food frequency questionnaire (FFQ), which included 78 foods and recipes. The FFQ was tested for its validity and reproducibility with satisfactory results [In each centre, a structured questionnaire was administered to both cases and controls by trained interviewers. The questionnaire included questions about sociodemographic factors, dietary and lifestyle habits , anthropometric measurements, menstrual and reproductive factors, a personal medical history, and a family history of cancer. As for anthropometric measures, the questionnaire collected information on body shape at 12 years , and self-reported height and average weight at age 30 and 50, as well as before diagnosis (cases) or interview (controls). Body mass index (BMI) was calculated as weight (kg) divided by squared height  of breast cancer and the corresponding 95% confidence intervals (CI) for each individual recommendation, for the overall WCRF/AICR score, and for the diet WCRF/AICR score were estimated using unconditional multiple logistic regression models. We fitted a first model with terms for age, study centre, and education, and a second one with further terms for parity, menopausal status and age at menopause, use of oral contraceptive and HRT, tobacco smoking, non-alcoholic energy intake (according to quintiles among controls), family history of breast cancer, and diabetes. When evaluating the association with individual recommendations, analyses were also adjusted for BMI, physical activity, and alcohol intake . We performed tests for trend including the variable in its ordinal form. In addition, we carried out a sensitivity analysis by excluding alternately each component in turn from the original 2018 WCRF/AICR score to evaluate the relative importance of each recommendation. The potential effect modification of menopausal status was tested using a likelihood ratio test comparing the likelihoods of models with and without terms for interactions between menopausal status and the WCRF/AICR score variable. We also estimated the population attributable fraction, representing the proportion of breast cancers that would be avoided if the whole population were highly adherent to the WCRF/AICR recommendations .The aforementioned analyses were conducted using the SAS software, version 9.4 .Using PubMed with terms breast, cancer/neoplasm/carcinoma and World Cancer Research Fund/WCRF in October 2019, we identified observational studies on the association between adherence to the WCRF/AICR guidelines (measured by means of an a priori score) and the risk of or mortality from breast cancer. Fifteen publications were identified and considered in the meta-analysis ,39,40,41p < 0.1) [2 statistics [2 > 50% representing substantial heterogeneity). We conducted both an extreme quantile meta-analysis  and a linear dose-response meta-analysis . Studies were included in the extreme quantile and/or dose-response meta-analyses based on data availability. One study providing only the RR for 1-SD increase in the score was also considered in the dose-response meta-analysis [We calculated the pooled RR and the corresponding 95% CI by means of fixed or random effects models, based on the results of the Cochrane Q test (heterogeneity was defined as p < 0.1) . Inconsiatistics  that meaanalysis . For theanalysis ,21,37 oranalysis . In the analysis . From thanalysis . A sensiThe statistical analyses for meta-analysis were conducted using the STATA software .The distribution of selected characteristics in breast cancer cases and controls is shown in Adherence to the recommendations on physical activity, wholegrains, vegetables, fruit and beans, fast foods and other processed food high in fat starches or sugar, sugar sweetened drinks, and alcohol was associated with a significant lower risk of breast cancer, with significant decreasing trends for increasing adherence . AdherenSimilar results (but apparently less strong) were observed when analyzing the 2007 version of the score . The ORsIn a sensitivity analysis, consistent results were found when omitting each recommendation one by one from the score: the ORs comparing extreme categories varied between 0.54 and 0.69. In particular, the OR was 0.56  when removing from the score the recommendation on breastfeeding.2 = 73.5%)  and cohort studies , and for pre-  and post-menopausal women . When we included for the study by Nomura et al. [The description of the studies included in the meta-analysis is provided in = 73.5%)  panel A.a et al.  the resu2 = 70.2%) RR reduction, based on 16 studies (15 publications) including the present one (2 = 49.4%) for cohort and 0.83  for case–control studies. The exclusion of each study in turn did not appreciably influence the summary result, and the estimated RRs were always significant. In particular, the pooled RR was still 0.91  when omitting the pooled analysis by Jancovic et al. [In the linear dose-response meta-analysis, each 1-point increase in the score was associated to a 9% .p = 0.143).No significant publication bias was detected (In the present large case–control study, higher adherence to the diet, adiposity, and physical activity recommendations provided by the WCRF/AICR Third Expert Report was associated with reduced breast cancer risk, independently of menopausal status. The results from the sensitivity analysis suggest that the association was not driven by adherence to one specific recommendation, but rather by the combined and synergic effects of the various score components. The meta-analysis indicates that women who highly adhere to the recommendations had an approximately 30% lower risk of breast cancer compared to those with low adherence and that each 1-point increment in the WCRF/AIRC score is associated with a significant 9% reduced risk. Published studies vary in design, baseline population characteristics, data collection, number and definition of recommendations operationalized in the score, and adjustment factors; the observed heterogeneity is therefore not surprising. In any case, they are largely supportive of the preventing role of following the WCRF/AICR guidelines on breast cancer. Indeed, estimates of the RR of breast cancer comparing extreme score categories were below unity in all but one studies , and werOnly a few reports investigated the association between the 2018 release of the WCRF/AICR recommendations and cancer risk ,46,47,48Our findings are in agreement with the conclusions of a systematic review  and withIn our case–control study, we observed a significant inverse association between a score reflecting adherence to the WCRF/AIRC dietary recommendations and breast cancer, in agreement with the study by Lavalette et al. , which rTo improve the comparability of our results with those from future studies relying on the 2018 WCRF/AICR guidelines, in the construction of the score, whenever possible, we followed the standard scoring approach recently proposed by a NCI-led collaborative group, which included, among the others, researchers from AICR and WCRF International . HoweverThe current analysis is based on data collected between 1991 and 2008 while looking at associations with more recent recommendations. Thus, the observation that the protection associated to the adherence to the WCRF/AICR recommendations was found in a population unaware of those guidelines supports the absence of major information bias and hence the validity of the association. The data were collected at multiple centres across two countries. However, similar structured questionnaires and coding manuals were used in all study centres, and interviewers were centrally trained, thus improving the reliability of data collection across study centers. In addition, a comparison across countries indicated a similar distribution of age, menopausal status, and family history of breast cancer, while Swiss women were more educated and more often nulliparae than Italian ones [Hospital controls may have different dietary habits from those of the general population, but we minimized bias by excluding from the control series patients admitted to hospital for conditions which may have led to long-term diet modifications. The strengths of the present case–control study lie in the satisfactory reproducibility and validity of the FFQ ,28,57, tIn conclusion, the present work provides quantitative evidence that greater adherence to the nutrition-related WCRF/AICR recommendations is favorably related to breast cancer risk, and thus suggests that encouraging adherence to the guidelines is a valuable public health strategy for breast cancer prevention.


The pressure pain threshold (PPT) may be an efficient approach to screen and evaluate orofacial pain. However, the results of previous PPT studies have varied greatly. The aim of this paper was to determine whether the PPT is an efficient approach for screening and evaluating orofacial pain.  The search yielded 123 articles. After removal of duplicates and screening of abstracts, 32 articles were selected for further evaluation. The Cochrane Collaboration tool for assessing the risk of bias was used for the evaluation of the studies. 2/s to 2 kg/cm2/s. Descriptions of the PPT examination points also varied, from very precise and repeatable to a simple listing of anatomical points. The number of measurements varied from 1 to 5 at each visit. The intervals ranged from 5 seconds to 15 minutes. However, some studies confirmed that the pressure algometer is an effective tool for determining the source of orofacial pain.  The studies covered a total of 4403 adult patients, aged 16-62, and 30 children. The studies investigated the reliability and validity of the PPT  in TMD patients. The PPT was investigated in relation to headache, menstrual cycle, oral contraception, occlusal interference, and occlusal appliances. Generally, the risk of bias was low to unclear. Some structural limitations were inherent in the studies, such as small samples and short duration of the testing involved. Also, the analyzed studies lacked consistency in study design and patient management. Pressure increase values differed from 20 kPa/s to 50 kPa/s and from 0.5 kg/cm Based on the analyzed articles, the authors argue that the PPT is not an efficient approach for screening and evaluating orofacial pain. What is more, it should not be used as the only diagnostics tool for patients with orofacial pain. Importantly, however, additional factors should be considered in the future for the evaluation of the PPT, including body symmetry and posture, hormone levels and the menstrual phase in women, and the use of medications and its influence on the PPT. Further clinical trials should also be performed on the PPT, examining head and neck pain patients, with more precise study design and larger samples. According to the definition of pain proposed by the Subcommittee on Taxonomy of the International Association for the Study of Pain, pain is a subjective sensation which is individual and depends on numerous contributing factors. Pain in the orofacial region influences everyday life, largely by limiting the ability to chew or speak, which calls for the investigation of the problem to improve diagnosis and treatment of orofacial pain patients . MyofascThe PPT may be an easy and efficient method to screen and evaluate orofacial pain . The PPTThis review assesses the efficacy and usefulness of the pressure pain algometer in patients experiencing orofacial pain, on the basis of clinical trials performed in a recent 20-year period (1997-2017). Importantly, the number of such clinical trials remains limited. By the application of the PICO method , the focused question was developed, namely, whether pressure algometry is an efficient approach for screening and evaluating orofacial pain. There has been no systematic review to date of the usefulness of the pressure algometer among orofacial pain patients.registration number CRD42017079566).The protocol for this systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) (Inclusion criteria are as follows: articles published in a recent 20-year period (1997-2017), written in English, and covering human research.Exclusion criteria are as follows: articles published earlier than 1997, not written in English, animal studies, studies with the use of medications, and articles examining receptor interactions.Literature search was performed from 1 December 2017 through 12 January 2018, covering PubMed, Dentistry and Oral Sciences Source, Web of Science, ProQuest, Scopus, Medline (EBSCO), and ScienceDirect. The selection key is presented in the PRISMA diagram .The primary search strategy involved the identification of four primary keywords and then was adapted to other databases by adding two secondary keywords. The primary keywords were pressure threshold, masseter muscle, facial pain, and tmj. The secondary keywords were temporal muscle and algometer.The search strategy equation for PubMed: (“Pain Threshold”[Mesh] AND “Temporomandibular Joint”[Mesh]) AND . Adding temporal muscle and algometer (secondary keywords) to the search phrase returned “0” articles. Thus, only primary keywords were used in this search.The search strategy for Scopus: TITLE-ABS-KEY  AND  OR LIMIT-TO  OR LIMIT-TO  OR LIMIT-TO  OR LIMIT-TO  OR LIMIT-TO  OR LIMIT-TO ). Adding temporal muscle and algometer (secondary keywords) to the search phrase returned “0” articles. Thus, only primary keywords were used in this search. Nine articles were identified with this search strategy, two of which were older than 20 years. The years specified for the search strategy are the dates of publication of the articles found. The Scopus database dictionary uses the phrase “pressure threshold” instead of “pain threshold”; thus, the keyword for the search strategy was modified.The search strategy for Medline: . The search with the primary keywords returned 36 articles. After adding temporal muscle and algometer (secondary keywords), the search returned only one article. Thus, only primary keywords were used in this search.The search strategy for ProQuest: pain threshold AND masseter muscle AND facial pain AND tmj AND temporal muscle AND algometer.The search strategy for Dentistry and Oral Sciences Source: pain threshold AND masseter muscle AND facial pain AND tmj. Adding temporal muscle and algometer (secondary keywords) to the search phrase returned “0” articles. Thus, only primary keywords were used in this search.The search strategy for ScienceDirect: pain threshold AND masseter muscle AND facial pain AND tmj AND temporal muscle AND algometer. The search strategy for ScienceDirect yielded 54 titles, of which 35 were articles.In total, 74 articles were screened by two researchers (the two authors whose names appear first) according to the above criteria, excluding duplicates. When the two researchers disagreed as to the selection, the third author made the decision, whether the article should be included into the review. Ultimately, 32 studies were eligible for further review. The Cochrane Collaboration tool for assessing the risk of bias was used for clinical trial evaluation.The following keywords were used: algometer, facial pain, masseter muscle, pain threshold, temporal muscle, and tmj. The Scopus database dictionary uses the phrase “pressure threshold” instead of “pain threshold,” and the authors modified the keyword for the search strategy accordingly.The Cochrane Collaboration tool for assessing the risk of bias was used for the evaluation of clinical trials .A narrative synthesis of results was performed. No meta-analysis could be performed due to the heterogeneity between studies .The GRADE approach was used for assessing the risk of bias across the studies.The initial search was performed on 10 January 2018. It identified a total of 123 articles, of which 32 full-text articles were taken for further evaluation. Of these, 25 comprised randomized controlled trials, two were OPPERA case studies, two were case-control studies, and the remaining three were research reports. The reporting of this systematic review adhered to the PRISMA Statement .The studies investigated the reliability and validity of the PPT  in TMD patients. The PPT was investigated in relation to headache, menstrual cycle, oral contraception, occlusal interference, and occlusal appliances. Some studies compared pressure algometry and manual palpation. Others focused on factors that could change PPT values, such as physical therapy, counselling, low-level laser therapy, mechanical and electrical stimulation, orthognathic surgery, or transcutaneous electrical nerve stimulation.The studies included a total of 4403 adult patients, aged 16-62, and 30 children.The observation period varied among the studies, from 1 day to 1 year.The collaboration tool for assessing the risk of bias was used for the evaluation of clinical trials . QualityChaves et al. observed that algometry has better intra- and interexaminer reliability than manual palpation . A subseAyesh et al. found no sex-related differences , 20, whiFarella et al. investigated masticatory muscle pain during, immediately after, and 1 day after sustained muscle contraction in a group of healthy participants. They found a reduced PPT of the jaw muscles only after long-lasting and low-level effort . In contIn another study, Farella et al. examined changes in the PPT of the jaw muscles after orthognathic surgery for class III malocclusion. After surgery, PPTs of the masseter and temporalis muscles did not change significantly from baseline values, and there was no clear connection between surgery and the PPT . Costa e2 (±0.47) for the right and 0.98 kgf/cm2 (±1.0) for the left masseter of an average TMD patient [Vignolo et al. investigated the influence of menstrual cycle on the PPT of the masticatory muscle. They found that the menstrual phase did not influence PPT, but oral contraceptive use raised PPT values . Convers patient , signifi patient . Silveir patient . Ferreir patient . In 2017 patient .Generally, the risk of bias among individual studies was low to unclear. Since those biases were likely to lower the confidence in conclusions, we had to downgrade the levels of evidence by 2 points. Nevertheless, evidence from the clinical trials is still of high quality according to the GRADE approach.2/s to 2 kg/cm2/s. In five articles, the pressure increase rate was not mentioned.Among the studies covered by 32 full-text articles, 11 used the Somedic algometer, four used the Wagner algometer, six used the Kratos digital dynamometer, and seven used a variety of other models. Four studies did not describe the exact model of the device used. We also found discrepancies regarding the pressure increase rate. In nine studies, the pressure increased at a rate of 30 kPa/s, in three at a rate of 40 kPa/s, in three at a rate 20 kPa/s, and twelve used 50 kPa/s. Pressure increase values grow from 20 kPa/s to 50 kPa/s and from 0.5 kg/cmDescriptions of the PPT examination points also varied, from very precise and repeatable to a simple listing of anatomical points . The number of measurements, intervals, and relevance of each examination also differed among the respective studies. The number of measurements varied from 1 to 5 at each visit. The intervals ranged from 5 seconds to 15 minutes. Some studies argued that the first measurement was not valid because of its higher numeric value and did not use it for further analysis, while others used all results to calculate average values. In terms of the presence of the control point for the PPT measurement outside the area under examination, the authors found that the majority of the studies (13 articles) did not meet this condition.Orofacial traumaSystemic disordersCervical disorders Neurologic disordersDrug or alcohol abuseUse of antidepressants, hormonal medications, muscle relaxants, and painkillersWearing orthodontic bracesMore than five headaches per month in the 3 months before enrolmentEvoked pain in more than three muscle locations  or in more than one tmj Complaints suggesting episodic neuropathic painPregnancyMissing more than two posterior teethPresence of full or removable partial dentureSevere malocclusion (overbite and overjet > 6 mm)Unilateral or anterior crossbiteDiscrepancy of centric relation to maximum intercuspation > 5 mmRheumatoid diseasesTMD treatment performed in the last three monthsMost articles had similar exclusion criteria which were as follows:There were exceptions according to the exclusion criteria if a study investigated patients with respect to the connection between headache and TMD or the long-term effects of orthognathic surgery.This systematic review has some underlying limitations. Most importantly, the articles lack in methodological homogeneity regarding pressure increase rate, the number of measurements, and measurement intervals. Additionally, different algometers were used in the respective studies.Overall, based on the analyzed articles, the authors state that the PPT is not an efficient approach for screening and evaluating orofacial pain. What is more, it should not be used as the only diagnosis for patients with orofacial pain. The papers identified for this review lack consistency in terms of study design and patient management. Many additional factors should be considered in the future prior to evaluation of PPTs . Notably, medication use is a growing factor in the ageing society, such that its influence on the PPT should also be thoroughly scrutinised. Further research is required regarding other treatment interventions, such as splint therapy, or combinations of specialised physical or pharmacotherapy. As some studies have confirmed, the pressure algometer is an efficient and effective tool in screening and evaluating orofacial pain patients , 21, 32.


Background: Modular organization reflects the activity patterns of our brain. Different disease states may lead to different activity patterns and clinical features. Early onset depression (EOD) and late onset depression (LOD) share the same clinical symptoms, but have different treatment strategies and prognosis. Thus, explored the modular organization of EOD and LOD might help us understand their pathogenesis.Method: The study included 82 patients with late life depression  and 90 healthy controls. We evaluated the memory, executive function and processing speed and performed resting-stage functional MRI for all participants. We constructed a functional network based on Granger causality analysis and carried out modularity, normalized mutual information (NMI), Phi coefficient, within module degree z-score, and participation coefficient analyses for all the participants.Result: The Granger function network analysis suggested that the functional modularity was different among the three groups (Pauc = 0.0300), and NMI analysis confirmed that the partition of EOD was different from that of LOD (Pauc = 0.0190). Rh.10d.ROI  and Rh.IPS1.ROI  were shown to be the potential specific nodes in the modular assignment according to the Phi coefficient .Conclusion: This study reveal that the functional modularity and partition were different between EOD and LOD in Granger function network. These findings support the hypothesis that different pathological changes might exist in EOD and LOD. Late life depression (LLD) is a common mental disorder in the elderly, and the morbidity is ~3.6–4.6% is a non-invasive method that helps us to visualize the activity of the brain through the Blood oxygen level dependent (BOLD) signal. Furthermore, rs-fMRI could reflect the fundamental characteristics of individual brain activity. Functional activity was correlated with structural features Sporns, . Thus, tFunctional connectivity is a method of using the BLOD signal to measure the activity consistency between brain regions. It is also a common way to define edges in a functional network. Currently, the main method used to describe functional connections between brain regions uses the Pearson coefficients of the main time series of two regions. However, the activity of the human brain presents time sequence changes even at the resting stage, and the current functional connection based on the Pearson coefficient ignores the time sequence property. Thus, we applied Granger causality (GC) analysis to describe the functional connection between brain regions. GC is a classical statistical method that was first applied in economics to detect the directional influence between different components. This method was recently applied in the analysis of fMRI data, which can help us determine the direction of the network connection and provide a more accurate functional brain network based on the time dependency information process in the human brain in a resting state  to quantify the similarity of their modular organization, and Phi coefficient to detect the specific nodes in the modular organization. Last, within module degree z-score and participation coefficient was used to describe their within and between modular connectivity. We hope to discover the differences in the functional connections between EOD and LOD.Eighty two LLD patients and 91 healthy control (HC) individuals were recruited in The Affiliated Brain Hospital of Guangzhou Medical University and a local community from September 2014 to January 2018. One of the HCs was rejected due to not undergoing a fMRI scan and removed from this study . All of the participants were of Han Chinese ethnicity and right-handed. Before the study, we obtained written informed consent from all of the participants. Research ethics permission for this study was given by The Affiliated Brain Hospital of Guangzhou Medical University ethics committee. The participants (LLD and HC) were the same as those used in our previous study  age >60 years; (2) diagnosis according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), criteria for major depressive disorder; (3) diagnosis was confirmed by well-trained psychiatrists from the Affiliated Brain Hospital of Guangzhou Medical University; and (4) capability to participate in a battery of neuropsychological tests. Exclusion criteria were as follows: (1) incapable of finishing the neuropsychological tests; (2) a history of major psychiatric disorders, such as bipolar affective disorder and/or schizophrenia, except depression; (3) a family history of major psychiatric disorders, such as bipolar disorder and/or schizophrenia, except depression; (4) a pre-existing primary neurological disease, such as stroke or brain tumor; and (5) a physical disease that can cause emotional problems, such as hypothyroidism or anemia.We further divided the LLD patients into two groups, EOD and LOD. Those patients with an onset age of depression of 60 years or greater were defined as the LOD group, while the rest were defined as the EOD group.To exclude those with mild cognitive impairment, who showed damage in functional connections greater than that expected for the elderly , the Auditory Verbal Learning Test-delayed recall score, the Trail-Making Test, the Stroop Color and Word Test, the Digit Span Test, the Symbol-Digit Modality Test, the Logical Memory Test, and examination of the participants' medical records.Cognitive function was separated into 3 domains: executive function, processing speed, and memory. The detail of each domain calculation was the same as that described in our previous article  in the Affiliated Brain Hospital of Guangzhou Medical University. To exclude cerebral infarction, tumors, and major white matter lesions, T2-weight imaging was performed before rs-fMRI scanning. Foam padding and earplugs were used to reduce head movement and scanner noise.Before rs-fMRI scanning, participants were told to rest and keep their eyes closed during scanning. A gradient-echo echo-planar imaging (GRE-EPI) sequence was used to perform rs-fMRI. The detailed parameters are as follows: TR = 2,000 ms, TE = 30 ms, FA = 90°, matrix = 64 × 64, slice thickness = 4 mm with inter slice gap = 0.6 mm, 33 interleaved axial slices, FOV = 220 mm × 220 mm and 240 time points.2 (matrix = 256 × 256 × 188).A 3D spoiled gradient echo sequence was used to obtain high-resolution T1-weight images. The detailed parameters are: TR = 8.2 ms, TE = 3.8 ms, slice thickness = 1 mm, and FOV = 256 × 256 mm3 per voxel and smoothed by a Gaussian kernel with a 6 mm full width at half-maximum. The time series was extracted by Matlab and represented by a 4 dimension matrix, and then the global signal was removed by global scaling. The white matter and cerebrospinal fluid signals were removed as covariables. Finally, the fMRI signals were detrended and filtered with a temporal band-path of 0.01–0.1 Hz.Data preprocessing for rs-fMRI was performed with GRETNA v2.0 , which describes 179 cortical areas in each hemisphere. The subcortical areas referred to 14 subcorical areas according to Desikan atlas. Finally, total 372 nodes, and their MNI coordinates were determined, the detail was showed in The GC calculation was performed by a Matlab GCA toolbox programmed by Wen et al.  to perfot and Bt can be represented by the following autoregressive models respectively:For two time series AThey can transform into the following unrestricted bivariate AR model:t2 and ηt2 are:The contemporaneous covariance matrix of εAfter Fourier transforming and proper ensemble average, the spectral density matrix of (1), (2) was followed:*: complex conjugate and matrix transpose; H (ω): transfer function matrix.Finally, according to Geweke , the twoA→B is the granger causal influence from node A to node B, GCB→A is the granger causal influence from node B to node A. Finally, 372 × 372 directed GC connective matrices were constructed for each subject.When GCThe threshold procedure was performed before network analysis. Because of the uncertain threshold definition of the GC network, we applied sparsity to construct the series of networks under a threshold rank. The threshold procedure was performed by GRETNA v2.0 . Every node in the network was determined, and False Discovery Rate (FDR) correction was performed. In the current study, we detected the specific nodes in the 2% sparsity threshold network .The within-module degree z-score and participation coefficient were calculated at each node for each individual according to the identified modules. The module with <1% of the total number of nodes was excluded. The calculation of the within module degree z-score and participation coefficient was performed as described in the work of Guimerà and Nunes Amaral  and perfThe group differences in age, years of education and HRDS were determined by one-way ANOVA. The gender data was analyzed by the chi-square test.1 or group2, in current study was EOD and LOD) was randomly assigned to groupx1 and groupx2 (x represented the number of permutation circles).The area under the curve of the modularity for different sparsity thresholds was calculated. The statistical analysis of all network properties was performed as the area under the curve. The area under the curve can provide a scalar that does not depend on a specific threshold selection and avoid the problem of absence definite threshold selection in network analysis. To determine the group effect of the modularity properties, the permutation test  was applied to the modularity, NMI and Phi coefficient. The significance level of permutation test was the position of the actual NMI and Phi coefficient of EOD and LOD under the distribution of NMI and Phi coefficients in randomized groups assignment. At each permutation circles, the testing subjects .Group differences in cognitive function , the within-module degree z-score and participation coefficient were analyzed by ANCOVA to remove the effect of age, years of education, gender and HDRS. To further determine the relationship between cognitive function, disease course and modularity, partial correlation was applied, and the effects of age, years of education, gender, and HDRS were removed. Furthermore, the relationship between the modularity and cognitive function  was confirmed by multiple regression. Cognitive function was set as the dependent variable, and modularity was selected as the independent variable. Age, years of education, gender, and HDRS were entered in the regression equation as covariances.The demographics, neuropsychiatric data and permutation test of the modularity, within module degree z-score and participation coefficient analyses were analyzed by IBM SPSS Statistics V22.0. The permutation test of the NMI and Phi coefficient was conducted with a custom Matlab script.P = 0.001 & P = 0.002). According to the LSD post-hoc comparisons, EOD was lower than LOD and HC in age (P < 0.001 & P = 0.008); HC was higher in years of education than EOD and LOD (P = 0.001 & P = 0.010). No significant difference was found in the distribution of gender among the three groups (P = 0.197). LLD groups (EOD and LOD) were shown to have higher HDRS than HC (P < 0.001), while EOD had a lower HDRS than LOD (P = 0.009). Significant differences were found in processing speed and memory among the three groups (P = 0.014 & P = 0.018), while no significant difference was found in Executive function (P = 0.217). According to LSD post-hoc comparisons, LOD and EOD was shown to lower processing speed more than HC (P = 0.006 & P = 0.036), while EOD demonstrated a lower memory function than HC (P = 0.005). A negative correlation was found between HDRS and memory  and processing speed , while no correlation with HDRS was found in executive function (P < 0.05). The LLD groups (EOD and LOD) showed higher CDR than the HC group (P < 0.001), while no difference was found between EOD and LOD according to LSD post-hoc comparisons (P = 0.340).The demographics and neuropsychiatric data are shown in 2 = 6.531; P = 0.163) and benzodiazepines . The details are shown in No difference was shown between the EOD and LOD in antidepressant treatment . According to the LSD post-hoc comparisons, EOD was lower than LOD in modularity (Pauc = 0.0190). The partial correlation analysis demonstrated that modularity was positively correlated with memory function  in the HC group.The modularity of the GC network among the three groups is shown in Pauc = 0.0387, 10,000 samples, The detail was showed in According to the NMI, we analyzed the modular partition between EOD and LOD by permutation testing. The area under the curve of the within group NMI in the range of the sparsity thresholds was significantly higher than randomized effect through permutation testing . Among them, Rh.10d.ROI, which belonged to the polar frontal cortex , and Rh.IPS1.ROI belonged to the intra parietal sulcus . The other nodes that belonged to the same module as Rh.10d.ROI and Rh.IPS1.ROI are shown in According to the Phi coefficient, we detected 2 ROI (Rh.10d.ROI and Rh.IPS1.ROI) with significant trends in different module between the EOD and LOD in the 2% sparsity network by permutation testing. The result did not pass the 5% FDR correction threshold for 372 nodes . Rh.OP2-3.ROI, Lh.47s.ROI, and Lh.FFC.ROI trended significantly differently between EOD and LOD in terms of the participation coefficient (P < 0.005). The details of the nodes with significant trends between EOD and LOD are shown in P = 0.000494, Pfdr = 0.183748).No differences were found in the within module degree z-score and participation coefficient according to FDR correction. Several nodes were found to trend differently in terms of the within module degree z-score and participation coefficient between EOD and LOD. The details are shown in In the current study, we constructed a functional network for 82 LLD  and 90 HC participants according to the GC analysis and analyzed the modularity among them. First, we found that the modularity of LOD was increased compared to that of EOD in the GC network. Second, according to the NMI analysis, the partition of LOD was significantly different from that of EOD. Finally, Rh.10d.ROI and Rh.IPS1.ROI were trended to be the specific nodes associated with the modular assignment according to the Phi coefficient.According to this study, the modularity of LOD was increased compared to that of EOD according to the GC network, and that indicated that the time-dependent modularity was different between EOD and LOD. Both EOD and LOD did not show differences compared to HC in terms of modularity, which is different from the finding of previous studies. Certain studies with various findings exist on the modularity changes in LLD (Bohr et al., The higher within group NMI coefficient compared to the randomized effect in the current study, indicated that the module arrangement was different between EOD and LOD. The NMI is within a range of 0–1. A larger NMI indicated that the partitions were similar between the two networks. According to the description of Alexander-Bloch et al. , the sigWe specified the two regions that showed a trend of discrepancy in the partitions between EOD and LOD by an analysis of the Phi coefficient. Rh.10d.ROI belonged to the polar frontal cortex. Recent evidence indicate that the frontal cortex not only affects motor ability but also sensory integration, behavioral strategizing, working memory, and decision-making (Ebbesen et al., The change in the weight modularity might not only result from different partitions, but also differences within and/or between module connections. This can be tested with the within module degree z-score and participation coefficient. However, no difference was found in these properties in the current study. In addition to the findings of the NMI analysis in the current study, it was indicated that the different modularity values between EOD and LOD were typically caused by the differences in the modularity arrangement. However, some regions showed different trends between EOD and LOD. Among them, the Rh.Accumbens.area appeared to be the most likely to be different in terms of the within module degree z-score between EOD and LOD. The accumbens is involved in brain reward circles (Russo and Nestler, There are some limitations of the current study. First, the participants were not medication-naive subjects. However, the medication record did not differ between the EOD and LOD. Thus, we believe that the effect of medications had limited effects on the results of the current study. Second, we did not repeat our experiment at a different time resolution. However, the relationship between time resolution and Granger function network has not been fully investigated, and our future study will try to explore whether this effect exists. Third, the current study on Granger causality analysis was based on linear model, which has been widely used. However, it is widely assumed that functional connectivity is highly non-linear (Marinazzo et al., In this study, we found that the functional modularity was different between EOD and LOD. Our findings in terms of NMI for the partition, the within module degree z-score and participation coefficient confirmed that the modularity change between EOD and LOD was mainly caused by the change in the partition but not within and between modular connections. These findings support the hypothesis that different pathological changes might exist in EOD and LOD.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by The Affiliated Brain Hospital of Guangzhou Medical University ethics committee. The patients/participants provided their written informed consent to participate in this study.NM was responsible for the data analysis. NM and YW were writing the drafts of manuscript. YN supervised experiment design and the drafts of the manuscript. NM, YW, XZ, BC, MZ, and QP were involved in data collection. All authors approved the final version of 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.


Interpretation: The best accuracy in differentiating the etiology of B-line artifacts was obtained with the use of both types of transducers (linear and convex), complemented with the observation of the conversion of B-line artifacts to Z-line.Background: This study concerns the application of lung ultrasound (LUS) for the evaluation of the significance of vertical artifact changes with frequency and pleural line abnormalities in differentiating pulmonary edema from pulmonary fibrosis. Study Design and Methods: The study was designed as a diagnostic test. Having qualified patients for the study, an ultrasound examination was performed, consistent with a predetermined protocol, and employing convex and linear transducers. We investigated the possibility of B-line artifact conversion depending on the set frequency (2 MHz and 6 MHz), and examined pleural line abnormalities. Results: The study group comprised 32 patients with interstitial lung disease (ILD) (and fibrosis) and 30 patients with pulmonary edema. In total, 1941 cineloops were obtained from both groups and analyzed. The employment of both types of transducers (linear and convex) was most effective  97%, negative predictive value (NPV) 91%, LR(+) 27,19, LR(−) 0.097, area under curve (AUC) = 0.936,  Lesions affecting the interstitium are most frequently caused by pulmonary edema (cardiogenic and non-cardiogenic) and interstitial lung disease (ILD) . Such leIn this study, vertical artifacts were analyzed (depending on the set operating frequency), as well as pleural line abnormalities. The first goal was to compare the length of vertical artifacts evaluated with a convex transducer at two extreme frequencies: 2 MHz, and then 6 MHz. The second goal was to assess pleural line abnormalities, with the employment of a linear transducer in both patient groups.B-line artifacts are significant in diagnosing many diseases that affect the pulmonary interstitial space and alveoli ,6. TheseThe study was conducted as a prospective cohort study. Approval from the local ethics committee (number: NKBBN/474/2018 and NKBBN/473/2018) and the informed consent of all participants in the study was duly obtained. Approval date for both 10 October 2018.Two groups of patients were examined: those patients diagnosed with ILD secondary to systemic sclerosis (group A), and patients diagnosed with pulmonary edema due to the exacerbation of congestive heart failure or to acute heart failure (group B). The exclusion criteria for patients with recognized ILD were as follows: comorbidity of congestive heart failure, pneumonia, and noncardiogenic edema. For patients diagnosed with pulmonary edema, the exclusion criteria were: pulmonary fibrosis, ILD, pneumonia, and noncardiogenic edema. The findings were anonymized and entered into a database by independent members of the research project. Written informed consent was obtained from those patients who agreed to participate. Duration of symptoms, examination findings, comorbidities, treatment, laboratory test results and echocardiography examination results, chest X-rays, and (in the case of ILD) high resolution computed tomography (HRCT) results were recorded. Patients were evaluated with LUS, and findings were recorded on standardized forms. LUS examinations were performed by three independent operators who are clinicians experienced in sonography . Ultrasound examinations were recorded and re-analyzed by clinicians and physics specialists. An ultrasonography device , with a 2–6 MHz convex curved transducer, and a 4–12 MHz linear transducer, was used. Patients were evaluated with the application of LUS performed in the same manner, and with the same technical criteria: (a) speckle reduction, compound imaging, and tissue harmonic imaging were switched off; (b) the focus of the image was positioned at the pleural line level; (c) imaging depth was set at 15 cm for a convex transducer, and at 6 cm for a linear transducer; (d) gain and time gain compensation (TGC) were adjusted in mid-scale. Moreover, when the lungs were examined with a convex transducer, vertical artifacts were evaluated with two extreme frequencies: 2 MHz, and then 6 MHz. When a convex transducer was employed, the sonomorphology of all artifacts, in both groups, was compared to each other, and analyzed statistically. When a linear transducer was employed, pleural line abnormalities were evaluated. Sonographic examinations were performed in the supine position and through the intercostal spaces on both sides of the chest. The probes were applied at four points over the front of the chest, and eight points over the posterior–lateral part of the chest. www.r-project.org (accessed on 26 February 2021)), version 3.6.0, using the following software: stat, plyr, ggplot2, pROC. The results were presented as the mean (standard deviation) for continuous variables and count (frequency) for discrete data. A p-value < 0.05 was regarded as statistically significant. Discrete data were compared for the groups with Pearson’s χ2 test, with appropriate modifications . For ultrasonographic features differentiating pulmonary fibrosis from heart failure, independently and in complex models, a receiver operating characteristic (ROC) curve was plotted, and the area under the curve (AUC) was calculated, determining whether it differed statistically by 0.5 with the application of the DeLong test. AUCs for differentiating parameters and predictive models were compared with the DeLong test. For quasi continuous variables  optimal cut-off points were determined with two methods (“closest topleft” and Youden). For all diagnostic parameters, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and the likelihood ratio for a positive LR(+) and negative result LR(−) were calculated. For statistically significant models, logistic regression was performed, calculating the odds ratio for a positive result of the tested model and a respective Akaike information criterion (AIC) value. AIC allows for the comparison of different models, where the lower its value, the better a given model is adjusted to the experimental data. Data analyses were performed in R statistical software (open source (GNU license) statistical environment available with libraries  at A complete predictive model should take into account as many differentiating elements as possible in different chest areas and the examination technique. We considered three complex models: A—change in the image of the length of the vertical lines artifacts in three or more areas, and lack of consolidation as a fibrotic feature; B—change in the image of length of the vertical artifacts in three or more areas, lack of: consolidation, irregularity, fragmentation, or blurring of the pleural line in at least two points as a feature of pulmonary fibrosis.C—change in the image length of the vertical artifacts in three or more areas, or irregularity, fragmentation, or blurring of the pleural line in at least two points, as a feature of pulmonary fibrosis.All models were created by taking into account the ultrasound protocol: use of the convex transducer to visualize vertical artifacts, followed by a linear one and the assessment of the pleural line. Models were limited to the anterior and posterolateral areas of the chest, which makes it possible to use them in the diagnosis of severe conditions, where ultrasound evaluation of the posterior surface of the chest is impossible. All models require the assessment of vertical artifacts and the pleural line in at least six points: upper, lower, and posterolateral bilaterally. The statistical properties of these models are presented in A total of 32 consecutive patients diagnosed with ILD secondary to systemic sclerosis qualified for the study, 17 females and 15 males, with an average age of 56 (21.2 SD) years. Diagnosis of systemic sclerosis was based on current ACR/EULAR 2013 criteria. ILD in this patient group was diagnosed on the basis of: patient’s clinical picture, abnormalities in immune tests, HRCT as well as pulmonary function tests, bronchofiberoscopy, and echocariography. Infection as the cause of lesions affecting the interstitium was excluded based on microbiological tests.30 consecutive patients with a clinical diagnosis of exacerbation of left ventricular failure and acute pulmonary edema qualified for the study, 13 females and 17 males, with an average age of 69 (21 SD) years. Pulmonary edema was diagnosed on the basis of clinical symptoms , high NT-proBNP  level, and typical abnormalities indicating edema visible in a chest X-ray and echocardiography. During the study, 789 video clips (cineloops) were obtained and analyzed from patients with pulmonary edema, as well as 1152 cineloops from patients with ILD secondary to systemic sclerosis. While, 876 cineloops containing vertical artifacts evaluated with a convex transducer, and 644 cineloops assessing a specific area with a linear transducer were selected from the collected material, respectively. The recorded cineloops were assessed by clinicians and an engineer specializing in physics. Following the analysis of the video recordings, 128 cineloops were rejected due to inappropriate ultrasound device settings. The remaining cineloops were analyzed as regards the length of the artifacts (convex transducer), and determining whether a given artifact meets the definitional criteria of B-line (long artifact) or Z-line (short artifact). Moreover, the sonomorphology of the pleural line was analyzed in all patient, and evaluated with a linear transducer. B-line artifacts are detected in patients with cardiogenic pulmonary edema and ILD. In this study, B-line artifacts were evaluated with a convex transducer, at a depth of 15 cm, consistently with the settings described in the methodology section. The ultrasound frequency was changed during the examination, and the evaluation was performed at two extreme values: 2 MHz and 6 MHz.In the cineloops obtained from patients with both pulmonary edema and ILD, B-line artifacts were almost always visualized at the frequency of 2 MHz (consistent with the adopted definition of B-line artifact), in 68% of the examined points in patients with pulmonary edema, and 63% of the examined points in patients with ILD, respectively. Z-lines were visible only in single points: one (0.4%) in heart failure, and 11 (3%) in pulmonary fibrosis, whereas in three cases (0.8%) Z-lines coexisted with B-lines. At the frequency of 6 MHz, cineloops recorded for patients with ILD presented Z-lines in 62% of the evaluated points and B-lines in 13%, whereas in 10% of the examined points the findings were mixed . In patients with cardiogenic pulmonary edema, at the frequency of 6 MHz, B-line artifacts were present in 62% of the evaluated points, and Z-lines in 24%, including the mixed profile of B and Z in 16% of the examined areas . Consequp < 10−6).The change of the ultrasound frequency from 2 to 6 MHz leads to a shortening or even the disappearance of vertical artifacts (conversion to A lines was observed in three cases), and this phenomenon is more characteristic for pulmonary fibrosis than edema . Statistically, both methods yield analogous results (to compare: AUC p = 0.67).Differentiating the etiology of B-line artifacts (pulmonary edema versus pulmonary fibrosis) with the use of extreme frequencies (2 MHz and 6 MHz) is possible, both by detecting Z-lines at the frequency of 6 MHz  2.57, LR(−) 0.50), and by observing the change of the B-line profile to the Z-line when the frequency is increased  2.58, LR(−) 0.51, AUC= 0.687, Both groups (A and B), having been examined with a convex transducer, were re-evaluated with a linear transducer. Complete data obtained from 641 projections were analyzed statistically.p < 10−6).In patients with cardiogenic pulmonary edema, the pleural line was evaluated in 260 points. In 257 (98.8%) points, no pleural line abnormalities were detected. Only in three (1.2%) points were irregularities in the pleural line observed. Moreover, in 23% (60) of the evaluated areas, subpleural consolidations (up to 2–3 mm in diameter) were found in patients with cardiogenic pulmonary edema. These small consolidations correlated statistically significantly with vertical artifacts that, in the majority of cases, converted from B-lines to Z-lines when the frequency was changed from 2 MHz to 6 MHz in the convex probe  and blurred pleural line in 22% (84) of all evaluated points; the apparent thickening of the pleural line (>2 mm) was detected in only one (0.26%) area. Irregular and/or fragmented pleural line was present in 97% (230 out of 236) of the patients in the group in which B-lines converted into Z-lines (when the frequency was changed from 2 MHz to 6 MHz) .p = 0.0002.These findings indicate that an irregular and fragmented pleural line is a feature that differentiates pulmonary fibrosis from cardiogenic pulmonary edema. Detection of this feature in a single evaluated point allows for diagnosis of pulmonary fibrosis with a specificity of 99%, a sensitivity of 68%, PPV 99%, NPV 68%, LR(+) 60, and LR(−) 0.32, at AUC = 0.836 and An attempt at diagnosis: a differentiating model:Although both features described above differentiate fibrosis from edema, a single observation point is not sufficient.We proposed the best final model B, shown in It has been suggested in a previous paper ,12 that The characteristics which distinguish vertical artifacts are: brightness, length, lateral width, and internal structure. In this study, only the length of vertical artifacts has been analyzed, depending on the change in ultrasound frequency.The length of an artifact is an interesting parameter, even though it represents really complex information. It depends on the duration of the trap response which, from a theoretical point of view, is infinite. Once a US pulse has been partially trapped by an acoustic trap, the latter re-radiates the trapped energy during an infinite time interval. Therefore, the question is: Why do we sometimes observe artifacts which reach the bottom of the screen and sometimes shorter artifacts? The answer lies in the signal to noise ratio (SNR). The amplitude of the trap signal decreases during a time interval until the signal is no longer distinguishable from the noise, and there are no possibilities for the time gain compensation (TGC) to make it visible. Therefore, now the question becomes: How much does the trap signal decrease during a time interval? This is an interesting question, and the answer should open our minds to the world of ultrasound artifacts. As an example, The analysis of LUS findings in the case of diseases involving interstitial space presently poses a serious challenge for clinicians. In many diseases that affect the interstitium and alveoli, vertical reverberation artifacts are detected. B-line artifacts are found, for instance, in: cardiogenic pulmonary edema, noncardiogenic pulmonary edema, and ILD  ,15,16,17So far, the literature in the diagnosis of pulmonary fibrosis has been based mainly on B-line artifacts . It has We observed a change in the length of vertical artifacts in both examined groups, and the concurrent presence of pleural line abnormalities. In the first examined group (A), conversion of B-lines to Z-lines was usually accompanied with pleural line abnormalities and/or small subpleural lesions. In this patient group, both B-line to Z-line, at two extreme frequencies (2 MHz and 6 MHz) this most likely results from generating artifacts in acoustic traps, that are adjacent to the pleural line, by means of a single large channel and multiple channels. Probably both types of traps are present at the pleural line, given the apparent shape of the pleural line, which appears irregular and blurred.Changes that occurred during the conversion of B-line artifacts in the second patient group (B) were much more diversified. A large number of B-lines did not undergo conversion with a change in ultrasound frequency. Concurrently, some B-line artifacts converted to Z-lines, or B- and Z-lines. However, a correlation between the conversion of B-line artifacts to Z-lines (or B- and Z-lines) and coexisting pleural line abnormalities was observed in this group as well. This was most likely associated with the presence of microconsolidations .This study also demonstrates that differentiating a cardiogenic etiology of B-line artifacts from a pulmonary etiology should be based, both on the analysis of the artifact length after the conversion, and on the evaluation of pleural line abnormalities. Accounting for both findings results in a much higher accuracy in differentiating the causes of lesions affecting the insterstitium.The only analyzed feature was the artifact length. It is possible that more factors  are significant in differentiating the etiology of vertical artifacts; however, these factors were not analyzed in this study.The second limitation is the selection of patients for the study group. Patients with chronic pulmonary congestion, but in a stable clinical condition, were not included in the study.The third limitation is given by the lack of information on the pulse power spectrum and on the modulation transfer functions of the probes.The visualization and sonomorphological analysis of vertical artifacts with the application of a convex transducer employing two different, extreme frequencies (2 MHz and 6 MHz) may be useful in differentiating lesions affecting the interstitium (cardiogenic pulmonary edema vs lesions due to ILD). However, a higher accuracy is achieved when the pleural line and subpleural lesions are concurrently evaluated with a linear transducer.


Many app-based interventions targeting women with breast cancer have been developed and tested for effectiveness. However, information regarding the evaluation of the usage of these interventions is scarce. A better understanding of usage data is important to determine how women use apps and how these interventions affect health outcomes.This study aimed to examine the usage duration and login frequency of an app-based intervention, the Breast Cancer e-Support (BCS) program, and to investigate the association between usage data and participants’ demographic and medical characteristics.This study is a secondary data analysis of a randomized controlled trial assessing the effectiveness of the BCS program. The BCS program contains four modules: Learning Forum, Discussion Forum, Ask-the-Expert Forum, and Your Story Forum. A total of 57 women in the intervention group accessed the BCS program during their 12-week chemotherapy. The app’s background system tracked the usage duration and login frequency for each forum and the entire BCS program.F1,45=10.09, P=.003, B=115.34, 95% CI 42.22-188.47) and education level  were positively associated with the usage duration of the entire BCS program. Family monthly income was positively associated with the usage duration of the Learning Forum  and the login frequency of the entire BCS program . Employment was negatively associated with the usage duration of the Ask-the-expert Forum  and the Your Story Forum  and positively associated with the login frequency of the entire BCS program . No statistical differences were found between BCS usage data and cancer stage, BMI, comorbidity, types of surgery, or cycles of chemotherapy.The total usage duration per participant ranged from 0 to 9371 minutes, and the login frequency per participant ranged from 0 to 774 times. The Discussion Forum and the Learning Forum were the most frequently used modules. The general linear model showed that age, education, family monthly income, and employment were associated with BCS usage duration and/or login frequency. Age (Overall, this study found considerable variability in the usage of app-based interventions. When health care professionals incorporate app-based interventions into their routine care for women with breast cancer, the learning and discussion functions of apps should be strengthened to promote engagement. Additionally, characteristics of women with breast cancer, such as age, level of education, income, and employment status, should be taken in consideration to develop tailored apps that address their particular needs and therefore improve their engagement with the app.Australian New Zealand Clinical Trials Registry ACTRN12616000639426; http://www.ANZCTR.org.au/ACTRN12616000639426.aspx Chemotherapy often causes undesirable side effects in women with breast cancer, including fatigue, pain, sweating, swollen hands, and anxiety ,2. In ChConnected Health, a health care delivery model to maximize health care resources, provides channels for participants to interact with clinicians and receive health-related services via new technology . Mobile We previously developed an app-based interactive program, called Breast Cancer e-Support (BCS) . This prA better understanding of app usage is critical to elucidate women’s preferences for different forums and the ways the BCS program might affect health outcomes . The usaWomen with different characteristics, such as demographic and health related factors, are expected to have different usage patterns for app-based interventions . TherefoThe primary aim of this study was to examine the usage data of the BCS program by assessing the usage duration and login frequency in women randomized in an intervention group. The secondary aim was to investigate the associations between usage data and demographic and medical characteristics.This study extracted data from a multicenter randomized control trial and focused on the analysis of 57 women randomly assigned to the BCS intervention group. All participants had to (1) be diagnosed with breast cancer, (2) be receiving chemotherapy, and (3) have access to the BCS program for 12 weeks. Women who had a concurrent serious physical illness or chronic mental illness were excluded from the study.The BCS app program, which could be used on both iPhone and Android mobile phones, aimed to provide information and social support to improve women's symptom management during chemotherapy. The intervention was conducted from May to November 2016. The full detailed description of the BCS program has been published .The BCS program has four modules: Learning Forum, Discussion Forum, Ask-the-Expert Forum, and Your Story Forum. The Learning Forum offers evidence-based knowledge of breast cancer and management strategies for related symptoms. The Discussion Forum provides an anonymous interaction platform for women to communicate with peers and health care professionals. A seasoned health care professional moderates online discussion and provides expert advice when needed. The Ask-the-Expert Forum provides health consultation, where health care professionals respond to women’s queries within 24 hours. The Your Story Forum presents videos of encouraging stories that include strategies for overcoming the challenges during chemotherapy . A moderAt baseline, women filled out paper questionnaires that collected demographic characteristics including age; marital status; education; employment; family income; BMI; and medical characteristics such as cancer stage, types of surgery, comorbidity, complications, and cycles of chemotherapy. Medical records were used to confirm the medical variables.The usage data of the BCS program were measured as usage duration and login frequency; data from each forum and the entire BCS program were recorded for each individual for 12 weeks. Usage duration was defined as the time, in minutes, between login and logout for each forum and the entire BCS program. The operational definition of login frequency was the number of times that each woman logged into each forum and the entire BCS program during the 12-week intervention period. The app’s background system tracked the usage data. If women were surfing on other functionalities of mobile phones or mobile phones were in standby mode, the app ran on background operational mode and the app background thread stopped calculating the usage data.All data analyses were performed using IBM SPSS 25.0. The mean (SD), medium (IQR), and maximum values were used to describe usage duration and login frequency. As the usage data were highly skewed, a general linear model was used to calculate the associations between usage data and demographic and medical characteristics. An α level of .05 of statistical significance was set for all analyses.A total of 57 women were included in this study. The mean age was 46.2 years (SD 8.5 years). All women were married, and 77% (44/57) were unemployed at the time of the study. Regarding educational level, 28% (16/57) had completed middle school, followed by elementary school , and high school . The monthly family income was in the range of US $149 to $738 for 60% (34/57) of the women and <US $148 for 25% (14/57) of them. Many of the women  were diagnosed with stage II breast cancer, followed by stage III breast cancer . A majority  had undergone mastectomy and only a few  had undergone breast conserving surgery.BCS usage data showed great variability. Only 4% (2/57) of the women did not log in the BCS program. For the whole BCS program, usage duration ranged from 0 to 9371 minutes, and frequency of logins varied from 0 to 774 times. The Discussion Forum and the Learning Forum were the most popular forums for women to log in and use. F1,45=10.09, P=.003, B=115.34, 95% CI 42.22-188.47) and the Learning Forum   and the Discussion Forum   and the Ask-the-expert Forum   , the Learning Forum , and the Discussion Forum   and the Your Story Forum  , the Learning Forum , the Discussion Forum , and the Your Story Forum   . Educati2265.21)  as well 7-38.06) . Family 2359.51)  and the -243.91) . Employm –83.11)  and posi9-16.51) . No statIn this study, we found considerable variability in usage duration and frequency of the BCS program among women with breast cancer receiving chemotherapy. The large difference between median and mean usage data indicated usage polarization among the women. Additionally, we found that the Discussion Forum and the Learning Forum were the most popular forums. Age, education, family income, and employment were associated with women’s usage data.Although BCS usage varied considerably, this study reported better usage duration and login frequency than a self-guided 4-month web-based intervention, called BREAst cancer ehealTH (BREATH), in which the total usage duration ranged from 0 to 2324 minutes  and the frequency of login ranged from 0 to 45 times  . MoreoveWe found usage polarization in the BCS program, which is consistent with the results of a study that explored the usage data of a web-based self-management intervention . Usage pIn this study, women used the Learning Forum and the Discussion Forum the most during their 12-week access to BCS. Research has found that patients with cancer use mHealth as an information resource and for emotional support ,29,30. TContrary to a previous study regarding eHealth use and age , we founConsistent with some studies ,21,23,34In this study, women with a higher family income used the Learning Forum and the Discussion Forum more than those with a lower family income, which is in agreement with other studies ,23,37. OA previous study found that employed participants showed more interest in eHealth  and beneOne strength of this study was the presentation of a method that directly and objectively captured the usage data of mobile apps. Thus, there was no reporting bias for mHealth intervention usage. Another strength was that this study analyzed the usage of each module in the program and its associations with women’s demographic and medical characteristics. The findings could help researchers understand participants’ preferences and explore strategies to improve app design.As for the limitations, the study extracted usage data from a randomized control trial, and the sample size was small, which limited the generalizability of our results. Additionally, a previous study showed that the usage of apps changes over time . Given tThe insights gained from this study allow us to provide recommendations for further advances in the design and content of app-based health interventions. Overall, this study illustrated considerable variability in the usage of app-based interventions. When health care professionals incorporate app-based interventions into their routine care for women with breast cancer, the learning and discussion functions of apps should be strengthened to promote engagement. Additionally, characteristics of women with breast cancer, such as age, education level, income and employment status should be taken in consideration to develop tailored apps that address their particular needs and therefore improve their engagement with the app.