Among the local community food store environment factors, the sufficiency of food stores (odds ratio (OR) = 1.988, 95% confidence interval (CI] = 1.211–3.262), freshness of foods , and variety in foods  were significant factors affecting the risk of malnutrition. For frailty, the freshness of foods , variety in foods , and small purchase of foods  were significant environmental factors. In conclusion, we found that the perceived food store environment in the local community can influence the occurrence of malnutrition and frailty in vulnerable, urban older adults.This study aimed to identify food environment factors in the local community that could affect the levels of nutritional status and frailty in 372 older adults (at least 65 years old) experiencing food insecurity and enrolled in the integrated Community Health Promotion Program (CHPP) in two districts of Seoul. The local food environment was assessed using perceived food store accessibility questionnaires. In order to quantify nutrient intake, the 24-h recall method was applied. Malnutrition was measured using the Mini Nutritional Assessment tool, while frailty was assessed using the Frailty Measurement Questionnaire developed for the CHPP. Malnourished or frail elderly adults commonly had a lower intake of cereals and potatoes, meats, and vegetables than those who were not, and their resulting intake levels of energy, protein, iron, and vitamin groups were also significantly lower (all  The elderly population  in the Republic of Korea accounted for 14.9% of the total population in 2019, showing a rapid increase from 7% in 2000. The pace of elderly population growth is the fastest among OECD countries [A clinically recognizable state of increased vulnerability resulting from ageing can be defined as frailty, which has been operationally defined as a syndrome characterized by weight loss, decreased grip strength, severe fatigue, slow walking speed, and a low level of activity ,4. In a The most prominent characteristic of frailty is muscle loss  and, wheAnother predisposing factor affecting health and malnutrition in the elderly is food insecurity: a state of being without reliable availability to a sufficient quantity of adequate food . AccordiConsidering the effects of the food environment on healthy food choices and food insecurity, understanding the local food environment factors affecting malnutrition and frailty in the elderly is crucial for the development of community nutrition services and intervention strategies. Thus, this study aims to identify local food environment factors that may affect the levels of malnutrition and frailty in the urban elderly population from low-income families experiencing food insecurity.The study was conducted from July to August 2018, and involved 372 subjects enrolled in the integrated Community Health Promotion Program (CHPP) in 2 districts of Seoul  and who were supposed to participate in the supplemental food assistance program, Seoul city’s newly launched program in September 2018. The CHPP provides integrated health management services to people aged 65 or older who have hypertension or diabetes, among national basic livelihood act recipients, based on nurse home visits. This service aims to administer continuous health and risk factor management, and to introduce customized local resources . The elderly population in the 2 districts was approximately 92,000, while the CHPP was provided to approximately 13,300 older adults in the 2 districts, accounting for a coverage rate of 14.5%. Of the CHPP participants, the number of older adults who regularly visited for disease management was approximately 5600 (42.1%). Among them, the supplementary food assistance program was provided to 407 people with food insecurity, who were referred by visiting nurses of CHPP and voluntarily participated in the program. The standard for the visiting nurse’s referral was based on the guidelines of the CHPP , which jTrained interviewers conducted face-to-face interviews based on home visits. Sex, date of birth, whether they lived alone or not, income category, the presence of three or more chronic diseases, the presence of a physical disability, cooking ability, and level of social activities were investigated.1, vitamin B2, niacin, calcium, iron, and sodium were calculated [1, vitamin B2, niacin, calcium, and iron, and Dietary Goal (DG) for sodium. The food intakes of subjects were measured using a 24-h recall method for the quantity of food consumed during a day. The nutrient intake was calculated using the CAN-PRO 5.0 software  for experts, and total energy, protein, vitamin A, vitamin C, vitamin Blculated . The qualculated  were useMalnutrition was measured using the Mini Nutritional Assessment Tool, wherein a good nutritional state is represented by a score of 24 or higher, at risk of malnutrition by a score from 17 to 23.5, and malnutrition by a score of 17 or lower . FrailtyFor assessment of the food environment in residential areas, a perceived food store accessibility questionnaire was developed, based on the Five A’s of food access ,29: AvaiThe developed questionnaire consisted of 6 items regarding the quantitative sufficiency of food stores around the house (1 item on availability), reasonableness of the cost of food sold at the food stores (1 item on affordability), delivery service availability at the food store, as well as convenience of small purchases (2 items on accommodation), variety of food sold at local food stores, and freshness (2 items on acceptability). The questions were answered on a 5-point Likert scale, consisting of Strongly agree (5 points), Agree (4 points), Neither agree nor disagree (3 points), Disagree (2 points), and Strongly disagree (1 point). A four-point or higher answer was categorized into “Positive food environment”, otherwise it was categorized into “Negative food environment” (3 points or lower). The number of positive responses for the 6 items was used as a summary measurement for the local community food store environment. t-test were performed for the univariable analysis, in order to compare the distribution of covariates and food store accessibility according to malnutrition and frailty. Multiple logistic regression analysis was conducted to determine whether food store accessibility in the local community influenced malnutrition and frailty, even after adjusting for other confounding variables. All the statistical analyses were conducted using the IBM SPSS Statistics 23.0 software  and were tested at an alpha error level of 0.05.The demographic, socioeconomic, physical, and social characteristics, food and nutrient intakes, and food store accessibility were summarized and compared in terms of malnutrition and frailty. The results of categorical variables are presented as frequencies (N) and percentages (%), while the results of continuous variables are presented as means and standard errors. A Chi-square test and independent In the entire study population, 32.8% were malnourished and 67.2% were at high risk of malnutrition, with none of the subjects being in a good nutritional state. Malnutrition was higher in women than in men, and a significantly higher percentage of those aged 75 or older were malnourished. p = 0.012). Subjects who had restricted mobility had a significantly higher percentage of malnutrition rather than risk of malnutrition, and a significantly higher percentage of them showed frailty rather than pre-frailty (p < 0.001). The subjects who could not cook showed a significantly higher percentage of malnutrition than risk of malnutrition (p = 0.008). There was no significant relationship between malnutrition or frailty based on living alone, household income category, number of chronic diseases, social activity, and participation in the national food support program.Frailty was observed in 14.5% of all subjects, with women showing a higher percentage than men and those aged 75 or older showing a higher percentage than those under 75 years of age. Differences in the level of frailty were not found for sex, and were only observed for age (p < 0.001), meats (p = 0.006), and vegetables (p < 0.001), with malnourished subjects having a lower intake of these food groups than those at risk of malnutrition. The percentage of DRI for nutrient intakes that showed significant differences among malnutrition levels were energy (p < 0.001), proteins (p < 0.001), vitamin B1 (p < 0.001), niacin (p < 0.001), iron (p < 0.001), and sodium (p = 0.002), with malnourished subjects consuming less of these than those at risk of malnutrition. The food sources that showed significant differences between the levels of malnutrition were cereals and potatoes (p = 0.018), legumes (p = 0.045), meats (p = 0.039), fish and shellfish (p = 0.042), and vegetables (p = 0.031), with a lower intake for subjects in the frailty group than those in the pre-frailty group. In terms of the percentage of DRI for nutrient intake, the pre-frailty group showed a higher percentage of energy (p < 0.001), proteins (p < 0.001), vitamin B1 (p = 0.027), niacin (p < 0.001), and iron (p = 0.008) than the frailty group.Food groups that showed a difference in intake, depending on the level of frailty, were cereals and potatoes (p < 0.001), freshness of foods (p = 0.002), variety in foods (p = 0.002), and small purchase of foods (p = 0.005) were malnourished, compared to those at risk of malnutrition, than those who had a positive perception of the above. The sum of food store accessibility items was significantly lower in the malnourished subjects than that of those who were at risk of malnutrition. p = 0.009), freshness of foods (p = 0.003), variety in foods (p = 0.001), and small purchase of foods (p < 0.001) showed a correlation with a higher percentage of frailty.A negative perception of the sufficiency of food stores  and frailty (OR = 0.826 95% CI = 0.709–0.961) by approximately 14% and 17%, respectively.In this study, we attempted to identify whether perceived food store accessibility, as a local community food environment factor, could affect the level of malnutrition or frailty in the vulnerable elderly population who had lower-income status and were experiencing food insecurity. The results showed that, when food store accessibility was positively perceived, the malnutrition and frailty risks decreased. Among food store accessibility factors, the ones that particularly affected the risk of malnutrition were the perceptions that there were insufficient food stores in the area, food not being fresh, or the variety of food being lacking, for which the risk of malnutrition was significantly higher. The risk of frailty significantly increased when the elderly perceived that the food sold at the food stores was not fresh, that there was not enough variety, or that making small purchases of food was not easy. All of the subjects in this study had experienced food insecurity and were enrolled in the CHPP as part of a national public health program. The CHPP has been criticized, as there were few nutrition services specialized to diseases and that the food provided was also not sufficient ,31. The In the food-insecure elderly of this study, the risk of malnutrition or frailty was found to increase with increased negative perceptions of local community food store accessibility, which might imply that the local community food environment affected the food or nutrient intake of individuals, even for vulnerable elderly in an urban area. Previous studies have reported that the local community food environment is an important factor for food selection, quality of meals, and health outcomes ,19,36. IThe food environment factors that have shown correlations with food selection or dietary quality include physical accessibility, reasonableness of prices, and availability of a variety of food ,36,37,38In this study, we examined the food environment using perceived measurements of food store accessibility. Several studies have shown that the relationship between food environment and food purchasing and intake is more significant in perceived measures than that in objective measures, especially among disadvantaged populations ,40, suggIn this study, unmet food environment factors increased the risk of malnutrition or frailty, a finding that was still significant even after adjusting for demographic characteristics related to malnutrition and frailty, in addition to the intake of energy and food group intake related to outcome factors. This suggests that local community food environment factors could be explained by other mechanisms, in addition to food or nutrient intake. The interactions between individual and environmental factors may play important roles, in terms of the effects that the local community food environment has on eating behavior and the resulting health outcomes. For example, individual factors  or sThe results of this study were not stratified by sex, but analyzed and presented for the entire subjects. The proportion of women in the study was large and the subjects had several chronic diseases. Because the comorbidities with consequent frailty, as well as gender, would affect the overall outcomes in the elderly ,52, furtThere were several limitations in the interpretation of the results of this study. First, although the items measured in this study for the local community food environment were operationally developed based on theories and previous empirical survey tools, additional validation of the questionnaire in the survey is required. Specifically, physical accessibility was not included, as the subjects of this study lived in Seoul, which is a metropolitan city with easy physical access to local grocery stores . NeverthDespite these limitations, the study identified perceived food store environment factors in a local community that could affect malnutrition and frailty in the vulnerable, urban elderly with low income, and was the first to show that these factors could affect their nutritional status and somatic condition . These results suggest the need for food support programs and nutritional intervention projects targeting the elderly, as well as the application of additional strategies to improve the local food environment, demonstrating that they could be used as foundational data for developing such strategies. Particularly, in the midst of the current pandemic, continuous monitoring is required, as the local community food environment factors are expected to have a greater impact on the nutritional status or health outcomes of the elderly. This study demonstrated that the perceived food store environment in the local community can influence the occurrence of malnutrition and frailty in the vulnerable elderly. Specifically, the sufficiency of food stores in the local community, the freshness and variety of foods, and the ease of purchasing in small quantities were identified as significant factors. In the future, these results may serve as a basis for developing food support programs and establishing nutrition policies, taking into account the food environment characteristics of the local communities wherein elderly individuals with malnutrition and frailty live.


Background: Progressive supranuclear palsy (PSP) is a neurodegenerative disorder that, especially in the early stages of the disease, is clinically difficult to distinguish from Parkinson's disease (PD).Objective: This study aimed at assessing the use of eye-tracking in head-mounted displays (HMDs) for differentiating PSP and PD.Methods: Saccadic eye movements of 13 patients with PSP, 15 patients with PD, and a group of 16 healthy controls (HCs) were measured. To improve applicability in an inpatient setting and standardize the diagnosis, all the tests were conducted in a HMD. In addition, patients underwent atlas-based volumetric analysis of various brain regions based on high-resolution MRI.Results: Patients with PSP displayed unique abnormalities in vertical saccade velocity and saccade gain, while horizontal saccades were less affected. A novel diagnostic index was derived, multiplying the ratios of vertical to horizontal gain and velocity, allowing segregation of PSP from PD with high sensitivity  and specificity . As expected, patients with PSP as compared with patients with PD showed regional atrophy in midbrain volume, the midbrain plane, and the midbrain tegmentum plane. In addition, we found for the first time that oculomotor measures  were correlated significantly to midbrain volume in the PSP group.Conclusions: Assessing eye movements in a HMD provides an easy to apply and highly standardized tool to differentiate PSP of patients from PD and HCs, which will aid in the diagnosis of PSP. Progressive supranuclear palsy (PSP), first described in 1964 . The neuAn adequate eye movement-based diagnosis of PSP demands a high standardization of testing conditions , which is often difficult to achieve across institutions. Moreover, the usage of classical stationary high-resolution video-oculography demands that the patient sits still while the head is fixed. PD and PSP, although typically characterized as hypokinetic movement disorders, are often accompanied by postural instability and facial tremors are not uncommon in PD . Thus, tIn this study, we, therefore, investigated if recording eye movements in an HMD using a brief and simple saccade task can differentiate patients with PSP from patients with PD and healthy controls (HCs). These findings were compared to MRI-derived brain volumetry to correlate ocular motor dysfunction and regional brain atrophy.A case–control study was conducted. All tests in subjects assigned to one of the three groups  were performed in our hospital, a tertiary referral center.via the history of pre-existing conditions and a neurological examination. The HC subjects were not blood-related family members of patients with PD or PSP.The PSP group comprised patients diagnosed according to the clinical diagnosis criteria of PSP . As contAll patients underwent written informed consent about the study, neurological and general medical examination and also assessment of Unified Parkinson's Disease Rating Scale (MDS-UPDRS) , Hoehn aWe assessed saccadic eye movements in an HMD  with an integrated binocular eye tracker measuring at 250 Hz  . Each teSaccade onsets were detected using a built-in detector provided by SensoMotoric Instruments based on velocities. We excluded trials if (a) no saccade was detected, (b) saccades were anticipatory (latency <80 ms), (c) gaze deviated by more than 2.5° from the display center at the time of saccade onset, or (d) saccades amplitude was <1°. With these criteria, 25.8% of trials were discarded from the analysis. There were no significant differences between the three groups in the number of trials discarded.www.loni.ucla.edu/ADNI) recommendations for volumetric analysis, and axial T2-weighted turbo spin-echo sequences (3 mm slice thickness) to detect vascular lesions, acquired on 1.5 or 3T scanners. MR volumetry was performed in analogy to an already published protocols  T1-weighted 3D magnetization prepared rapid gradient echo (MPRAGE) sequence with 1 × 1 × 1 mm isotropic voxel size according to the Alzheimer's Disease Neuroimaging Initiative  for normally distributed data and non-parametric tests  if the data were non-normally distributed. Data are presented as mean ± SD and a significance criterion of p < 0.05 was used for all analyses.Statistical analyses were performed using the Statistical Package for the Social Sciences for Windows . Oculomotor and MRI data were first examined visually and statistically using the Shapiro-Wilk test for normality across participants. We planned to conduct parametric tests  the PSP group comprised 13 patients; 8 with probable and 5 with possible PSP according to the diagnostic criteria of PSP. As controls, 15 patients with PD as well as 16 HCs were included.A total of 3 of 15 patients with PD and 11 of 13 patients with PSP underwent SPECT examination with I-123 FP-CIT (DaTSCAN) during the course of their disease (some outside our clinic) and evidence of a reduction in striatal binding quotient compared with a reference region in the occipital cortex. As a reliable differentiation of Parkinson's disease from PSP and other Parkinson's diseases is methodologically not possible using DaTSCAN, a performed examination was not considered a prerequisite for inclusion in the study. The information of the number of performed examinations was presented additionally for the comprehensibility of the study population.There were no significant differences between the three groups regarding age, gender, and severity of disease measured by the MDS-UPDRS, Hoehn and Yahr scale, and also the LEDD. The duration of the disease and the PANDA scores differed between the PSP and PD groups in that the patients with PSP had a significantly shorter disease duration and higher PANDA scores see . Among tHowever, 9 subjects  had to be excluded due to insufficient oculomotor data  and 1 additional subject had to be excluded from the HC group due to a former history of stroke. The main reported reasons for discontinuing oculomotor testing were fatigue, problems with vigilance and concentration. The number of discarded trials showed no correlation with age, MDS-UPDRS, PANDA score, and LEDD.U-test 80.5, Z = 1.61, p = 0.106), gender , disease duration , LEDD , PANDA  as well as the MDS-UPDRS score .Regarding included and excluded patients with Parkinson's syndrome , there was no significant difference in age (Mann-Whitney group (PSP vs. PD vs. HC), eccentricity (5 vs. 10°), and direction (left vs. right vs. up vs. down), all of which are depicted in : horizontal vs. vertical) x 3 (group: PSP vs. PD vs. HC) mixed ANOVA on the velocity and gain data.For each trial of the oculomotor examination, we analyzed the mean velocity and gain (the ratio of saccadic amplitude and target distance) of the first saccade after target presentation as a function of F = 213.985, p < 0.001, F = 7.741, p < 0.01, F = 7.827, p < 0.01, Post-hoc t-test showed that the PSP group and the PD group differed in the mean velocity of vertical  but not horizontal saccades .Analysis of the mean saccadic velocity revealed a significant main effect of direction, F = 10.172, p < 0.01, F = 15.743, p < 0.001, F = 7.752, p < 0.01, Post-hoc t-test showed that the PSP group and the PD group differed in the mean velocity of vertical  but not horizontal saccades .The analysis of saccadic gain revealed a similar pattern. There was also a significant main effect of direction, diagnostic index multiplying the ratios of vertical-to-horizontal velocity and gain to differentiate patients with PSP from patients with PD and HCs. This index is calculated as follows:Based on these findings, we developed a novel F = 14.765, p < 0.001, t(26) = −4.73, p < 0.001, PSP < HC: t(27) = −5.64, p < 0.001, PD = HC: t(29) = −0.22, p > 0.05 , vertical velocity (r = 0.596), and the diagnostic index (r = 0.592) with the midbrain volume in the PSP but not the PD group. Moreover, Fischer r-to-z transformation revealed that correlation coefficients significantly differed between both groups for the diagnostic index  but not for vertical velocity  and vertical gain .Based on the significant differences between patients with PSP and PD observed for the oculomotor  and MRI assessment  we analyzed the relationship between oculomotor performance and MRI data separately for the PSP and also the PD group in a correlational analysis see . This anThe investigation of movements of the human eye has evolved steadily over the past 40 years and has become an important tool in the study of cognitive dysfunction and pathophysiology in neurological disorders, including Parkinson's disease. In addition to measuring saccadic eye movements –38, examIn this study, we tested for the first time a novel technology of eye-tracking in HMDs to assess gaze behavior in patients with PSP, PD, and HCs. Besides easy handling and portability, HMDs offer the additional benefit of an inherently standardized visual environment making the visual stimulation exclusively dependent on the programmed environment , 24. In We further crucially extended this finding by developing a new diagnostic index combining the ratios of vertical to horizontal gain and velocity in one single measurement. In our sample, the diagnostic index distinguished PSP from PD with high sensitivity and specificity. That is, patients with a diagnostic index below 0.47 were highly likely to suffer from PSP whereas almost all subjects with an index above 0.47 were either patients with PD or HCs. We see the decisive advantage of this new index especially in the diagnosis of PSP during early stages of the disease before impairments of vertical saccades are followed by impairments of horizontal saccades . MoreoveThe results of the MRI assessment confirmed regional atrophy in PSP in the midbrain volume and the midbrain as well as the midbrain tegmentum plane –15. SeveThis study has some potential limitations. First, the PSP and the PD group differed in disease duration. Despite the shorter disease duration patients with PSP showed unique oculomotor dysfunctions and patients with PD with a longer disease duration resembled the group of HCs. Second, a relatively large number of patients (9/54 = 17%) were not able to complete the oculomotor examination either due to reported fatigue or problems with vigilance and concentration. These patients had to be excluded because the number of valid trials was too low. This problem might be reduced by either shortening the oculomotor examination or by retesting. However, we verified that no systematic bias occurred by excluding patients demonstrating the absence of significant differences between included and excluded patients with regard to age, gender, disease duration, LEDD, mental assessment using PANDA as well as motor status using MDS-UPDRS score.It must be mentioned that a large number of the patients in our cohort had possible or probable PSP of the Steele–Richardson type. In many of these patients, disturbances of vertical eye movements could already be detected in the clinical examination, so our method validated the clinical finding. We believe, however, that our method has the potential to identify early stages of the disease when oculomotor symptoms are not yet visible. Further studies should therefore focus on the evaluation of abnormalities in the early phase of still inconspicuous clinical eye movements to improve subtype diagnosis. For patients with PSP, the clinical assessment was done using MDS-UPDRS rather than the Progressive Supranuclear Palsy Rating Scale (PSP-RS) or the newer Progressive Supranuclear Palsy Clinical Deficits Scale (PSP-CDS). In further studies using this method, the additional collection of these scores would be useful for further assessment of a possible association between the midbrain atrophy and clinical severity.The assessment of eye movements in HMDs provides a new, convenient, and highly standardized tool to differentiate patients with PSP from PD and HCs. Due to the high level of standardization, this novel technology has the potential to significantly improve the reliability of oculomotor diagnostics in the clinical setting. Our easy to compute diagnostic index differentiates PSP from PD and might especially enhance diagnostics during the early stages of PSP. Finally, we have provided evidence for the first time that the degree of vertical ocular dysfunction correlates with the severity of midbrain atrophy. However, at this stage of development, patient exclusion due to discontinuation of oculomotor examination is still evident as well as the diagnostic discriminatory power in the early phase of the disease, which remains to be prospectively investigated. Further prospective and longitudinal investigations on a broader number of samples and timepoints are therefore mandatory to comprehensively assess the utility of eye-tracking in PSP diagnostics.The raw data supporting the conclusions of this article will be made available by the authors, upon reasonable request.The studies involving human participants were reviewed and approved by local Ethics Committee of Muenster (file reference: 2018-280-f-S). The patients/participants provided their written informed consent to participate in this study.AH, WS, W-RS, and AR designed the study and drafted the manuscript. AH, AA, and AR performed data acquisition. AH and AR performed statistical analysis. H-JH and RK performed MRI analysis. FZ, H-JH, and RK revised the manuscript. All authors contributed to the article and approved the submitted version.This study has been funded by a grant to Werner Schneider from the Cluster of Excellence Cognitive Interaction Technology CITEC  at Bielefeld University.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The incidence of acute mastitis (AM) in lactating women has been increasing year by year. If there is no timely and appropriate treatment, AM may develop into mammary abscess and septicemia. This special situation has aroused social attention. Chinese massage has been widely used in the treatment of AM in recent years, but there is no systematic review of the effect of Chinese massage on AM. We plan to explore the efficacy and safety of Chinese massage in the treatment of AM.We will use a computer to search the following 8 electronic databases  on November 30, 2021. Randomized controlled trials (RCT) of Chinese massage therapy for AM were screened. Primary outcome measure: overall clinical response rate, breast pain score. Secondary outcome measures: milk secretion, temperature, mass size and time to resolution, White blood cell count, C-reactive protein, and the incidence of adverse reactions. According to the inclusion criteria and exclusion criteria, the included literature will be independently evaluated by two researchers using the RCT bias risk assessment tool in the Cochrane evaluation manual Handbook5.4, and meta-analysis will be performed by RevMan5.4 software. Funnel plots were used to analyze whether the study had publication bias.We will evaluate the clinical effect of Chinese massage therapy on AM based on RCTsThis study will provide evidence-based evidence for the effectiveness and safety of Chinese massage in the treatment of AM.INPLASY2021120019. Studies show that the main cause of acute mastitis is milk deposition and infection, and the main pathogenic bacteria is Staphylococcus aureus.,5 Factors such as women's decreased physical resistance after childbirth, unhealthy dietary patterns, inappropriate breast-feeding methods and posture, and poor milk flow are considered to be important factors leading to the emergence of AM.  If AM cannot get timely and correct treatment, it will not only affect the baby's breastfeeding, but also lead to the occurrence of breast abscess, sepsis and other dangerous situations.–9 Breastfeeding is the preferred method of feeding newborns up to six months of age, as advocated by the World Health Organization, and is beneficial to both mother and baby. Studies have shown that mastitis severely affects women who breastfeed, so timely and effective treatment of AM is especially important. At present, western medicine for AM in the early stage of the main treatment is anti-infection treatment, although large doses of antibiotics can achieve anti-inflammatory effect, reduce the relevant symptoms. However, the overuse of antibiotics affects the therapeutic effectiveness of AM and breastfeeding. If mammary abscess is present, the patient's recovery and the infant's feeding will be affected by the treatment. Therefore, how to safely and effectively treat patients with AM has become an urgent problem to be solved.Acute mastitis (AM) is an acute suppurative breast disease common in lactation women. According to the incidence survey of acute mastitis in lactating women, about 10% of women worldwide are affected by it. Modern medicine believes that massage can improve the mammary gland blood circulation and lymph circulation, and can also promote the patency of mammary gland ducts. The problems of patients’ milk stasis and pain can be solved by Chinses massage. However, there has been no systematic review and meta-analysis of the effects of Chinese massage on AM. Based on the RCT, this study will evaluate the effectiveness and safety of Chinese massage in the treatment of AM by using meta-analysis, aiming to provide more evidence-based evidence for the clinical treatment of AM.Chinese massage plays a role in dredging meridians, promoting qi and blood circulation, and enhancing the body's resistance to disease. In recent years, it has been reported that the effect of Chinese massage on acute mastitis is exact.22.1Our protocol will be based on the preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015.https://inplasy.com/). The registration number is INPLASY2021120019.This systematic review and meta-analysis protocol has been registered on the INPLASY website  further read the title and abstract of the literature to exclude the literature that did not meet the requirements. The selected literature was comprehensively read to determine the final literature to be included in the study. Any differences arising during the screening process will be discussed with a third party (Can Lyu) and the final decision will be made. The process of literature screening is shown in Figure 2.5.2Two researchers (Longsheng Ren and Ruiying Guo) independently extracted data information. Any disagreement will be discussed and decided with third party (Can Lyu). Information extracted included: first author, year of publication, age, duration of disease, duration of treatment, outcome indicators, sample size, interventions, adverse reactions, etc. The extracted information was compiled into Excel tables for data collection. If the data information in the literature is incomplete or inconclusive, we will attempt to complete the information by contacting the original author by email or telephone. If experimental data cannot be obtained by contacting the authors, we will exclude the study.2.5.3Two researchers (Longsheng Ren and Ruiying Guo) independently evaluated the quality of the included literature according to the RCT risk assessment tool in the Cochrane Evaluation Handbook 5.4. The main evaluation items include random sequence generation, assignment concealment, blindness, selective reporting results, incomplete results data, and other biases. Each assessment item is divided into three sections: “low risk”, “unclear risk” and “high risk”. All differences that exist will be resolved through our discussions with third parties (Can Lyu).2.5.4P < .05 was considered statistically significant. P values and I2 values will be used to test for heterogeneity in the included study literature. I2 < 50% was taken as the standard for no heterogeneity or small heterogeneity, and fixed effect model was used for analysis. If heterogeneity exists or is large, I2 > 50% is taken as the standard, and random effect model is used for analysis. If heterogeneity exists, sensitivity analysis or subgroup analysis will be performed to determine the source of heterogeneity. Descriptive analysis will be used when meta-analysis is not possible.Meta-analysis of the data from the included studies will be performed by using the data processing software RevMan 5.4 of the Cochrane Collaboration Network. The relative risk (RR) of the 95% confidence interval (CI) will be calculated using dichotomous variables, and the mean difference (MD) of the 95% confidence interval (CI) will be calculated using continuous variables. 2.5.5Factors such as age, course of disease, duration of treatment and different interventions will be analyzed by subgroup to explore the source of heterogeneity.2.5.6Sensitivity analysis will be used to explore the significant heterogeneity in the studies and identify the sources of heterogeneity.2.5.7If more than 10 studies were included in the meta-analysis, we will use Revman5.4 software to draw funnel plot to analyze whether there is publication bias in this study and analyze the results.2.5.8In this study, the Grading of Recommendations Assessment, Development, and Evaluation (grade) method will be used to evaluate the quality of outcome evidence. The grade of evidence quality will be divided into four categories: very low quality, low quality, medium quality and high quality.3,16 In modern medicine, the effect of antibiotic treatment for early AM is relatively limited. On the one hand, the curative effect will be reduced due to the development of drug resistance in patients. On the other hand, patients will have anxiety due to the use of antibiotics to affect breastfeeding, which has a great impact on the physical and psychological of patients. In order to solve the problem of AM treatment is not enough and improve the quality of life of patients and infants, we believe that AM can be treated by Chinese massage. It has been found that the duration and treatment effect of AM can be improved by promoting breast empties.,19 Chinese massage has the function of dredging mammary duct and promoting the emptying of mammary gland. It can improve the circulation of breast local blood and lymph fluid, promote the absorption of oedema and inflammatory products, reduce the pressure inside the mammary gland. At the same time, the application of Chinese massage can also reduce patients’ concerns about the use of drugs affecting lactation, and has a significant effect on the treatment of AM.The incidence of AM is increasing. According to a survey, the probability of nursing women suffering from AM is as high as 33%, and the probability of mammary abscess occurring if the treatment is improper or delayed is 3–11%, and even sepsis and other serious problems will occur.However, the Chinese massage for AM lacks the support of evidence-based medicine. Therefore, our study will conduct a systematic evaluation and meta-analysis on the effectiveness and safety of Chinese massage treatment of AM, aiming to provide a stronger evidence-based basis for clinical practice.Conceptualization: Qiang Wang, Jie Zhang.Data curation: Longsheng Ren, Ruiying Guo, Can Lyu.Formal analysis: Longsheng Ren, Ruiying Guo.Investigation: Longsheng Ren, Ruiying Guo, Can Lyu.Methodology: Longsheng Ren, Danyang Zhao, Zhihao Dong.Project administration: Qiang Wang, Jie Zhang.Resources: Longsheng Ren.Software: Longsheng Ren, Ruiying Guo, Can Lyu.Supervision: Qiang Wang.Validation: Zhihao Dong, Zenglin He.Visualization: Longsheng Ren.Writing – original draft: Longsheng Ren, Can Lyu, Qiang Wang.Writing – review & editing: Longsheng Ren, Qiang Wang.


We aimed to determine the relationships between diet, physical activity, and the progression of liver fibrosis. (2) Methods: The 349 participants were categorized by their FibroScan-aspartate aminotransferase score, and they completed a questionnaire regarding their diet and physical activity. (3) Results: There were 233 patients in the negative-on-screening group, 78 in the gray zone group, and 38 in the positive-on-screening group. The frequencies of consumption of soybeans and soybean products and of light-colored vegetables were lower in the positive group; whereas the frequencies of consumption of snack food and fried sweets, jelly and pudding, fried food, and butter, lard, and beef tallow were higher. The odds ratios for the fibrosis progression in patients who consumed fried food ≥4 times/week was 2.21. The positive group also showed lower physical activity level (PAL) and exercise /hour/week). The patients who undertook Ex at >7.5 had an odds ratio of 0.21 for the fibrosis progression. (4) Conclusion: High consumption of fried food and low Ex are risk factors for the fibrosis progression in NAFLD. In recent years, the number of people with obesity has been increasing in Japan because of the westernization of dietary habits and a lack of exercise. Furthermore, the prevalence of liver abnormalities has been increasing, according to the results of the recent national survey of human health check-up data; and an increase in the prevalence of non-alcoholic fatty liver disease (NAFLD) is thought to be the major factor driving this .NAFLD is a phenotype of the metabolic syndrome that manifests in the liver . NAFLD cDietary habits have a substantial influence on the development of hepatic fibrosis in NAFLD. Previous studies have shown that saturated fatty acids and trans-fatty acids in fatty foods have adverse effects on the liver in NAFLD ,5, and tPhysical activity also influences the development of liver fibrosis in NAFLD. This represents the sum of the activities of daily living, such as work, housework, commuting, and schooling; and exercise, such as participation in sports, which is planned and deliberate, or regular physical activity for the purpose of maintaining and improving physical fitness . We haveLiver biopsy is the gold-standard method for the definitive diagnosis of liver fibrosis . HoweverThe FibroScan-aspartate aminotransferase score (FAST score) is derived from a combination of the results of liver stiffness measurement (LSM); liver fat content , measured using ultrasound elastography (FibroScan); and serum aspartate aminotransferase activity . The FASIn this study, we conducted a questionnaire survey of diet and physical activity in patients with NAFLD. The participants were categorized according to the tertiles of the FAST score  and theiThe participants comprised 431 patients  who attended the outpatient clinic for lifestyle-related diseases at the Tsukuba University Hospital between January 2017 and March 2021 . They weDiagnoses of NAFLD were made by means of interview, ultrasonography, and ultrasound elastography. In total, 248 participants  were diagnosed as having NAFLD, and 101  did not have NAFLD. The participants provided written informed consent to complete the questionnaire.®, Kenpakusha Co. Ltd., Tokyo, Japan) was used. The questionnaire was administered by a researcher who verbally explained the response procedures and precautions to the participants, and the results were collected by mail.We conducted a questionnaire survey of the diet and physical activity of the participants using the Food Frequency Questionnaire, based on food groups  . To analIn addition to the foods included in the five food categories of the Food Balance Guide  , we addePhysical activity level (PAL) and exercise (Ex) were calculated based on the responses to the physical activity questionnaire. PAL is an indicator of the intensity of average daily activities such as housework, commuting, and school work, and was calculated by dividing the energy expenditure calculated using the doubly-labeled water method by the basal metabolic rate of the participant. In adults, PAL is defined as I (low): 1.50, II : 1.75, and III (high): 2.00 . Ex is a2. The following sarcopenia-related indices were calculated: SMI  [The measurement of body composition was analyzed by bioelectrical impedance analysis (BIA) . The meaht [m]2) ; SI (limht [m]2) ; and SV ht [m]2) , an indeht [m]2) .Most measurements were performed as described previously . Paramet®  with a 3.5-MHz M probe for participants with BMI < 30 kg/m2 and with a 2.5-MHz XL probe for those with BMI ≥ 30 kg/m2. According to the validity criteria [Liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) were determined by using a Fibroscan−1.65+1.07×ln(LSM)+2.66×10−8×CAP3−63.3×AST−1/1 + e−1.65+1.07×ln(LSM)+2.66×10−8×CAP3−63.3×AST−1 [The FAST score  is a sco.3×AST−1 . The par.3×AST−1 .Analyses were performed using SPSS version 26 . Data are summarized as means ± standard deviations. The statistical significance level was set at 5%. To compare the basic characteristics and measured parameters among the groups, the Kruskal-Wallis and Mann-Whitney U-tests were used for continuous data, and the chi-square test for categorical data. The Dunn-Bonferroni test was used for multiple comparisons. The relationships of the FAST score with the frequency of food intake, PAL, and exercise level were analyzed using Spearman’s rank correlation coefficient. Furthermore, binomial logistic regression analysis was performed using models in which the progression of hepatic fibrosis  was used as the outcome, and a frequency of food intake of ≥4 times/week, a PAL of ≥2.0, and an amount of exercise of ≥7.5 METs/hour/week were used as factors. The results are presented as odds ratios (ORs) with 95% confidence intervals (CIs).p < 0.001), and that the sex composition in the positive and gray groups was different from that in the negative group (p < 0.05).The participants were placed into three groups using their FAST scores as follows: a negative-on-screening (negative) group, a gray zone (gray) group, and a positive-onscreening (positive) group . Comparip < 0.05, negative vs. positive; p < 0.01). The prevalence of hypertension also significantly differed among the three groups and was higher in the gray and positive groups than in the negative group (both p < 0.05). Finally, the prevalence of dyslipidemia significantly differed among the three groups and was higher in the gray group than in the negative group (p < 0.05).The prevalence of lifestyle-related diseases in the three groups was compared . The preThe body mass, body composition, physical performance, blood biochemistry, liver fat content and elasticity, and liver fibrosis scores of the three groups are shown in The sarcopenia indices SMI and SI, and the sarcopenia-obesity index, SV ratio, were compared among the groups . The SMIThe waist-hip ratio and visceral fat cross-sectional area of the groups were also compared . The waiThe serum AST, alanine aminotransferase (ALT), and gamma-glutamyltransferase (γGT) activities, which reflect liver dysfunction, were compared among the groups . The actAll the parameters related to glucose metabolism increased in value with BMI. Specifically, fasting glucose, HbA1c, insulin, and HOMA-IR were higher in the gray and positive groups than in the negative group. For parameters related to lipid metabolism, serum HDLC concentration was significantly lower in the positive group than in the negative group, but the LDLC concentration did not significantly differ. The serum TG concentration was significantly higher in the positive group than in the negative group.Transient elastography was used to evaluate liver fat content and fibrosis. CAP has been reported to reflect the fat content of the liver  and tendLiver fibrosis markers and liver fibrosis scores were also compared among the groups. Type IV collagen deposition was higher in the gray and positive groups than in the negative group and M2BPGi was significantly higher in the positive group than in the negative group. FIB-4 index did not significantly differ, although it tended to be higher in the positive group; and NFS also did not significantly differ, although it tended to be lower in the positive group.Grip strength was measured as an index of muscle strength, and knee extension strength was measured as an index of muscle strength that reflects lower limb support, which is important for mobility and balance. Both parameters were higher in the positive group than in the negative group.The levels of the inflammatory markers CRP and ferritin were compared among the groups. CRP was higher in the gray and positive groups than in the negative group, and ferritin was higher in the positive group than in the negative group.We next compared the frequency of consumption of various foods by participants in the three groups . For soyp = 0.038), green and yellow vegetables , light-colored vegetables , simmered food , snack foods and fried sweets , ice cream , jelly and pudding , fried food , sesame , salty snacks , and pickles  with the FAST score.We next analyzed the relationships between the FAST score and the frequency of consumption of the food types. The analysis showed significant correlations of the frequencies of consumption of soybeans and soybean products  and Ex .We analyzed the relationships of the FAST score with PAL and Ex performed. Correlation analysis showed that the FAST score significantly correlated with PAL  and Ex ≥ 7.5 .The relationship of the consumption frequency of food types with liver fibrosis was investigated using binomial logistic regression analysis . A multiThe prevention of the progression of NASH by lifestyle modification is an important issue in daily clinical practice. This study shows that patients with suspected NASH and advanced hepatic fibrosis, who were identified using the new FAST score, consumed soybeans and light-colored vegetables less frequently, and fried snacks and fried foods more frequently. Furthermore, they were found to have a low PAL and to do little Ex.Hashidume et al.  reportedAccording to the Food Composition Index , light-cThe physiological effects of dietary fats differ according to the type of fatty acid they contain; therefore, it is important to focus on adjusting the frequency of intake of types of fatty acids, rather than to simply reduce total fat intake . SpecifiIndividuals who consume a large quantity of fried foods, snack foods, and/or fried sweets are likely to accumulate fat in their livers and experience fibrosis through the effects of the saturated fatty acids and trans-fatty acids contained in these foods on their intestinal tract and adipose tissue. This may explain the associations identified in this study. In contrast, there were no differences in the frequencies of the consumption of fish oil, perilla oil, egoma oil, and flaxseed oil, which contain high levels of n-3 polyunsaturated fatty acids; peanut oil, almond oil, olive oil, and canola oil, which contain high levels of monounsaturated fatty acids; or sesame oil, safflower oil, cottonseed oil, and soybean oil, which contain high levels of n-6 polyunsaturated fatty acids. This implies that variations in the consumption of these oils did not affect the progression of liver fibrosis in the participants.It has been reported that exercise at ≥10 Ex reduces visceral fat mass  and liveThe strength of this study is that it is one of the few that compares the results of surveys on food intake frequency and physical activity status, anthropometric data, and clinical laboratory data by classifying participants into three groups on the basis of the FAST score cutoff values: negative screening, gray, and positive screening. The novelty of this study is that in the screening-positive NASH group with advanced liver fibrosis, which was narrowed down using the new FAST score, a high frequency of fried food intake and even lower physical activity were found, which were speculated to be risk factors for the development of liver fibrosis.This study had several limitations. In particular, first, we used the FFQ, a method of recording food intake frequency, as the dietary survey method. This approach has been reported to be associated with errors, owing to day-to-day variation  and undeA survey of diet and physical activity in patients with NAFLD showed that in those with suspected NASH and advanced hepatic fibrosis, frequent consumption of soybeans and soybean products was associated with less liver fibrosis, whereas the consumption of fried food was associated with more fibrosis. Furthermore, low PAL and Ex were associated with more hepatic fibrosis. Therefore, the dietary habits and physical activity status of patients should be considered and optimized as part of the management of NAFLD in daily clinical practice.


Echinococcus, is the most pathogenic zoonotic parasitic disease in the world. In Tibet of the People’s Republic of China, echinococcosis refers principally to two types of severe zoonosis, cystic echinococcosis (CE) and alveolar echinococcosis (AE), which place a serious burden on public health and economy in the local community. However, research on the spatial epidemiology of echinococcosis remains inadequate in Tibet, China. Based on the recorded human echinococcosis data, maps of the spatial distribution of human CE and AE prevalence in Tibet were produced at city level and county level respectively, which show that the prevalence of echinococcosis in northern and western Tibet was much higher than that in other regions. We employ a geographical detector to explore the influencing factors for causing CE and AE while sorting information on the maps of disease prevalence and environment factors . The results of our analysis showed that biological factors have the most impact on the prevalence of echinococcosis, of which the yak population contributes the most for CE, while the dog population contributes the most for AE. In addition, the interaction between various factors, as we found out, might further explain the disease prevalence, which indicated that the echinococcosis prevalence is not simply affected by one single factor, but by multiple factors that are correlated with each other complicatedly. Our results will provide an important reference for the evaluation of the echinococcosis risk, control projects, and prevention programs in Tibet.Echinococcosis, caused by genus  Echinococcosis, a worldwide zoonosis caused by genus Echinococcus, is highly endemic in Tibet of China. CE and AE as two main types of Echinococcosis are causing serious health burdens, thereby attracting more attention to public health in Tibet. This work provides detailed geographical information about CE and AE prevalence based on the recorded human echinococcosis data from CDC. A geographical detector was employed to explore the potential environmental factors that influence these diseases and to quantify the specific contribution of each factor as well as discovering the interaction between factors. The results showed that biological factors have the most impact on the prevalence of echinococcosis, of which the yak population contributes most to CE while the dog population makes the most contribution to AE. Besides, the interactive results greatly improved the explanation of the two diseases, indicating that the echinococcosis prevalence is not simply affected by one factor, but by various interrelated factors. Such research can be beneficial to the evaluation, control projects, and prevention programs of the echinococcosis risk in Tibet. Echinococcus (family Taeniidae) in the adult or larval stages [Echinococcus spp. or contacting with contaminated environment indirectly [Echinococcus granulosus (E.granulosus) and Echinococcus multilocularis (E.multilocularis) respectively, are the two main types of echinococcosis, which may result in asymptomatic infections that lead to severe and even fatal disease [Echinococcosis is considered to be the most pathogenic zoonosis caused by cestode species of the genus l stages , 2. Trandirectly , 4. Cyst disease . The asy disease , until t disease . Human A disease . Given s disease .Echinococcosis is a near-cosmopolitan zoonosis, which imposes a huge burden on public health management . CE has China as one of the most important and highly endemic regions for both CE and AE holds a high percentage of the global burden of echinococcosis . It is fThis study was approved by the Ethics Committee of CDC. All the data analyzed in this study were anonymized to protect patient confidentiality.The Tibet Autonomous Region (Tibet) is located in the southwest of the People’s Republic of China, bordering provinces of Xinjiang, Sichuan, Qinghai, and Yunnan , stretchEchinococcosis data used in this study was obtained from the Chinese Center for Disease and Prevention (CDC), which was derived from an epidemiological survey in Tibet between 2012 and 2016. A stratified and proportionate sampling method was employed to select samples in 380 villages of 74 counties in Tibet, and a total of 80384 residents were selected. Among them, 1202 were examined positive for CE while 153 were tested positive for AE by B-ultrasonography diagnostic. The overall human prevalence of CE and AE in Tibet were 1.5% (1202/80384) and 0.19% (153/80384) respectively. Detailed information including age, sex, occupation, etc is also included in the disease data. Data used in this study had been de-identified to protect patient confidentiality. Other detailed information about the disease data can be found elsewhere .E.granulosus and E.multilocularis respectively during the entire life cycle of echinococcosis transmission. The transmission of CE and AE relies on both the sylvatic cycle and the synanthropic cycle. CE primarily maintained in the synanthropic cycle, which involved livestock such as cattle (yak) and sheep that are regarded as the most important intermediate reservoir hosts while canines (mainly domestic dogs) are the main ultimate hosts in Tibet [E. multilocularis [in Tibet . For AE,ocularis , 10. In ocularis . Humans ocularis , 28. Meahttp://www.resdc.cn) and shown in High altitude grasslands on the Tibetan Plateau enable pastoralism to flourish, which is associated with recognized risks of human echinococcosis for livestock and dogs. Echinococcosis transmission can occur in different landscape types where various physical and biological factors combine to determine the intensity of the parasite transmission , 21. On E.granulosus and E. multilocularis eggs were sensitive to fluctuation in both temperature and humidity [http://data.cma.cn), based on which annual average precipitation, annual average minimum (maximum) temperature, and annual average relative humidity were obtained on ANUSPLIN-SPLINA software. Classified maps of minimum (maximum) temperature, relative humidity, and precipitation were pictured in Some previous studies have found that the activity and survival time of humidity , 30. MorE.granulosus and E.multilocularis [As the most important domestic reservoir hosts, yak, and sheep that are susceptible to echinococcosis in Tibet, play important roles in the transmission of human echinococcosis , 25. In ocularis , 32. Thehttp://www.resdc.cn). Classified maps of population and GDP were shown in Some studies have found that socioeconomic factors are associated with the prevalence of human echinococcosis , 22, 23,The geographical detector was proposed by Wang et al in 2010 , which ii}. The mean value and variance of disease prevalence over sub-regions of layer H are denoted as h and Where the CE and AE prevalence were composed of N units. L denotes the number of strata. Nequals 0 . Meanwhiq(X1∩X2) refers to the interaction of factor X1 and X2. In this study, the package “geo-detector” in R version 3.5.2 (64-bite version) was used to employ the geo-detector method, which can be downloaded from the website of http://geodetector.cn/. The website also provided the excel version enclosed examples of datasets. More detailed information about the geographical detector method can be found elsewhere [The geographical detector is composed of risk detector, factor detector, ecological detector, and interaction detector. The risk detector indicates where the risk areas are. The factor detector quantifies the impact of an environmental factor on the risk of disease prevalence. And the ecological detector explores whether stratum A is more significant than stratum B in controlling the spatial distribution of disease prevalence. The interaction detector reveals the interactive effect of two factors on the disease prevalence. lsewhere , 34.The prevalences of human echinococcosis at different levels in Tibet are presented in The spatial distribution of human CE prevalence at the city level was shown in The human AE prevalence at the city level based on geographical distribution was depicted in The q-statistic listed in The interactive q-statistic values of related factors for CE and AE were presented in Same with AE, the q-value for yak, sheep, and dog population were 0.22, 0.06, and 0.37 respectively while the interactive value of yak and sheep population was 0.52, and that of yak and dog population was 0.55, of sheep and dog population was 0.58, all of which greatly improved the explanation for the prevalence of AE. Besides, we found that when any factor interacts with the dog population, the interactive q-statistic value would increase surprisingly. For instance, the interactive effects value of dog population and population was 0.57, GDP (0.57), minimum temperature (0.47), maximum temperature (0.47), relative humidity (0.49), precipitation (0.50), terrain (0.43), Land use (0.44) and NDVI (0.49). Furthermore, even of those factors with little impact, interactions between them would enhance their separate effects on AE prevalence. For example, the q values of the sheep population and population were 0.06 and 0.05 respectively, but their interactive value was 0.38. Almost all the interactive values listed in As one kind of neglected zoonosis, echinococcosis seriously endangers human health and imposes a heavy burden on many countries due to the considerable morbidity rates and high economic losses. CE has a wider geographical distribution and a higher prevalence rate compared with AE, whereas the global burden of AE  was much higher than CE . The much lower human health burden of CE compared with AE was almost entirely due to the low mortality rate of CE relative to AE , 12. HowBased on the data derived from an epidemiological survey of CDC in 2012 and 2016, the spatial distribution patterns of CE and AE prevalence in Tibet were mapped at different geographical scales. Maps at city level indicated that both CE and AE regions of northern Tibet  are high endemic areas, which may be because that these areas are mainly dominated by animal husbandry. Also, the county-level maps showed that CE was prevalent in all counties of Tibet while AE occurred in about 64% of counties, which also underlines counties of Anduo, Baqing, Cuoqin, Cuomei, and Zuogong presenting high co-endemicity of CE and AE, therefore, it can provide important information for the government on regionalization of key prevention and control efforts.E.multilocularis in dogs in Western Sichuan province, along with a reduction in human AE. However, there is no change in the prevalence in small mammals[In addition, the geographical detector method was used to explore the risk factors for CE and AE in this study. The results showed that biological factors  influence the most in the prevalence of echinococcosis. For CE, it is perhaps a little surprising that there was no such a direct association strongly related to dogs, whereas the dogs are the obligatory definitive host of this parasite. However, there is an interaction between dogs and yaks or sheep AB&C in , which ml mammals, which il mammals, 38. In Furthermore, it should be noted that although other factors  contribute little to the prevalence of echinococcosis based on factor detector, the interaction between them and those biological factors can significantly increase the interpretability of disease prevalence , and further conduct detailed studies on echinococcosis considering the differences of age groups, which is of great significance to the epidemic research of infectious diseases.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.S5 Table(DOCX)Click here for additional data file.


Insidious-onset acromegaly may easily be overlooked by non-specialists of acromegaly and cause diagnostic delay. This study aims to examine the association between diagnostic delay and advice from doctors before any confirmed diagnosis and subsequent comorbidities, and elicit patient-perceived reasons for misdiagnoses.An online nationwide cross-sectional study was conducted through China Acromegaly Patient Association. Growth Hormone (GH) and Insulin-like Growth Factor 1 (IGF-1) levels at diagnosis and cancerous, endocrine-metabolic, musculoskeletal, cardiovascular, respiratory, and psychiatric comorbidities were reported by patients. The association between diagnostic delay and pre-diagnostic advice from doctors as well as subsequent comorbidities after diagnosis were examined.In total, 447 valid responses were collected. Overall, 58.8% patients experienced misdiagnoses, and 22.6% had diagnostic delay. Before arriving at any diagnosis, patients without treatment  or receiving treatment to symptoms only  had greater chance of being misdiagnosed, and hence had diagnostic delay. Patients believed insufficient specialists, limited awareness of acromegaly of non-specialists and poor doctor-patient communications were major reasons of misdiagnosis. Diagnostic delay were associated with higher GH level at diagnosis and endocrine-metabolic, musculoskeletal and cardiovascular comorbidities .Suboptimal pre-diagnostic advice for patients, reflecting limited awareness of acromegaly among non-specialists, may delay the diagnosis and increase comorbidities. Feedbacks on the patients’ final diagnosis from specialists to non-specialists should be considered, and doctor-patient communication and clinical decision-making process should be improved. Comorbidities should be screened and monitored particularly for patients with diagnostic delay. Acromegaly is a rare chronic condition caused by the excessive secretion of Growth Hormone (GH) and Insulin-like Growth Factor 1 (IGF-1) –4. HowevDiagnostic delay or long duration before diagnosis, suggesting a delay in initiation of management of their hormone level and detection of their comorbidities, might cause worse health outcomes of patients. A longitudinal study in Sweden found that a longer diagnostic delay  led to increased mortality and a greater number of comorbidities . Other tIn recent studies, the reasons for the diagnostic delay during the process of arriving at the correct diagnosis of acromegaly have been explored. In a few qualitative studies, the advice provided, or decisions and responses made by doctors, especially non-specialists, before the diagnosis could be the reasons for the misdiagnosis and the long diagnostic durations , 14. AddA nationwide cross-sectional survey was conducted in patients with acromegaly in China between 17 December 2019 and 6 January 2020. This study was approved by ethics committees from the Chinese University of Hong Kong and Peking Union Medical College Hospital (Reference number: SBRE-18-268 and SK-814). Informed consent was obtained from each participant prior to commencement of the survey.via instant messengers (e.g. QQ) and social media (e.g. WeChat). It was a self-administered survey in which a staff member from CAPA and a member of the research team were available online to answer the questions from the survey participants. The online survey platform was designed to guide participants to avoid missing questions unintentionally. An information sheet related to this study was provided at the beginning where the participants indicated their consent to participating the survey. All the data collected by this survey were retrieved from the online survey platform after completion, and the data were protected by passwords.The participants of the study were recruited through the China Acromegaly Patient Association (CAPA), a non-profit organization established by patients with acromegaly and their families in 2012 that has a nationwide network of patients. The survey targeted patients with acromegaly. For the study, only adult patients with acromegaly were included in the analysis. In the survey, a link for the web-based questionnaire was sent to each patient by the staff of CAPA through its patient network This survey focused on seven major factors. They included: 1) diagnostic information: calendar year of the first medical consultation for the condition and calendar year of receiving the diagnosis of acromegaly and whether the condition were misdiagnosed as other diseases; 2) pre-diagnostic advice from a doctor when the patient did not receive a confirmed diagnosis from the doctor; 3) initial symptoms resulting from acromegaly; 4) GH and IGF-1 levels at diagnosis and comorbidities including cancer, endocrine-metabolic, musculoskeletal, cardiovascular, respiratory, and psychiatric conditions at the time of survey ; 6) theiThis survey was part of the 2019 General Social Survey on People with Rare Diseases in China. The design, implementation, and quality control of the survey were monitored by a committee comprising clinical specialists on acromegaly, managers and staff of CAPA, and research team members with multidisciplinary backgrounds. The questionnaire was refined and finalized based on a three-round pilot survey of over 10 participants.The demographic and clinical characteristics of the patients were compared between the patients who experienced and did not experience diagnostic delays and misdiagnosis using the chi-square test for categorical variables and independent t-test or Wilcoxon rank-sum test for continuous variables. Two multiple logistic regression models for misdiagnosis and diagnostic delay were used to examine their associations with pre-diagnostic advice separately, with adjustment for demographics and number of initial symptoms. Those with missing values for misdiagnosis and diagnostic duration were excluded from the analysis. As there were very few members of CAPA who were not diagnosed with acromegaly, this study only included patients who had been diagnosed with acromegaly, while the patients who had already visited doctors for this condition but had not been diagnosed with acromegaly were not approached for the survey. This may lead to a selection bias that underestimates the likelihood of diagnostic delay. In the study sample, the closer the calendar year of the first medical consultation was to the survey date, the less likely the patients experienced a diagnostic delay. Therefore, the calendar year of the first medical consultation was also included as a covariate in both the regression models to adjust for this potential bias and for the improvement in diagnostic technology throughout the year.Multiple linear regression was used to examine the association of diagnostic delay with GH and IGF-1 levels (in logarithm form) at diagnosis, and multiple logistic regression was used for cancerous, endocrine-metabolic, musculoskeletal, cardiovascular, respiratory, and psychiatric conditions at the time of the survey. The GH and IGF-1 levels and comorbidities were dependent variables which stood for adverse outcomes of acromegaly whereas diagnostic delay, type of treatment received, GH level at the latest follow-up, smoking, and demographics were independent variables. Moreover, patients’ perceptions on reason for misdiagnosis and their sources of information on the hospital that gave them the diagnosis of acromegaly were summarized. Kaplan–Meier (KM) curves were also plotted with log rank test to summarize the length of diagnostic delay in the subgroups with different pre-diagnostic advice and adverse outcomes, which was defined as the number of years between the first medical consultation and the diagnosis of acromegaly with a half-year adjustment. SPSS 26.0  and Stata 15.0  was used for statistical analysis.A total of 474 patients completed the questionnaire. Among them, 454 adults were diagnosed with acromegaly while others who were also diagnosed with pituitary gigantism were excluded. Among the 454 patients with acromegaly, 7 patients provided invalid responses regarding the year of the first medical consultation and the year of diagnosis . Therefore, 447 patients were included in the analysis Table 1.vs. 36.1 ± 9.8 years, P=0.016), women (P<0.001), have more initial symptoms (P<0.001), have closer/later calendar year of first medical consultation (P=0.009), receive no treatment (P=0.015) or treatment to symptoms only (P<0.001) before diagnosis of acromegaly, have surgery (P=0.020) or radiotherapy (P=0.004) for treatment, have higher GH level at diagnosis (P=0.007), have musculoskeletal (P=0.003) and cardiovascular conditions (P<0.001) at the time of survey.vs 4.6% among those who did not have diagnostic delay, P=0.001) or receive treatment to symptoms only  before receiving any diagnosis, while they were less likely to be referred or recommended to other hospitals or doctors . The patients with experience of diagnostic delay were also more likely to have more initial symptoms (P=0.033), have closer/later calendar year of first medical consultation (P<0.001), experience misdiagnosis (P<0.001), have higher GH level at diagnosis (P=0.003), and have musculoskeletal conditions at the time of survey (P=0.006). However, there was no significant difference of age at diagnosis between patients with and without diagnostic delay .The univariate analysis also revealed that those who experienced diagnostic delay were more likely to receive no treatment or advice , followed by recommendations by their family members or friends (21.0%) and doctors (11.9%) Table 4.vs 43.4 ng/ml among those without diagnostic delay, P=0.003), but their IGF-1 levels were similar : 4.52 ± 2.71 vs 4.19 ± 2.89 among those without diagnostic delay, P=0.395)  (Elevated GH and IGF-1 level and comorbidities were considered as adverse outcomes of diagnostic delay. Patients who experienced diagnostic delay had a higher GH level at diagnosis (57.5 P=0.395) . Those wP=0.006) Table 1.From the multiple regressions for GH and IGF-1 level Table 5,This study highlighted suboptimal advices from non-specialists in acromegaly were associated with diagnostic delay, and found out how this delay is associated with increasing comorbidities at follow-up. The findings were obtained from the data collected from the first nationwide survey in China for patients with acromegaly. The study showed that different advices given by doctors before reaching a confirmed diagnosis were associated with different likelihoods of misdiagnosis and diagnostic delay. The findings suggested that the absence of treatments or advices could contribute to misdiagnosis, and eventually lead to diagnostic delay. The pre-diagnostic treatments for the symptoms of patients based on doctor’s personal experience, which could be based on misjudgments of the reasons of the clinical manifestations or merely targeted to the comorbidities caused by acromegaly, were more common and therefore had greater negative impacts on efforts to reach a correct diagnosis. It would not only lead to greater chances of subsequent misdiagnosis, but it could also result in a lengthy duration before reaching to a definite diagnosis of acromegaly.These suboptimal pre-diagnostic advices provided by doctors reflected a lack of awareness related to acromegaly across different specialties in the medical community , 17. AccPhysicians in the primary care setting or in other specialties who were the first contact point for the patients were found to play significant roles in initiating the evaluation that led to diagnosis of acromegaly in the end . In lighGiven the significant impact of pre-diagnostic advice from doctors, improving of their clinical decision-making process could also be helpful in reducing the diagnostic durations. Retrospectively speaking, based on this study, it would be advisable for doctors to invite consultations of other doctors or to refer the patients to the specialists that they believe could give insights to their conditions when they could not reach to a confirmed diagnosis. However, this requires ways to help non-specialists realize that limitations might exist in their current diagnosis and treatment methods, which could enable them to consider for asking consultations or making referrals to specialists . TherefoClinical decisions should be based on adequate information , and conFurthermore, the findings implied that the substantial adverse outcomes of elevated GH levels at diagnosis and subsequent endocrine-metabolic (except diabetes), musculoskeletal and cardiovascular comorbidities were associated with diagnostic delay. The increased comorbidities may reduce quality of life of the patients  and incrvs 16.8% in this survey (including both type 1 and type 2 diabetes)] (vs 18.1% in this survey) (vs 7.2%) ] , 29, 33, survey) , 33 and vs 7.2%) , 35, parvs 7.2%) , 37, desA few limitations of this study should be noted. First, this study adopted a cross-sectional design, one must exercise caution while drawing conclusions about causal relationships. Second, recall bias may exist as it asked the participants to recall their experience retrospectively, particularly for their initial symptoms. Third, selection bias also exists as those who have visited the doctors for this condition but have not received a confirmed diagnosis were not selected for the study. However, the calendar year of the first medical consultation was used as a covariate to reduce its influence, as stated in the Methods section. Selection bias was also caused by relatively younger age of the study sample at diagnosis, which may have fewer comorbidities compared with other studies using registry data. Lastly, whether or not the acromegaly is under control can affect the presence of comorbidities, so we used GH level at the latest follow-up before the survey as an indicator for controlled/uncontrolled condition. However, the GH level at the latest follow-up might not be representative for presence of uncontrolled conditions during the entire follow-up period after diagnosis. This issue can be addressed in longitudinal studies that recorded the GH level at multiple time points during the follow-up period.In summary, before arriving at any diagnosis for patients with acromegaly, absence of treatment of any kind and treatments to symptoms only, reflecting the limited awareness and knowledge of acromegaly of non-specialists who were the first contact point of the patients and insufficient information for clinical decision-making due to poor doctor-patient communication, were associated with subsequent diagnostic delays and misdiagnosis. Educating non-specialists about acromegaly, disseminating feedbacks on the patients from specialists to non-specialists, and improving doctor-patient communication and clinical decision-making process might reduce suboptimal pre-diagnostic advice. Diagnostic delay was also associated with worse health status at later stage, including higher GH levels at diagnosis and higher prevalence of endocrine-metabolic, musculoskeletal and cardiovascular comorbidities at follow-up. Screening of these conditions at diagnosis and regular monitoring efforts at follow-up should be performed to provide timely treatment and management particularly for patients with diagnostic delay.The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.The studies involving human participants were reviewed and approved by Survey and Behavioural Research Ethics, The Chinese University of Hong Kong (SBRE-18-268), and PUMCH Ethics Committee, Peking Union Medical College Hospital (SK-814). The patients/participants provided their written informed consent to participate in this study.KW, XG, SY, BX, SZ, and DD designed the study. KW, SY, HZ, and DD performed the survey and collected responses. BX, HZ, SZ, and DD supervised the implementation and quality control of the survey. KW performed the statistical analysis. KW and XG prepared the manuscript. BX, SZ, and DD revised the manuscript. All authors contributed to the article and approved the submitted version.This work was supported by the National Key Research and Development Program of China (Grant No. 2016YFC0901500) and the Center for Rare Diseases Research, Chinese Academy of Medical Sciences, Beijing, China (Grant No. 2016ZX310174-4). The funders did not involve in study design and collection, analysis, and interpretation of the results.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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