With the increase in the older populations, the number of bedridden older patients is becoming a matter of concern. Skin microbiome and skin physiological functions are known to change according to lifestyle and community; however, such changes in case of movement- and cleaning-restricted bedridden older patients have not yet been revealed. To address this issue, we analyzed skin microbiome and skin physiological functions, including pH, hydration, sebum level, and transepidermal water loss (TEWL), of bedridden older patients, compared with those of ambulatory older and young individuals. For this analysis, we enrolled 19 healthy young and 18 ambulatory older individuals from the community and 31 bedridden older patients from a single, long-term care hospital in Japan. The area of interest was set to the sacral (lower back) skin, where pressure injuries (PIs) and subsequent infection frequently occurs in bedridden older patients. We observed a higher number of gut-related bacteria, fewer commensals, higher skin pH, and lower TEWL on the sacral skin of bedridden older patients than on that of young or ambulatory older individuals. In addition, we observed that 4 of the 31 bedridden older patients developed PIs during the research period; a higher abundance of pathogenic skin bacteria were also observed inside the PI wounds. These findings imply distinct skin microbiome and skin physiological functions in bedridden older patients in comparison with healthy individuals and may suggest the need for more stringent cleaning of the skin of bedridden older patients in light of the closeness of skin and wound microbiome. Cutibacterium (formerly Propionibacterium) acnes is known to produce fatty acids, which in turn keep skin pH mildly acidic and prevent colonization of transient bacteria , as well as retaining the fluid within the body. It is now widely recognized that the skin barrier consists not only of the “wall” of skin cells but also of various bacteria . For exabacteria . Staphyletention . Depletiammation , and sevathogens . TherefoCutibacterium spp. has been found to be lower in older individuals . A PI is defined as “localized damage to the skin and underlying soft tissue over a bony prominence or related to a medical or other device” ; therefoThe aim of this study, therefore, was to compare the skin microbiome and skin physiological functions of bedridden older patients with those of ambulatory older people and young individuals. We further followed up the patients for 2 months to observe the onset of PIs and to reveal the relationship between skin and wound microbiome.This study was approved by the Medical Ethics Committee of Kanazawa University  and was conducted in accordance with the Declaration of Helsinki and the Microorganism Safety Management Regulations of Kanazawa University. Before the collection of skin microorganisms, all the participants or their family received an explanation for the research and provided written informed consent. All the collected samples were processed in a biosafety level-2 laboratory.This was a prospective cohort study. We recruited 19 healthy young , 18 ambulatory older individuals , and 31 bedridden older  patients. The healthy young and ambulatory older participants were recruited via the network of the researchers. The bedridden older patients were recruited in one long-term care hospital in Ishikawa prefecture, Japan, through the referral of the nurses or physicians in charge of the ward.We excluded participants who had skin disorders, including atopic dermatitis, psoriasis, and PIs, on the target region.Target regions were set as the sacral region of the skin, where PIs are reported to occur frequently in bedridden patients –23, and At the time of inclusion, the bedridden patient's demographic information, peak interface pressure, skin physiological functions, and skin bacteria of the target region were collected. The patients were followed up every week for up to 2 months to check if they had a new PI. We used the DESIGN-R scoring system  to assesParticipants' demographic and medical information, including age, sex, gastric fistula, underlying diseases, and medication, was collected through interview or from the medical record. Braden Scale scores  were assDerma Unit SSC3  was used to measure skin hydration, sebum level, and pH. Transepidermal water loss (TEWL) was measured using a VapoMeter® . All the measurements were performed three times, and the average was calculated. A Palm-Q  was used to measure the peak interface pressure of the sacral region.Skin bacteria were collected by the tape-stripping method based on the previous study . First, The whole DNA was extracted from the collected tapes and swabs based on the previous study . In brieEx Taq® Hot Start Version  and TaKaRa PCR Thermal Cycler Dice® Gradient (TaKaRa Bio Inc.). We chose the V3–V4 region for the target of amplification in this study according to the findings by Castelino et al. and Zeeuwen et al. who reported the advantage of using the V3–V4 region for skin microbiome studies (DRA007616).The extracted DNA samples were processed for 16S ribosomal RNA (rRNA) gene sequencing by the next generation sequencing (NGS) method . The hyp studies , 28. TheMicrobiome analysis was performed as described elsewhere  with sliThe operational taxonomic unit (OTU) selection, with 97% similarity threshold from the nonchimeric sequences, was performed using the “pick_de_novo_otus.py” command in Qiime (version 1.9.1) , using tU-test, Kruskal–Wallis test followed by Steel–Dwass post-hoc test using “pSDCFlig” command in the “NSM3” package  was used to perform all the statistical analyses . Box plo package , or Fish package  of R, al package . Canonic package  of R. SiP < 0.01), whereas no significant difference was found between ambulant older people and bedridden older patient groups . Some bedridden patients had cerebrovascular disease (18 out of 31), congestive heart failure (6/31), diabetes mellitus (3/31), and urinary tract infectious disease (3/31) as underlying diseases. These underlying diseases and gender did not significantly affect the skin microbiome . Six bedridden patients used antibacterial drugs; however, there were no significant differences in skin microbiome between the users and non-users of antibacterial drugs , and therefore, all participants were included for further analysis. Four bedridden patients developed PI during observation.Cutibacterium spp. and Enhydrobacter spp. were significantly lower in bedridden participants . Biplot revealed that bedridden older patients were prone to harbor more Escherichia–Shigella spp., Corynebacterium spp., and Staphylococcus spp., and less Cutibacterium spp. and Enhydrobacter spp.PCoA analysis of beta diversity showed that bedridden participants formed apparently different clusters from healthy young and ambulatory older people groups . Shannon index and Chao1 showed no significant differences among all groups . These comparisons were made after all sequences had been evenly rarefied at 13,783 depth .The value of observed OTUs and phylogenetic diversity were significantly higher in bedridden patients than in healthy young people and ambulatory older people . Skin pH (P = 0.043) and ambulatory older people (P < 0.01). TEWL (P < 0.01) and bedridden patients (P < 0.01) than in healthy young people.The data of skin physiological functions are shown in  Skin pH  was sign1). TEWL  was signP < 0.01). These results show that skin microbiome of bedridden older patients seems to be related to skin pH. The correlations between the relative abundance of each species and skin physiological functions are summarized in Next, we examined the relationship between skin physiological functions and skin microbiome using CCA. The CCA plot showed that the plots of bedridden participants were significantly placed along with the increase in skin pH  developed PIs during the observation period (2 months). The positions of PI onset were sacrum , coccyx , and right greater trochanter  .We examined the closeness of the skin microbiome at the baseline and that after the onset of PI in each participant. As one participant (ID 28) had a PI away from the measurement site , and no significant differences in skin physiological functions, peak interface pressure, or Braden scale total score , although these two groups were similar in age (P = 0.06). Cutibacterium spp. are known to grow in sebum-rich conditions by metabolizing triglycerides into free fatty acids for their colonization . These bacteria are commonly found in the gut or feces . Therefore, we assume that the higher abundance of gut-related bacteria detected on the bedridden patients' skin cannot be fully explained merely by contamination but that a reasonable portion of such bacteria may be colonized inside the skin and persist for a longer time. The microenvironment around the skin under the diaper may account for the increase in anaerobes , as the use of diapers can create occlusive conditions, making the partial oxygen pressure lower  in the ambulatory or wheelchair-aided older people of nursing homes  and more gut-related bacteria .In sum, the bedridden patients' skin showed dysbiotic conditions in terms of less commensals . Another possibility is, as described above, the sustained contact with urine and/or feces under a diaper. Skin commensals and urease in feces can break down the urea in urine into ammonia, which can cause an increase in skin pH    than the6.0–7.0) , and the6.0–7.0) , the mecEscherichia–Shigella spp., Enterococcus spp., and Klebsiella spp. showed significant positive correlations .All the sequence data are available on the DNA Data Bank of Japan (DDBJ; accession number is SN, KO, JS, and SO conceived the study and critically reviewed and edited the manuscript to the final version. SN, KO, TU, KS, EM, KM, MM, YM, MA, DA, and JS collected the samples and performed the experiments. SN, KO, TU, KS, EM, JS, and SO analyzed the data. SN and KO wrote the original draft of the manuscript. JS and SO acquired the funding and supervised the study. 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.


Garcinia mangostana L.), as a natural source of bioactive phytochemicals, is a potential AGP, but the effect of mangosteen-based treatment on antibiotic resistance in poultry has not been reported to date. Therefore, the aim of this study was to evaluate the effects of mangosteen peel extract as an AGP on body weight gain, feed conversion rate (FCR), and the antibiotic resistance in broilers.Antibiotic resistance poses a risk to human health and has therefore been the focus of research. One of the causes of this resistance is the use of antibiotics as feed additives for animal nutrition. The development of antibiotic resistance in poultry through nutrition feed has drawn attention to the need for alternative antibiotic growth promoters (AGPs). Mangosteen  was not administered any treatment in the feed, Group B was treated with 0.3 g/kg colistin as the AGP in the feed, and Group C was treated with 2% mangosteen peel extract as the AGP in the feed; the treatments were administered for 30 days. The observed parameters included the effect of the treatments on body weight gain, feed intake, FCR, and the presentation of antibiotic resistance before and after the treatments .Post-treatment, the body weight gain, and feed intake in the broilers were not significantly different among all the groups; however, the body weight gain and FCR were significantly different between the control group and the treatment groups in the 3rd week of treatment and were not significantly different between Groups B and C. The rate of antibiotic resistance to chloramphenicol increased significantly by 40% in Group B post-treatment, but no such increase was observed in Groups A and C.The findings of our study indicate that compared with using colistin as an AGP using mangosteen peel extract as a natural AGP did not have any significantly different effect on body weight gain, feed intake, and FCR (p>0.05) but had a significantly different effect on the rate of antibiotic resistance in broilers (p<0.05). This study indicates the usefulness of mangosteen for improving the overall growth and production performance of broilers without increasing their antibiotic resistance. Escherichia coli had increased to 52% in Indonesia [Antibiotic resistance is a serious global concern that has become a major challenge in human and animal research . In the ndonesia . Antibiondonesia . In the Based on the data of the application of antibiotic growth promoters (AGPs) in animal production consist neomycin, erythromycin, oxytetracycline, streptomycin and colistin, particularly in chicken production, the global consumption of antimicrobials has been predicted to increase by 67% between 2010 and 2030 ,6.Garcinia mangostana L.) peel, which comprises bioactive phytochemicals such as xanthones, benzophenones, flavonoids, bioflavonoids, phenols, and triterpenes [The development of antibiotic resistance in chickens has drawn attention to the need for alternative AGPs. AGPs from natural sources could play a key role in improving the growth and production performance of chickens. One of the natural plant sources that can be used as AGPs is mangosteen , feed intake, and antibiotic resistance in broilers.All experiments of this research study were approved by the ethical committee of our institution (reference number: 00034/04/LPPT/VII/2019).in vacuo using Rotary Evaporator . The extract was stored in a refrigerator.The mangosteen peel extract was prepared, as described previously . BrieflyThe study was conducted from June to August 2019 at Department of Microbiology, Faculty of Veterinary Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia.A total of 30 1-day-old broiler chicks (Cobb500) were divided into three groups. The chicks were kept for seven days to acclimatize. Within this period, they were fed commercial broiler starter diet only and given plain water. The number of 1-day-old chicks included in this study was calculated, according to Federer’s method . Group AEight standard antibiotic disks for ciprofloxacin, colistin, amoxicillin, streptomycin, chloramphenicol, tetracycline, ampicillin, and gentamicin were used against the isolated bacteria after the preparation of standardized bacterial inoculums matching the 0.5 McFarland standards (2×108 cfu/ml). The inoculum was spread on sterile Mueller-Hinton agar plates and incubated at 37°C for 24 h. The degree of sensitivity was determined by measuring the inhibition zone diameter, as described previously ,16. The The quantitative data from the different treatments in this study were statistically analyzed using analysis of variance (ANOVA), Kruskal–Wallis test, and marginal homogeneity test with p<0.05 were considered statistically significant.The results of the Kruskal–Wallis test showed that all the groups did not show significant differences in feed intake (p>0.05), but the control and the treatment groups showed significant differences in FCR in the 3rd week (p<0.05) . HoweverThe marginal homogeneity test showed that the broilers who were treated with colistin as an AGP (Group B) showed a significant increase in the rate of antibiotic resistance to chloramphenicol (p<0.05) between pre-treatment and post-treatment. However, the broilers who were treated with 2% mangosteen peel extract (Group C) did not show any increase in the rate of antibiotic resistance .st, 2nd, and 4th weeks of treatment; therefore, their nutritional efficiency was considered low because of the pathogenic microorganisms that remained in the digestive tract. This finding is similar to that reported by a previous study [The present study analyzed the effects of adding mangosteen peel extract to broiler feed on body weight gain, feed intake, FCR, and the presentation of antibiotic resistance. Colistin is widely used as a growth promoter in poultry production, but with the increasing incidence of antimicrobial resistance, natural sources such as mangosteen have been explored for their potential as AGPs. We found that the control and treatment groups showed significantly different body weight gain in the 3rd week of treatment. This finding is similar to that reported by a previous study , whereinus study  stating The rate of antibiotic resistance to ciprofloxacin, colistin, amoxicillin, streptomycin, tetracycline, ampicillin, and gentamicin pre-treatment and post-treatment was not significantly different (p>0.05) among all the groups. However, the rate of antibiotic resistance to chloramphenicol in Group B (colistin-treated group) was significantly different (p<0.05) from that in Groups A and C. The rate of resistance to chloramphenicol increased by 40% after the administration of colistin. This finding is consistent with that reported by a previous study , whereinAntibiotic resistance can occur through various mechanisms such as antibiotic inactivation, membrane permeability reduction, antibiotic target modification, and antibiotic transport modification . Furtheret al. [E. coli isolated from 1-day-old chicks showed resistance to penicillin and ciprofloxacin. A previous study [et al. [E. coli isolated from 1-day-old chicks is resistant to antibiotics, including tetracycline, ampicillin, gentamicin, enrofloxacin, ciprofloxacin, and streptomycin, with rates of antibiotic resistance reaching >80%.In this study, the rate of antibiotic resistance to chloramphenicol was found to be increased in the treatment group with colistin added as an AGP. According to a previous study , the admet al. , who shoet al. , whereinus study  has show [et al. , who shoAs stated previously , the preThe findings of our study suggest that compared with colistin, mangosteen peel extract used as an AGP did not have any significantly different effects on the body weight gain and FCR of broilers. However, the mangosteen peel extract significantly affected the antibiotic resistance of broilers. While the colistin-treated group showed a significant increase in the rate of antibiotic resistance to chloramphenicol post-treatment, no such increase was observed in the mangosteen peel extract-treated group, indicating significant differences in the rate of antibiotic resistance between these two groups. Therefore, mangosteen peel extract can be considered a useful natural AGP that can promote the growth and production performance of broilers without increasing the rate of antibiotic resistance.OH and TU designed and managed the study. OH and MA collected and analyzed samples. SA, OH, TU, and MA arranged, analyzed, and wrote the manuscript. All authors have read and approved the final manuscript.


Exercise improves glycemic control and functional capacity in elderly people with diabetes; however, its effect on health-related quality of life (HRQoL) and medical resource use remains unclear. This study aims to clarify the effect of exercise.Using the data from National Health and Nutrition Examination Survey between 2007 and 2016, we identified 1572 elderly people with diabetes for this cross-sectional population-based study. Demographic characteristics, health conditions, comorbidities, HRQoL, and medical resource were compared among four groups .The mean age of all participants was between 71.5 and 73.3 years. Male participants with higher education performed more exercise than their counterparts. The moderate- and high-intensity groups reported better general health condition than the no exercise group. Depression and worse health were more common in the no exercise group. Participants in the moderate-intensity exercise group had lower risk for depression than those in the no exercise group  after adjusting for demographic characteristics, health conditions, and comorbidities, whereas participants in the low- and high-intensity exercise did not have a lower risk. The no exercise group had the highest proportions of emergency, hospitalization, and total healthcare visits.Exercise is associated with better HRQoL, and lack of exercise is associated with higher medical resource use in elderly people with diabetes. Encouraging exercise is recommended in this population. The world’s population is aging, which affects all fields of societies, including health care system, medical expenditure, labor, finance, demands for goods and services, and family structures . In the Different forms of exercise, including aerobic, resistance, and flexibility, are the cornerstone of diabetic management, especially in elderly people with functional decline , 5. ExerThe National Health and Nutrition Examination Survey (NHANES), a program by the National Center for Health Statistics of the Centers for Disease Control and Prevention , containThe estimated population proportion for the target outcome is 20%, and the number of elderly people with diabetes is 12,000,000 in the United States . After cn = 1119): no habit of exercise; (2) low-intensity exercise (n = 195): having a positive habit of exercise but have not reached the level of moderate-intensity exercise; (3) moderate-intensity exercise (n = 118): at least 150 min of moderate aerobic activity  or 75 min of vigorous aerobic activity  every week; and (4) high-intensity exercise: at least 300 min of moderate aerobic activity or 150 min of vigorous aerobic activity every week. Family poverty index ratio was defined as the ratio of family income to poverty : 0.13, 95% CI: 0.02–0.92; Table The present study showed that male participants with higher education performed more exercise than their counterparts. Participants with moderate- and high-intensity exercise self-reported better general health condition than participants without exercise. Participants without exercise had the highest proportions of being overweight and cigarette smoking. Compared with exercise groups, the number of participants who reported depression over the last 2 weeks and worse health compared with the past year was higher in the no exercise group. In the comparison of medical resource use, participants without exercise had the highest proportions of emergency, hospitalization, and total healthcare visits: visited ED most often for healthcare, had ≥4 healthcare visits/year, were hospitalized overnight in the past year, and visited ED for asthma in the past year. Multivariate logistic regression analyses showed that the moderate-intensity exercise group had significantly lower risk of depression over the last 2 weeks than the no exercise group. The high-intensity exercise group had significantly higher risk of asthma attack in the past year than the no exercise group. Other differences among the four groups were not significant.The improvements of HRQoL including lower depression in participants with moderate-intensity exercise may be due to better glycemic control, increased muscle strength, increased power and functional capacity, and better cardiovascular function . The mecElderly people with diabetes have higher risk of depression than those without diabetes . People This study showed that participants without exercise had higher proportions of ED visit, total healthcare visit/year, and overnight hospitalization than the three exercise groups. These findings suggest that lack of exercise may predispose elderly people with diabetes to higher risk for frailty and subsequent complications . The risThe strength of this study is that it clarified an unclear issue by using population-based data. The limitations are as follows. First, the study adopted a cross-sectional design; as such, we could only figure out that exercise was associated with HRQoL, but the causal relationship could not be inferred. Second, the exercise level, comorbidities, HRQoL, and medical resource use were self-reported and therefore may have subjective bias. Third, the number of participants in the three exercise groups was relatively small. A higher number of participants is warranted for further investigation. Fourth, the result may not be generalized to other nations due to differences in culture, race, and medical resource.This cross-sectional population-based study showed that exercise was associated with better HRQoL and lack of exercise was associated with higher medical resource use in elderly people with diabetes. Exercises including aerobic and resistance training are suggested for elderly people with diabetes. However, further studies including cohort design and more participants must be conducted to validate the results.


Background: Previous studies have indicated that non-motor symptoms are primary problems in focal dystonia, but limited data are available about non-motor problems and their correlation with motor severity in generalized dystonia (GD).Methods: In the present study, we performed a case-control study and enrolled isolated inherited or idiopathic GD patients and age- and sex-matched healthy controls (HC). Clinical characteristics, motor symptoms, non-motor problems, including psychiatric co-morbidity, sleep problems, fatigue, and quality of life (QoL) were assessed in both groups using various rating scales and assessments.Results: Thirty-three patients with GD and 33 controls were enrolled. Significant higher scores on depression and anxiety (p < 0.001) were shown in GD compared with HC, whereas the frequency of obsessive-compulsive disorders approached that of HC (p = 0.238). Patients with GD also had significantly higher Pittsburg Sleep Quality Index (PSQI) and fatigue scores than HC, whereas no difference was observed in excessive daytime somnolence. In GD, QoL was more impaired, with statistically lower scores in both physical and mental components. Psychiatric rating scales did not correlate to motor severity or disease duration but might influence quality of sleep. Subgroup analysis suggests non-motor manifestations differ with different etiologies in GD.Conclusion: This study suggests that non-motor symptoms in GD, such as psychiatric problems, are likely to be primary determinants not correlated to motor severity, which may also affect quality of sleep and fatigue. Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. Dystonia is classified into different subtypes according to clinical characteristics or etiology . Based oPrevious studies have revealed that in addition to motor symptoms, non-motor symptoms (NMS) are highly prevalent in FD including cervical dystonia –4, blephAs NMS are regarded as phenotypes in some FD and dystonia may share—to some extent—common pathophysiology, we speculated that patients with GD also have non-motor problems, which are not related to motor severity. This single-center case–control study aimed to examine the NMS in inherited or idiopathic isolated GD, and to further explore whether NMS are part of the GD phenotype or secondary to the motor disorder by correcting for motor severity and disease duration, and to evaluate if the etiologies (inherited and idiopathic) of GD differ between patients.This single-center case–control  study included a total of 33 consecutive patients referred to our Department of Neurology in Peking Union Medical College Hospital. The inclusion criteria were (a) inherited or idiopathic GD fulfilling the international standard criteria  as deterThis study was approved by the Institutional Review Board and Ethics Committee at Peking Union Medical College Hospital and was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Informed consent was obtained from all participants or their legal guardians.Demographic information, age, and sex were obtained from both the GD patients and the HC at the time of evaluation. Additional information, such as disease duration, past history, and family history, was obtained from the patients during an interview conducted by neurologists. All dystonia patients underwent gene testing and brain magnetic resonance imaging. The motor severity of dystonia was assessed according to a standardized videotaped neurological examination using the Burke-Fahn–Marsden dystonia rating scale motor subscales (BFMDRS-M)  with aveAll participants underwent a psychiatric, sleep, fatigue, and QoL evaluation by the same doctor (SL). All the scales of evaluation were validated Chinese versions. The severity of depression, anxiety, and OCD was assessed in all participants with the Beck Depression Inventory (BDI), with higher scores indicating higher depression  , the Hamp < 0.05. Normally distributed data with equal variance were expressed as means ± SD and were compared using an independent two-sample t-test (t), and non-normally distributed data were expressed as median with interquartile range (IQR) and were compared using Mann–Whitney U-test. Fisher's exact test was used to compare the frequencies of non-motor disorders between the various groups of patients with dystonia and HC. No corrections for multiple comparisons were performed. Since sleep might be affected by psychiatric problems and pain, we used logistic regression models to further adjust for these factors, which were adjusted for any main confounding factor such as the BDI, pain, and HAMA. In addition, Spearman's rho correlation analysis was performed to further clarify the relationship of motor severity (BFMDRS-M and disease duration) and non-motor problems including HAMA, BDI, FSS, and ESS.Statistical analyses were performed using SPSS version 20.0  and differences were considered as significant at a two-side n = 16).A total of 33 GD patients  and 33 age- and gender-matched HC  were enrolled in this study. The median BFMDRS motor score was 49.75 (IQR: 34–66.5) with a mean disease duration of 11.48 ± 9.52 years. A genetic etiology was identified in 17 patients  while the rest had idiopathic dystonia (p < 0.001) and the anxiety  quantitative rating scales. Based on the subdivision described in the “Materials and Methods” section, a higher prevalence of aberrant scores on BDI  and HAMA  was observed in the GD group compared with HC. However, there was no difference between the two groups regarding their Y-BOCS scores  and FSS  than HC, but not on the ESS (p = 0.044). More patients met the criteria for fatigue compared to HC . The analysis of the subcomponents of the PSQI scores demonstrated that the patients of GD had a significantly poorer score in sleep latency, sleep efficiency, and sleeping medication compared to HC, while no significant difference was shown in other areas including sleep quality, duration, disturbances, and daytime dysfunction  or just adjusting for HAMA and BDI . Similarly, FSS did not retain an association with the GD status after adjusting for these factors .Since psychiatric problems and pain may affect the quality of sleep, we further corrected for these factors. A multivariable logistic regression analysis showed that the PSQI score was not associated with GD status after adjusting for HAMA, BDI, and pain [odds ratio (OR): 0.36, 95% confidence interval (CI): 0.88, p < 0.001). In addition, both SF-36 PCS and SF-36 MCS were lower in patients with GD than in HC (p < 0.001)  . An anal< 0.001) .p > 0.5)  and NMS  but found no relationship between them (p > 0.5) .p < 0.05) and depression , whereas the rate of such psychiatric problems in DYT6 and DYT-KMT2B was similar to that of HC. The FSS scores in DYT-KMT2B  and in idiopathic GD patients  seemed to be higher than in HC, but no difference was observed in DYT1 or in DYT6 patients. In addition, the DYT1 and the DYT6 patients were more likely to experience impairment in sleep with a relatively higher PSQI score than HC, whereas there seemed to be no significant difference in the number of “poor sleepers”.In a subgroup analysis based on different etiologies, we found a relatively poorer QoL in inherited as well as in idiopathic GD than in HC for both physical and mental aspects . Both DYThis present single-center case—control study was a unique study to fully assess non-motor problems, including psychiatric problems, fatigue, quality of sleep, and daytime sleepiness, in isolated GD in Chinese patients. We found higher depression and anxiety scores in patients with GD than in HC. The depression problem in GD agrees with the results reported by Lewis et al. in a study of 329 community-based dystonia patients (including 10.9% with GD)  and by HThe Chinese patients with GD, as assessed by SF-36, displayed a significantly poorer QoL both in physical and mental aspects compared to HC, further arousing attention on mental health in patients with GD. A detailed analysis of the subcomponents indicates that, unlike what is observed in FD such as cervical dystonia, pain is not common in GD .Regarding sleep problems, we found that the quality of sleep was more impaired in GD than in HC; however, no significant difference was found in terms of excessive daytime somnolence, which is in agreement with previous findings on focal dystonia , 30, 31.Some limitations of the study also deserve discussion. First, the cross-sectional design of the study is insufficient to draw definitive conclusions about a primary or secondary cause of non-motor disorders in patients with GD. The statistically significant results could only predict and reflect the potential characteristics of dystonia, but further pathophysiological studies are still required to better understand GD. Second, the results of the subgroup analysis are merely suggestive of differences in NMS patterns among GD etiologies as the sample size was too small. Thus, no safe conclusions can be made yet regarding this issue, and further studies, including more patients in each subgroup, need to be performed. Third, the exclusion of a previous diagnosis of psychosis and sleep disturbances or of the use of relevant medication might underestimate the frequency and the severity of psychiatric and sleep problems in GD. However, the aim of this exclusion was to try to reflect the characteristics of GD, but not as a comorbidity. In addition, the psychiatric rating scales could not guarantee the diagnosis of psychiatric problems, which makes further studies involving psychiatric diagnosis in demand. Finally, the cognitive function of patients with GD was not described or discussed in this article; we plan in future studies to conduct a battery of detailed cognitive evaluation in GD.In conclusion, psychiatric problems were common in the included study population and might likely be primary determinants in GD, which could also affect the quality of sleep and fatigue. Different phenotypes in etiology might have a different pattern in non-motor disorders. However, due to the relatively small sample size in the subgroup analysis, further studies are needed to explore how the genotypes of GD affect non-motor disorders.The datasets generated for this study are available on request to the corresponding author.The study was approved by the ethics committee of Peking Union Medical College Hospital. Written informed consents were obtained from all patients or their legal guardians in accordance with the Declaration of Helsinki.SL contributed to the conception of the work, data acquisition, and writing of the first draft. XW contributed to the design and organization of the work, manuscript review, and critique. LW, LQ, and YY contributed to the data acquisition, manuscript review, and critique. DZ contributed to the statistical analysis.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.


Microstructure imaging by means of multidimensional diffusion encoding is increasingly applied in clinical research, with expectations that it yields a parameter that better correlates with clinical disability than current methods based on single diffusion encoding. Under the assumption that diffusion within a voxel can be well described by a collection of diffusion tensors, several parameters of this diffusion tensor distribution can be derived, including mean size, variance of sizes, orientational dispersion, and microscopic anisotropy. The information provided by multidimensional diffusion encoding also enables us to decompose the sources of the conventional fractional anisotropy and mean kurtosis. In this study, we explored the utility of the diffusion tensor distribution approach for characterizing white-matter degeneration in aging and in Parkinson disease by using double diffusion encoding. Data from 23 healthy older subjects and 27 patients with Parkinson disease were analyzed. Advanced age was associated with greater mean size and size variances, as well as smaller microscopic anisotropy. By analyzing the parameters underlying diffusion kurtosis, we found that the reductions of kurtosis in aging and Parkinson disease reported in the literature are likely driven by the reduction in microscopic anisotropy. Furthermore, microscopic anisotropy correlated with the severity of motor impairment in the patients with Parkinson disease. The present results support the use of multidimensional diffusion encoding in clinical studies and are encouraging for its future clinical implementation. Parkinson disease (PD) is a neurodegenerative disorder characterized by motor symptoms  and a wide range of cognitive, neuropsychiatric, and autonomic dysfunctions . AdvanceDiffusion MRI (dMRI) is uniquely sensitive to tissue features on the micrometer scale and therefore has been widely used to study neurodegeneration in aging  and diseRegarding acquisition, both DTI and DKI use single diffusion encoding (SDE), which uses one pair of diffusion-sensitizing gradients. Multidimensional diffusion encoding , that caIn this study, we analyzed DDE data by using the covariance tensor framework  that worThe aim of this study was to identify the sources of DTI/DKI changes previously reported in aging and PD in terms of the DTD model parameters. We first analyzed correlation with age in healthy older subjects and then examined group differences between the healthy subjects and patients with PD. Finally, we investigated the correlations with the severity of motor impairment in the patients.Linking the MRI signal to specific tissue properties involves modeling, simplification of the complex reality relying on a few assumptions. By adopting the DTD model, we assume that the voxel consists of multiple, non-exchanging Gaussian compartments. More precisely, we model the diffusion within a voxel by a distribution of diffusion tensors  . In suchUnder the DTD model, the signal can be written as:S(B) is the signal, S0 is the signal without diffusion weighting, B is the b-tensor, and Dc is the diffusion tensor of each compartment. The bracket < > denotes the ensemble average over the voxel. The colon denotes a generalized scalar product between the two tensors, B:D = ∑i∑jBijDij.where Multidimensional diffusion encoding provides us means to extract summarizing statistics of the distribution of diffusion tensors. Eq. 1 can be expanded  to:D is the well-known, voxel-averaged diffusion tensor, and C is a fourth-order tensor called the covariance tensor. From D and C, several scalar parameters that summarize microstructural features, including DTI/DKI parameters, can be computed  denote the variance of eigenvalues of D, defined by using the eigenvalues λ1, λ2, and λ3 as at of FA :Unlike FA, μFA is not influenced by orientational dispersion and purely reflects the anisotropy (shape) of microstructural environments. In addition, a measure of orientational dispersion  is defined  as:OP equals 1 for perfectly aligned orientations and equals 0 for fully isotropic dispersion. FA is influenced by both μFA and OP :Furthermore, under the DTD assumption, mean kurtosis (MK), as defined in whereV(cD) is the variance of isotropic diffusivities among compartments (variance of sizes). The last term in Eq. 8 is a factor related to orientational dispersion and can be expressed as . Although the information represented by some parameters overlaps , having multiple forms of expression helps us to understand how the DTD parameters affect FA and MK (Eqs 7 and 12).In this study, we report MD, FA, MK, This study was carried out in accordance with the Declaration of Helsinki for experiments involving humans. The Institutional Review Board approved this study, and all subjects gave written informed consent prior to participation. Twenty-three healthy older subjects (63.1 ± 7.2 years old) and 27 patients with PD (66.1 ± 6.6 years old) were enrolled. Patients with PD were diagnosed by neurologists on the basis of clinical diagnostic criteria of the Movement Disorder Society . Motor fBecause DDE is a relatively new technique for clinical research, we also examined the stability of the dMRI parameters in terms of scan–rescan repeatability in a separate group of 4 young healthy subjects , who underwent two scans on different days within a week. In these subjects, we also acquired conventional SDE for comparison.2. One volume without diffusion weighting was also obtained. Thus, a total of 121 volumes were acquired. Other settings were image resolution = 3 × 3 × 3 mm3, TE = 93 ms, TR = 6300 ms, Δ = 18.3 ms, δ = 16.8 ms, mixing time = 24.9 ms, in-plane GRAPPA with acceleration factor 2, through-plane GRAPPA (SMS) with multiband factor 2, partial Fourier 6/8, 44 axial slices, and scan time 14 min. In addition, anatomical T1- and T2-weighted images were acquired and inspected by a neuroradiologist to rate Fazekas grade and to check for any other co-existing pathologies. SDE acquisition in the young subjects used the same b-values and 30 directions, resulting in a total of 61 volumes. The acquisition settings were identical to those of DDE, except Δ = 43.3 ms and δ = 36.4 ms. The scan time for SDE was 7 min.The subjects were scanned by using a clinical 3T scanner  equipped with a 64-channel head coil using a prototype sequence. DDE data were acquired using a monopolar spin-echo type acquisition. We used parallel (LTE) and perpendicular (PTE) pairs of diffusion sensitizing gradient blocks, with 30 uniformly distributed directions. Note that, under the DTD assumption, the direction of PTE can be characterized by the normal vector. For both LTE and PTE, we used two shells, which had b-values of 1000 and 2000 s/mmeddy in FSL (V(cD), the fitting was repeated by using data smoothed with an isotropic 3D Gaussian kernel with sigma = 0.7 × voxel size.Images were pre-processed by using FSL 6.0.1  and MRTry in FSL . The dMRy in FSL . In a smws), defined as ws is the within-subject standard deviation. To compute CVws across the white-matter voxels, each subject’s FA map was non-linearly registered into the Johns Hopkins University (JHU) template in FSL. The other dMRI parameter maps were also transferred into the standard space by using the same deformation. A white-matter mask was generated by thresholding the FA template at FA > 0.2. To mitigate partial volume effects with the gray matter and cerebrospinal fluid (CSF), the mask was further eroded by one voxel. We also report CVws for the mean value of each white-matter region of interest (ROI) that was used for the analyses of aging and PD .Using the scan-rescan data from the 4 young subjects, we computed the within-subject coefficient of variation  on the dMRI parameters by means of whole-brain voxel-wise analyses using tract-based spatial statistics (TBSS)  and atlaWe opted not to exclude voxels with WMH from the analyses for the following two reasons. First, evidence suggests associations between WMH and the severity of motor and non-motor symptoms in PD . The patP < 0.05, corrected for family-wise error (FWE) for multiple comparisons across voxels or ROIs. For the ROI-based analyses, we also report results without FWE correction (Puncorrected < 0.05) because these data may be informative for future studies with larger samples.For both the TBSS and ROI-based analyses, we fit linear models where the dependent variable was each dMRI parameter. First, we examined the effect of age in the healthy subjects, using sex as a nuisance covariate. Then, we examined the differences between the healthy subjects and the patients with PD, using age and sex as nuisance covariates. Finally, we examined the correlation with UPDRS-III score in the patients, using age and sex as nuisance covariates. Because motor impairment might be correlated with age, we checked for multi-collinearity using the variance inflating factor (VIF) . Althougws below 6–8% for most of the white-matter voxels ] showed greater CVws, falling in the range of 10–25% for most of the voxels. As for ROI-based measurements, CVws was below 2% in all ROIs for MD, FA, μFA, and OP  showed CVws below 6% for most of the ROIs, poorer repeatability was found in the internal capsule and corpus callosum with CVws around 10%, reflecting the challenges of dMRI in these regions due to partial volume effects with the CSF and the gray matter, Gibbs artifact, and CSF pulsation.MD, FA, and MK showed excellent repeatability, with CVr voxels . The val, and OP . MK and V(cD), positive correlation with age was seen in extensive regions of the white matter in both ROI-based analyses and TBSS  in the subcortical white-matter regions than the controls (Kiso and V(cD) of the parietal ROI remained significant after the FWE correction. The group differences were below the significance threshold for Kaniso and μFA for all ROIs. Slightly greater values of MK were observed in the patients in the PLIC and SCC. Smaller values of FA and OP were observed in the ALIC and PLIC, respectively. In TBSS, only OP revealed statistically significant results: the patients exhibited smaller values in the left internal capsule, the left cerebral peduncle, the left thalamus, and the right external capsule , and negative correlations for FA, MK, Kaniso, and μFA in GCC and SCC  in SCC  in SCC . For MD,Kaniso, and μFA, in agreement with previous studies that used SDE (Kiso and V(cD)]. The effects of aging and PD were in the same directions for most of the diffusion parameters and anatomical locations, such as increases of MD, Kiso, and V(cD) and decreases of FA, Kaniso, and μFA. This is biologically plausible, because neurodegeneration in aging and PD have many features in common, including a declined ability to homeostatically regulate proteostasis, neuroinflammation, mitochondrial dysfunction, oxidative stress, degeneration of the myelin sheath, accumulation of cellular debris, alteration of axonal transport, axonal swelling/beading, and loss of axons (Kaniso and μFA) might be useful to track white-matter degeneration related to the motor impairment in PD.This study investigated the utility of DTD parameters derived from DDE to characterize white-matter degeneration in aging and PD. Advanced age was associated with greater MD and smaller FA, MK, used SDE  and DDE used SDE . OP decrused SDE . Age-relof axons . The preKiso or a decrease of OP would lead to an increase of MK. We indeed observed slightly greater MK in the PLIC and SCC in the patients than in the controls. Although this appears to contradict previous reports of smaller MK in patients  showed some sensitivity to the group differences in several ROIs but their correlation with motor impairment was limited to the callosal ROIs  may be influenced more by the factors that differentiate PD from normal aging but are not proportional to disease progression.Interestingly, we observed  with PD , despitesal ROIs . Althougsal ROIs , and thasal ROIs . We specKaniso. Second, the expansion Eq. 2 is valid only in the vicinity of b = 0 (V(cD) and Kiso estimation, which needs to be addressed before clinical application of these metrics. Third, the acquisition used in this study was not controlled for the concomitant fields (transverse magnetic field components accompanying the applied gradient to satisfy Maxwell’s equations) , we assumed the effects of timing parameters were negligible. Though this has some support by earlier studies observing the effects of diffusion time were small in brain tissue for the range above 10 ms , more reof b = 0 , as in tof b = 0 . Althougof b = 0 . In addiuations) , which cuations) . This isuations) .Our study has several limitations. First, PD is a heterogenous disease whose clinical manifestations vary widely among individual patients . Robust In this study, we explored the utility of DDE-derived parameters for characterizing white-matter degeneration in aging and PD. Advanced age was associated with greater mean size and size variance of the compartmental diffusion tensors and with smaller microscopic anisotropy. We found the reductions of MK in aging and PD reported in the literature are likely driven by the reduction of microscopic anisotropy. Furthermore, microscopic anisotropy correlated with the severity of motor impairment in PD. We further showed that microscopic anisotropy can be estimated with excellent repeatability by using modern clinical scanners. In conclusion, multidimensional diffusion encoding can provide more comprehensive and clinically relevant information about the white-matter degeneration in aging and PD than conventional SDE-based methods.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation, to any qualified researcher.The studies involving human participants were reviewed and approved by the Institutional Review Board of Juntendo University School Hospital. The patients/participants provided their written informed consent to participate in this study.KKami and KKama contributed to conception and design of the study. KKama, KO, TH, TO, and HT-A organized the data acquisition and quality control. KKami, SM, and CA performed the image processing. KKami performed the statistical analysis and wrote the first draft of the manuscript. KM, TF, MH, NH, and SA revised the subsections of the manuscript. All authors contributed to the final manuscript revision, read and approved the submitted version.KM is an employee of Siemens Healthcare K.K. TF is an employee of Siemens Healthcare GmbH. The remaining 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.


Home chemotherapy programs for children with cancer are safe and feasible, and their impact on the quality of life has been reported in different countries. A home chemotherapy program was implemented between 2011 and 2019 in an Italian region. This pilot study investigates its safety and feasibility, along with parental satisfaction.Patients between 0 and 18 years diagnosed with malignancy were included. Deceased patients and patients whose families moved abroad or interrupted contact with the service were excluded. Adverse events comprised immediate deterioration of the patient’s condition, equipment failure, errors in drug storage, dose or patient identification and personnel safety issues. Parental satisfaction was explored through an email survey of 32 Likert-type and short open questions.Thirty-five patients received 419 doses of intravenous chemotherapy at home . No adverse events were reported. Twenty-three families out of 25 eligible completed the survey. Most reported being “very satisfied” with the possibility of maintaining a work/domestic routine and reducing time and financial burden of hospital access. Most were “very satisfied” with the opportunity for their child of being less troubled by the treatment. Besides, most reported being “very satisfied” with the chance for healthy siblings of maintaining their routine and coping with their brother/sister’s disease. Most perceived the program as safe. All families recommended extending the program to all children in the region.This first Italian study supports home chemotherapy as safe and effective, positively influencing the quality of life for children and their families.The online version contains supplementary material available at 10.1186/s13052-021-00993-x. While cancer is still a leading cause of death in childhood and adolescence in high-income countries , 2, advaIn Italy, a successful experience of home care for children with hematological malignancies and after hematopoietic stem cell transplant at the “Giannina Gaslini” Institute in Genoa has been published: children were taken care at home with blood drawing, central venous catheter (CVC) medications, supportive treatment and end-of-life care, but the program did not include chemotherapy administration , 11.In the Friuli Venezia Giulia Region, since 2011, a home assistance program run by the Pediatric Home Care Team (PHCT) from the Pediatric Department at the Spoke Hospital of Pordenone takes care of children with complex needs, both oncological and not, from the Pordenone province and the nearby Udine and Venice provinces. The team provides different services at home, including intravenous chemotherapy, blood tests, CVC medication, assessment of compliance with oral medications and dose adjustments on behalf of the Hub Oncology Centre, supportive treatment , psychological support for children and families, and end-of-life care. Home chemotherapy delivery has been one of the main activities since it started in 2011. Then, the project gradually expanded, comprising children with non-oncological complex needs. A pediatrician and two pediatric nurses, all from the Pordenone hospital Pediatric staff, and a psychologist work 5 days a week from 8.00 am to 4.00 pm, with the pediatrician available on call until 8.00 pm. For emergencies, at night and during the weekends, patients rely on the on-duty staff at the Pediatric Department of the Pordenone Hospital. The Pordenone hospital thus works as a Spoke hospital, admitting children for the complications of oncological treatments , but also planning the activity of the PHCT. The drugs chosen for home administration are cytarabine, vincristine and vinblastine because they have sufficient stability, do not require prolonged infusions or any specific support therapy (i.e. hyper-hydration) and do not carry a significant risk of immediate adverse reactions (i.e. anaphylaxis or acute toxicity) , 13. TheThis research aims to explore the safety and the impact of home-delivered chemotherapy on the quality of life of children and their families.Azienda Sanitaria Friuli Occidentale, ASFO) in Friuli Venezia Giulia, Italy.We performed a retrospective evaluation on children who received chemotherapy at home by the PHCT in the Local Health Authority of Pordenone  or end-of-life care.We retrospectively collected informations on family socio-demographics , patients’ age at diagnosis, number of family members, distance from the nearest hospital and the Hub Oncology Centre, number of working days lost due to therapies, the possibility of having paid leave for the primary caregiver and obtaining financial support from charities in order to depict a broader picture of the families.Regarding the primary outcome, we reviewed the clinical records to document adverse events. Adverse events include immediate acute deterioration of patient’s condition , equipment failure , errors in drug transport or storage, staff safety issues , errors in dosing or patient identification. We did not focus on predictable side effects of chemotherapy  because we assumed that they occurred at the same rate as the treatment administered in the hospital setting.As for family satisfaction, we collected qualitative data on the impact of home-delivered chemotherapy on the family routine and the overall quality of life, and the perception of safety and effectiveness. We used a 5-item Likert-type scale ranging from “not at all satisfied/completely disagree” to “very satisfied/strongly agree” to assess parental satisfaction on different aspects and short open questions. The full questionnaire is provided in the Supplementary Information files ; categorical data (including the Liker-type questions) as number and percentage.We collected data on primary and secondary outcomes between February, 1st 2020 and April, 30th 2020. As for the safety analysis, 35 patients met the inclusion criteria, 22 males and 13 females, with a median age at diagnosis of 6 years . The most common diagnosis was acute lymphoblastic leukemia (ALL) with 32 cases, followed by Wilms tumor (2 cases) and soft tissue sarcoma (one case). Five patients with ALL experienced disease relapse. We, therefore, considered 40 chemotherapy protocols for a total amount of 419 doses administered at home in the reference time interval. Figure All patients had a central venous catheter inserted at the Hub Oncology Centre.We did not report any acute deterioration of the patients’ condition, nor equipment failure, nor errors in drug transport, storage or disposal, nor errors in dosing, patient identification or staff safety issues.As for the secondary outcomes (satisfaction), we first considered all 35 patients. We excluded three patient for contact problems, three patients who completed their treatment abroad and four deceased patients. In the end, we enrolled 25 families to participate in the questionnaire. The diagnoses were ALL (22 cases), Wilms tumor (two cases) and soft tissue sarcoma (one case). There were 16 males and nine females.Twenty-three families answered the anonymous questionnaires (dropout rate 8%). Median age at diagnosis of children for the response group was 5 years . Most children were less than 7 years old at the time of diagnosis.There were 19 Italian and four foreign families, but all use the Italian language to communicate with the team.2 , the inclusion of different diagnostic groups (leukemias and solid tumors) and the analysis of specific issues related to the impact of childhood cancer on family life.Furthermore, this is the first published report regarding a home chemotherapy program for children with cancer in Italy. The National Health System in Italy ensures full coverage of direct medical expenses for patients with cancer, with foundations and charities often providing additional financial support. Nevertheless, all families must face other costs. Our findings suggest that home-delivered chemotherapy may help reduce this burden. Ultimately, this is an example of cooperation and integration between Hub Centers and peripheral hospitals, which could result in resource rationalization and cost reduction for both families and the Health System.Our sample covered years between 2011 and 2019: during data collection and analysis, the pandemic COVID-19 hit Italy, as it did in the whole world, posing unique challenges to the health care services . The enoFuture trends of research should address cost-effectiveness with more specific outcome measures, the effect of home-delivered chemotherapy on children and families prospectively and include a higher number of patients with solid tumors.This study shows that a home chemotherapy program is safe, feasible and useful for maintaining a good quality of life for children and families.Additional file 1: Supplementary file 1. Full questionnaire in English.Additional file 2: Supplementary file 2. The blue area represents the area covered by the Pediatric Home Care Team. Padova (Veneto) and Trieste (Friuli Venezia Giulia) are the two Hub Oncology Centers. Pordenone (Friuli Venezia Giulia) is the town in which the service is based at the local hospital. Adapted from: https://www.mapsdirections.info/it/. Last accessed on June 17, 2020.


Allergic rhinitis (AR) is an inflammatory disease of nasal mucosa caused by IgE mediated inflammatory mediators and various immune active cells and cytokines after exposure of specific individuals to allergens. In recent years, its prevalence rate has increased gradually. Therefore, we must pay attention to carry out early intervention. However, there are still some side effects in the current drug therapy of AR, and the recurrence of AR cannot be well controlled. Some Chinese herbs have anti-allergic, anti-inflammatory and immunomodulatory effects, and have a better effect on the nasal symptoms of perennial and persistent rhinitis. The curative effect of allergic decoction on AR has been confirmed clinically. However, due to the lack of reliable evaluation means for its safety and effectiveness, it is necessary to carry out a systematic evaluation of allergic decoction in the treatment of AR, so as to lay a foundation for further research in the future.The following databases will be searched from their inception to August 2020: Electronic database includes PubMed, Embase, Cochrane Library, Web of Science, Nature, Science online, Chinese Biomedical Database WanFang, VIP medicine information, and China National Knowledge Infrastructure. Primary outcomes: nasal symptoms  and ocular symptoms . It can be measured by any appropriate scales or other forms of tools, such as the Total Nasal Symptom Score. Data will be extracted by 2 researchers independently, risk of bias of the meta-analysis will be evaluated based on the Cochrane Handbook for Systematic Reviews of Interventions. All data analysis will be conducted by data statistics software Review Manager V.5.3. and Stata V.12.0.The results of this study will systematically evaluate the efficacy and safety of Guominjian for patients with AR.Through the systematic review of this study, the evidence of the treatment of AR by Guominjian has been summarized so far, so as to provide guidance for further promoting the application of Guominjian in patients with AR.This study is a systematic review, the outcomes are based on the published evidence, so examination and agreement by the ethics committee are not required in this study. We intend to publish the study results in a journal or conference presentations.https://osf.io/24w8n).September 12, 2020.osf.io/24w8n.( At present, the treatment of AR mainly includes environmental control, drug therapy, immunotherapy and surgical treatment. For AR medications including antihistamines , glucocorticoid , oral drug leukotriene, decongestants , nasal spray resistance to choline medicine and mast cell stabilizer and so on, these drugs by acting on allergic some molecular targets of mucous membrane inflammation, blocking immune inflammatory disease caused by allergens, so it can effectively control the symptoms of AR, in the process of the clinical use of less side effects, high security. One or more may be used alone or in combination depending on the characteristics or clinical severity of the lesion. Immunotherapy, on the other hand, is a treatment method that can effectively relieve the nasal symptoms and improve the quality of life of AR patients by giving high-dose specific allergen continuous stimulation to the body and finally achieve tolerance to allergen stimulation. It can also prevent the formation of new allergens and reduce the risk of AR progressing to asthma. Some Chinese herbs have anti-allergic, anti-inflammatory and immunomodulatory effects and are safe and effective in improving the nasal symptoms of perennial and persistent rhinitis. Guominjian is a classic prescription for treating AR in the field of traditional Chinese medicine. At the same time, it can also be used for other allergic diseases. This prescription has a remarkable anti-wind table, the effect of dispel evils. Modern studies have shown that the prescription also antagonizes the itching caused by dde, the increased vascular permeability caused by histamine, lowers the IgE level in the blood, down-regulates the expression of PAR-2mRNA, stabilizes mast cell membranes, and inhibits mast cell degranulation. Although its effectiveness and safety have been proven in clinical practice, but lack of exact theoretical basis. Therefore, this study intends to evaluate the efficacy and safety of Guominjian in the treatment of AR through systematic evaluation and meta-analysis, and to explore its possible theoretical basis.Allergic Rhinitis (AR) is a common type of Rhinitis. Epidemiological studies show that in Asia, AR affects a large number of people, ranging from 27% in South Korea to 32% in the United Arab Emirates.22.1https://osf.io/24w8n). The protocol will follow the statement guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMAP), Changes will be reported in the full review as required.The protocol has been registered in OSF(Open Science Framwork) Preregistration. September 12, 2020.osf.io/24w8n. and ocular symptoms . It can be measured by any appropriate scales or other forms of tools, such as the Total Nasal Symptom Score.The secondary outcomes are quality of life , global non-nasal symptoms , use of conventional medication , laboratory indicators, and any expected or unexpected adverse events.33.1The following data bases will be searched to identify eligible studies: PubMed, Embase, Cochrane Library, Web of Science, Nature, Science on line, Chinese Biomedical Database WanFang, VIP medicine information, and China National Knowledge Infrastructure. The time range is: the starting time is determined according to the first literature available, and the deadline is August 2020.3.2In order to get more complete evidence, we will also retrieve other related documents by manually, such as medical textbooks, clinical laboratory manuals and so on. If it is necessary we will contact with trail author to obtain the latest clinical data. Moreover, studies associated with the review will be identified via evaluating related conference proceedings. The research flowchart is shown in Figure 3.3The following search terms will be used: randomized controlled trial/ randomized controlled trial; AR/Affection of AR; traditional chinese medicine/TCM; Guominjian/Guominjian therapy/Guominjian treatment. different retrieval strategies in Chinese and foreign databases will be used. Language restrictions are Chinese and English. There is no publication restriction. Here we take the search strategy in PubMed as an example and list in Table 44.1All articles in the search results were independently evaluated by 2 independent researchers  according to inclusion and exclusion criteria. Reviewers will then independently extract and collect the data included in the study using pre-designed data collection forms. Discrepancies will be discussedand resolved by consensus with a third author (SZ).4.2The following informations will be extracted from each study:(1)Normal test characteristics: title, author, year.(2)baseline data: sample size, age, gender, diagnosticcriteria, course of disease.(3)interventions: acupuncture therapy, control of intervention details, intervention. If the information is not enough, we will contact experts and authors in this field to get relevant information.4.3 The Cochrane System Evaluator's Manual give the evaluation criteria for authors to evaluated the randomized controlled trials quality. Assessing the risk of bias:The risk of bias will be assessed by 2 independent authors (YX and HL), together with completing the STRICTA checklist.(1)random sequence generation;(2)allocation concealment;(3)blinding of participants and personnel;(4)blinding of outcome assessment;(5)incomplete outcome data;(6)selective outcome reporting;(7)other bias.Any disagreement will be discussed or consulted with a third reviewer. Each them will be described from 3 levels: “high risk,” “low risk” and “unclear.”4.4The dichotomous outcomes will be expressed by the Odds ratio(ORs), while the continuous data will use the Standardized mean difference(SMD). All these outcomes report 95% confidence intervals.4.5We will take the method of contacting corresponding authors to obtain the missing data. If there is no response, we will analyze only the available data and describe the reason and impact of this exclusion in the paper.4.6The bias of publication will be explored through funnel plot analysis. If the funnel plot show asymmetry, it will be evaluated via the Egger and Beg tests, and P value <.05 means the publication bias is significant.4.7Q value statistic test, I2 statistic test, H statistic test). The I2 statistic test method shows us When I2 is 0, it means that studies are completely homogeneous, If I2>50%, it indicates there is heterogeneity in studies.There are 2 main methods for testing heterogeneity, namely graphical method  and statistical test . To test the heterogeneity of the research results, when the 4.9We will undertake subgroup analysis based on the different types of interventions and controls, characteristics of study or patient, and different outcome measurements.4.10Sensitivity analysis can not only assess the stability and reliability of the conclusions of the Meta analysis, but also assess whether the changes in the results are related to the impact of a single study. If the stability of the conclusion is poor, we can achieve When the heterogeneity test results are heterogeneous, we need to clarify the source of the heterogeneity by subgroup analysis. The effects of different types of therapy including design scheme, severity of illness, age, sex, andmild or severe AR were analyzed. We will also delete low-quality and/or medium-quality studies to check the robustness of theresults the purpose of increasing stability by changing the analysis model, inclusion and exclusion criteria, or excluding a certain type of literature.4.11We will publish the system review results in peer-reviewed journals, disseminated in meetings or in peer-reviewed publications. Aggregated published data will be used to exclud data of individuals, so there is no need for obtaining the ethical approval or patients’ informed consent.5 In addition, a number of studies have also shown that allergy decoction can significantly improve inflammatory factors in antagonists,–8 effectively improve patients’ allergic symptoms, and thus improve their quality of life.AR is a kind of caused by specific individual after exposure to an allergen mediated by IgE release of inflammatory mediators and the activity of a variety of immune cells and cytokines involved in the occurrence of inflammation in nasal mucosa disease, the main clinical symptoms include nasal itching, sneezing, flow stuff, nasal congestion, in addition to the nasal symptoms, some patients can merge bronchial asthma, resulting in asthma, cough, shortness of breath, chest tightness and other symptoms, lung clinically AR often interact with asthma and its influence, endangering human health. Some patients may have itchy eyes, tears, red eyes and burning eyes and other eye symptoms. There is a certain theoretical basis for the clinical efficacy of AR decoction. Study has shown that both low dose and high dose of allergic decoction can significantly alleviate the allergic reactions in model mice.In recent years, clinical experience has proved that Guominjian is an effective and safe way to treat AR. Relevant studies have proposed its possible mechanism of action, but the mechanism is still unclear, and most of the literature has not clearly pointed out the mechanism of Guominjian's treatment of AR. Therefore, it is very necessary to carry out standardized and unified experimental design in clinical studies to evaluate the efficacy, which can not only guide the application of Guominjian in AR, but also explore the mechanism of Guominjian's action in the treatment of AR.In summary, systematic review and meta-analysis are helpful to determine the application of Guominjian in the treatment of AR, and reduce the waste of medical resources, patients’ time and money. This study can not only provide a basis for the introduction of treatment guidelines for AR, but also promote the application of Guominjian treatment to benefit more patients.We are grateful to Dr Zhang for technical support and advice.Conceptualization: Yi-min Xiong; Haoran Li; Shu-nan Zhang.Data curation: Yi-min Xiong; Haoran Li.Formal analysis: Yi-min Xiong; Haoran Li.Methodology: Yi-min Xiong; Haoran Li; Shu-nan Zhang.Project administration: Shu-nan Zhang.Resources: Yi-min Xiong; Haoran Li.Software: Yi-min Xiong; Haoran Li.Supervision: Shu-nan Zhang.Writing – original draft: Yi-min Xiong.Writing – review & editing: Shu-nan Zhang.


Background: Health literacy is a determinant of health and assessed globally to inform the development of health interventions. However, little is known about health literacy in countries with one of the poorest health indicators worldwide, such as Afghanistan. Studies worldwide demonstrate that women play a key role in developing health literacy. Hence, this study's purpose is to explore health literacy of women in Afghanistan and the associated factors.Methods: From May to June 2017, we randomly recruited 7–10 women per day at the hospital in Ghazni, a representative province of Afghanistan. Two trained female interviewers interviewed 322 women (15–61 years old) orally in Dari or Pashto on a voluntary basis and assessed their health literacy using the HLS-EU-Q16, associated socio-demographics, and health behavior.Results: Health literacy of women (among educated and illiterates) is low even compared to other Asian countries. Health literacy is linked to age and education. We found mixed evidence of the relationship between health literacy and contextual factors, help-seeking, and health-related behavior.Conclusion: This study provides novel data on health literacy and astonishing insights into its association with health behavior of women in Afghanistan, thus contributing to health status. The study calls for recognition of health literacy as a public health challenge be addressed in Afghanistan and other low-income countries affected by crises. Recently, health literacy (HL) moved from the margins to the mainstream of health research because of its relevance for quality of care, disease prevention, and quality of life. Health literacy is a critical determinant of health, an asset for public health and an outcome of health promotion activities such as health education . Hence, Various understandings of health literacy exist, the most prominent of which are those of the WHO , the InsBesides differences in levels of health literacy between countries, research shows that a substantial proportion of people have difficulties dealing with health information even within each country worldwide . The EurHowever, little empirical evidence exists on the determinants of health, health behavior, or their interplay with health literacy in Afghanistan. Afghanistan's public health indicators are among the worst globally: e.g., infant mortality rate is 62/1,000, up to three-times higher than in neighboring countries . Due to In health literacy research, a few studies target women in low and middle-income countries , but litTherefore, we wanted to examine the following assumptions: (a) Due to lack of/or interrupted school education, literacy and health literacy levels of many women in Afghanistan might be low. (b) Due to one of the lowest literacy rates worldwide, the level of health literacy in Afghanistan could be one of the lowest around the world. Hence, we used the HLS-EU-16 to facilitate comparability with findings from other countries, particularly in the European and Asian health literacy surveys , 20. (c)What is the health literacy level of women in Afghanistan?How high is Afghans' health literacy in comparison to other countries?What are the main determinants of health literacy in Afghanistan?Is health literacy associated with help-seeking and with health-related behavior?Our aim is to present descriptive results of our health literacy survey in Afghanistan, to compare it with population health literacy of populations globally, and to discuss the complex relationship between literacy, health literacy, and health behavior for crisis-affected low-incoming countries. Notably, the study identifies practical approaches to meet the need to improve the population's health literacy and make healthcare, disease prevention, and health promotion more accessible to the people of Afghanistan , 33, 34.We have conducted the survey in Hazarajat in four of the most densely populated districts of Ghazni province: Jaghori, Malistan, Nahoor, and Qarabagh. These districts are representative of the geography of Afghanistan with a study area of ~7,355 square kilometers and an altitude difference of more than 2,000 m. Only one hospital—the Shuhada Hospital—and 25 health centers operate in these districts.Various security-related, geographical, and cultural challenges in Afghanistan pose difficulties for research among Afghan women outside the main cities. Firstly, women should conduct interviews with women. Secondly, it was impossible for female interviewers to travel to villages and interview randomly selected women because of security reasons . TherefoFurthermore, we also interviewed male heads of households in their villages, but this sample is described in other articles , 36. TheDue to our desire to look at health and health literacy from various perspectives, we have created a questionnaire and selected questions based on the content, relevance and cultural appropriateness. The questionnaire comprised 102 items, including 45 socio-demographic and health-related items, 15 items of the European Health Literacy Questionnaire (HLS-EU-Q16), 18 items of Quality of Life (WHOQOL-BREF) , 8 itemsWe used the HLS-EU-Q16 questionnaire developed by Pelikan et al. , shortenIn general, the very high Cronbach's alpha α = 0.991  of the Health literacy scale can be regarded as valid for appropriate internal consistency of the items .For data management, we adhered to the guidelines of the HLS-EU survey on inclusion and exclusion criteria and restricted the samples to participants 15 years and older, and to those answering at least 80% of the questions . Hence, *50/3. Additionally, we subdivided the health literacy score of the short HLS-EU-Q into three levels at the cut-off of 25 and 37.4 points . 0–25 points were defined to be the lowest level as “inadequate HL,” 25–37.4 as “problematic HL” and 37.5–50 as “sufficient HL” , we calculated the level of health literacy based on the mean value of the answers given per person. The score 1 symbolized the lowest mean score  and 4 the highest mean score . Unlike the proposed procedure in the HLS-EU , we did ient HL” , 40. We (r) for two continuous-variables, point-biserial correlation coefficient (rpb) for one binary variable and one continuous-level variable, odds ratios (OR) for bimodal variables, and chi-square tests (χ2) for multi-optional variables using estimated percentage and absolute numbers. To assess the proportion of variance in HL, which is explained by sociodemographic data, we performed a multivariate linear regression model for general health literacy index as a dependent variable and education, age, main occupation (housewife or own occupation) and marital status as predictors.We examined the relationship between health literacy and other factors, namely age, education, further sociodemographic data, and health-related behaviors, by calculating bivariate correlation. Thereby we used pearson correlation coefficient N = 242 women), Malistan (N = 77), Nahoor (N = 3), and Qarabagh (N = 2). At the time of the interview, 58.7% reported being sick, whereas 41.3% were not ill but were accompanying another person. The participants' age varied between 15 and 61 years (average 30.33), with more than half of the participants between 20 and 29 (N = 144) and only 26 women aged 50 and above.A total of 322 women at the hospital from the following districts participated in the study: Jaghori  had formal or higher education.Concerning contextual factors, the women interviewed in the hospital reported that 41.0% had access to a river, 97.8% to a road and 43.8% to a car. Most, but not all women had access to information and communication technologies such as electricity (89.1%), phone (88.8%), TV (75.5%), and the Internet (23.3%).Noteworthy differences exist in the self-reported responses related to the HLS-EU-Q16 scale, as some items (activities) were classified by the majority of respondents as easier and other items (activities) as more difficult. Women had the greatest difficulties with tasks related to evaluating recommendations e.g., “judging when to get a second opinion” (Item 5) (64.60% of women said it was rather or very difficult) and “judging which everyday behavior is related to health” (Item 16) (60.56%). However, most women (54.3%) reported that “understanding the advice on health given by family members” (Item 14) was the easiest of all tasks. Nevertheless, rarely all respondents found all items very/rather difficult or very/rather easy , followed by age , marital status , not working at home . Women with some education were 73.5 times more likely to have sufficient HL (Odds Ratio (OR) = 73.5  than illiterates. However, in order to be able to explain the correlation of health literacy with age and education qualitatively, a more detailed examination of the sample in the different age groups and their educational levels is necessary at first. Women in Afghanistan are particularly affected by the historical changes in the country and their impact on the education sector. While under Taliban rule women were denied access to schooling, after 2001 massive investments were made in expanding the education system and girls'education. The unequal distribution in access to education is reflected in our sample. When analyzing the association of HL with various factors, we found a very heterogeneous picture. Based on raw correlations, HL was associated with age and education. The highest bivariate correlation existed between health literacy and education (R2) . Only 29.1% of women reported using contraceptives, while women with sufficient health literacy were 2.81 times more likely  to use contraceptives than women with problematic and inadequate HL. The use of contraceptives was to a great extent perceived as a sin, with nearly one in two women (45.03%) agreeing with the statement. We found a moderate correlation between evaluating contraceptives as a sin and a lower HL level . As a result, women with higher education were 0.24 times more likely to consider the use of contraceptives as a sin ] than illiterate women. Concerning the period of pregnancy and birth, only 19% of women reported to be aware of the complexity of the pregnancy period. The HL level has a moderate positive association with an awareness of the complexity . Controlled for education, none of these four items are significant anymore. Concerning reproductive health, information on the prevention of unplanned pregnancy (34.75%) was not common among women, but a positive association existed with having information and a higher HL level  than women with a lower HL level.The level of health literacy was associated with the help-seeking behavior during pregnancy. Women with a higher HL level were more likely to seek help from the doctor  and to eat vegetables and fruits on a daily basis. In contrast, women with lower HL were more likely never to eat vegetables or fruit. Controlled for age and education, the association with fruit consumption remained significant, but not with tea or vegetable consumption.Every research project in Afghanistan faces various difficulties, which are even more challenging in remote areas outside the large cities . In light of these challenges, we endeavored to achieve the highest standard of research in the given context while collecting data relevant to research and practice concurrently. Nonetheless, our study is limited in terms of method, context and data collection process, as well as policy relevance. The first limitations are related to the method and instrument used. Consistent with a standardized health literacy assessment, we used the HLS-EU-Q16 questionnaire and assessed the level of health literacy among women at the hospital in Central Afghanistan. However, this questionnaire only captures one side of health literacy the individual's perspective on his/her own skills and abilities and does not assess the demands and complexity of the health system and situation. Therefore, we can only conclude that women's health literacy level is low, but we cannot specify why. Possible explanations for the low level of HL are lack of education, lack of sufficient health centers in this region, high demands of the hospital, lack of health knowledge and health awareness campaigns etc. but this is not empirically proven in longitudinal studies or studies that assess both sides of health literacy  Afghans, 29.9% had inadequate, 40.7% problematic and 29.6% sufficient health literacy as measured by the HLS-EU-16 questionnaire . HoweverIn general, our findings are consistent with the extensive scientific evidence, indicating that determinants of health, particularly educational attainment, are major factors explaining the level of HL . ContrarAdditionally, this study provides unique insights into everyday health topics such as reproductive health, help-seeking behavior and dietary pattern of women in Ghazni Province. These findings may help explain the high rates of under-five mortality , maternal mortality , and stunted children (40.9%) . The stuWhile illiterate people are usually excluded in research studies due to existing barriers, we have succeeded in including illiterates by means of face-to-face interviews. In accordance with the traditional understandings of functional HL and its measures such as TOHFLA or REALM, illiterates should have virtually no health literacy . Though Many health policy approaches assume that improving access to technical infrastructure in remote areas leads to an improvement in health literacy. This assumption could not be confirmed in our data because, first, access to information and communication technology in rural and remote areas of Afghanistan is low generally  and, secLastly, this research also provides new insights into the development of General Generalized Resistance Resources (GRR) to cope with adversity and to combat chaos (entropy) . Health A salutogenic perspective will shed new light on the interplay between life orientation and the development process of health literacy, particularly in countries of the Global South.The study aimed to increase evidence for HL in Asia and crisis-affected countries, by providing novel data on health literacy in Afghanistan. Compared to other Asian countries, the self-reported HL level of women in the Ghazni Province in Afghanistan is low. This could be explained by the high illiteracy rate, a consequence of political events in Afghanistan. Although  level of education is the strongest predictor of a person's individual HL level, this study clearly reveals that illiterate people can be health literate and behave healthily.This cross-sectional study illuminates contextual factors, various health-related behaviors, and health literacy and their interrelationship. The forthcoming studies and interventions contribute to enhancing our understanding of the complex relationship between literacy, HL, health behavior, quality of life etc. However, cross-sectional studies such as this cannot inform us about the process of acquiring and shaping health literacy or health behavior. In our view, more research—including ethnographic research—is needed both to thoroughly investigate the relationship between contextual factors, health literacy, help-seeking behavior, and health-related practices in everyday life and to explore the development of health literacy and behavior in daily lives. Hereby, a salutogenic understanding of people's competencies and resources of action is promising. Based on this deeper understanding, further interventions to improve health literacy in schools and in daily practice should be developed. The recommendation to implement more interventions to further improve women's HL is in line with the Afghan Government's strategy: “gender mainstreamed in all health promotion interventions and effective health literacy messaging to women and girls” . FinallyThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent from the participants' legal guardian/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements.SH: data analysis and writing the article. AJ: data collection and reviewing the article. EJ: data collection. LS-N: reviewing the article. KS: reviewing the article. DS: reviewing the article. UB: writing the article. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.