IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. It is considered that the pathogenesis of IgAN involves the ‘multiple hit theory’ and the immune-inflammatory mechanism; however, these theories have certain limitations. The gold standard for diagnosing IgAN is still renal biopsy. Although renal biopsy is accurate, it is traumatic and is associated with some risks and limitations, so there is a need for non-invasive diagnostic methods. According to recent studies, microRNAs (miRNAs) play important roles in the occurrence and development of IgAN; thus, they provide the possibility of the noninvasive diagnosis of IgAN and also have some value in predicting prognosis. This review summarizes the current research status of miRNAs in the occurrence, development, diagnosis, and prognosis of IgAN. We also highlight some interesting and challenging points that require further study. Approximately 20–40% of patients with IgAN develop the end-stage renal disease (ESRD) within 10–20 years .The research of microRNAs (miRNAs) in IgAN began with the study of miRNAs in urine sediment of patients with IgAN by Wang et al. in 2010 . That st2.2.1.Gd-IgA1 plays an important role in the pathogenesis of IgAN. Most studies about miRNAs and the pathogenesis of IgAN are related to gd-IgA1.It has been demonstrated that C1GALT1 could regulate the production of gd-IgA1 in IgAN ,11. Usinin vitro experiments are required to verify this hypothesis. In addition, Chunmei L speculated that overexpression of miR-320 decreased Cosmc expression in B cells [Cosmc is a unique molecular in mammalian galactosyltransferase . Accordi B cells .HMGB2 participates in four IgAN-related pathways, namely, the inflammatory response, defense response to bacteria, diversification of immune receptors, and cell surface receptor signaling pathways ,18. Zhai2.2.About 35–50% of patients with IgAN have elevated serum IgA levels, which are closely related to B and T cells. It is believed that p-IgA in IgAN is produced by polyclonal B cells, while IgA secreted by B cells is regulated by T cells. Dysfunctional immune regulation of T cells can cause uncontrolled and excessive production of IgA by B cells . PreviouCosmc gene and the production of gd-IgA1, eventually leading to the deposition of IgA in the kidneys. Jin et al. [MiR-155 is a multifunctional immunomodulatory miRNA ,23; it in et al.  proved tn et al.  may regun et al.  and miR-n et al.  promote in vitro cell culture can solve this problem.In general, the available studies on the relationship between miRNAs and immune regulation were not able to directly measure the content of miRNAs from differentiated lymphocyte subsets because of the low content of miRNA in lymphocyte subsets. Perhaps expanding the sample size or testing 2.3.There are some miRNAs whose mechanism in IgAN has not yet been demonstrated. However, it has been shown that these miRNAs are associated with the pathogenesis of other kidney diseases, or there are clues that they may play a role in the pathogenesis of IgAN. Therefore, these miRNAs also have a great research value, providing a direction for future research. For example, miR106b5p and miR175p regulate cellcycle progression and apoptosis ,30. MiR-In conclusion, miRNAs are likely involved in several pathways of IgAN pathogenesis, and multiple miRNAs are involved in one pathogenesis pathway as well. C1GalT1, Cosmc, FOXP3, and PTEN are the main targets of miRNAs, which are regulated by multiple miRNAs and participate in multiple pathways. Overall, miRNAs and their targets comprise a complex network involved in the pathogenesis of IgAN. In order to better understand the pathogenesis of IgAN, it is necessary to find a ‘central’ miRNA and its target, which is highly specific and associated with multiple classic pathways of pathogenesis. We summarized IgA pathogenesis related to miRNAs in 3.3.1.in situ hybridization in renal tissue, it was further confirmed that miR-21-5p was expressed in the area of interstitial fibrosis, and the increase in miR-21-5p expression was related to the severity of interstitial fibrosis. However, the study lacked a validation cohort and disease controls; moreover, it did not profoundly explore how mir-21-5p affects renal interstitial fibrosis. Another study [The miR-29 family plays an important role in the progression of IgAN. Previous studies in rats or mice have shown that downregulation of miR-29 family members could exacerbate renal interstitial fibrosis, while their overexpression can attenuate fibrosis ,34. It her study  revealeder study ,39. IgANer study . Some scer study . Howeverer study  showed tSome other miRNAs have also been implicated in renal interstitial fibrosis in IgAN. In IgAN, through epithelial-to-mesenchymal transition (EMT), activated renal tubular epithelial cells can turn into activated fibroblasts, thereby favoring renal fibrosis . PreviouIn general, the previous studies focusing on miRNAs and IgA nephrotic interstitial fibrosis were mainly based on clinical correlation analysis. However, renal interstitial fibrosis is not specific to IgAN; it is a necessary stage in many chronic kidney diseases. Therefore, future studies should pay attention to the mechanisms of interstitial fibrosis in IgAN regulated by specific miRNAs. We summerized the role of miRNAs in the renal interstitial fibrosis of IgAN in 3.2.Inflammation plays an important role in IgAN and is closely related to disease progression and poor prognosis ,47. Gd-I3.3.in vivo and in vitro. Recently, a study [In addition to the aforementioned mechanisms of interstitial fibrosis and inflammation, other mechanisms are gradually being discovered. It has been shown that diffuse glomerular endothelial cell hyperplasia is related to capillary hyperplasia, glomerular sclerosis, and severe proteinuria . Glomeru a study  showed t a study .In conclusion, miRNAs are involved in IgAN through a complex network. A single miRNA can be involved in both pathogenesis and progression of IgAN, while different miRNAs are connected by the same targets. For example, in IgAN, the miR-200 family participates in renal interstitial fibrosis by ZEB1 and ZEB2, and in inflammation by TWEE/Fn14 . MiR-21 4.A large number of studies have reported that miRNAs are related to the severity of IgAN renal damage. However, few studies have determined that these miRNAs are specific to IgAN kidney damage compared with other forms of nephropathy.The association between urine miRNA and the severity of IgAN has been most studied. Wang et al.  reportedRenal miRNAs have been also explored in relation to the severity of IgAN. A study  has repoSome miRNAs in blood have been linked to the severity of IgAN. Plasma miR-148a-3p level has been reported to positively correlate with eGFR . Not onl5.Currently, kidney biopsy is still the gold standard for diagnosing IgAN. Although accurate and specific, kidney biopsy is expensive and traumatic. Therefore, reliable and non-invasive diagnostic biomarkers are needed for IgAN. Many studies have explored miRNAs in blood as diagnostic markers, and promising results have been obtained. For example, Serino et al.  studied n = 93) than in the normal group (n = 82) or disease control (n = 40). These three miRNAs had good specificity and sensitivity for the diagnosis of IgAN, in which the AUC value of miR-486-5p was the largest at 0.935. The combination of the three miRNAs increased the AUC value to 0.940. Through CD235a magnetic bead sorting, it was also determined that these miRNAs mainly come from urethral red blood cells. Another study [However, miRNAs in urine have a greater advantage than miRNAs in the blood because they are easy to collect and have very convenient detection technology. Duan et al.  reporteder study  showed ter study  exploredIn fact, there are many miRNAs with diagnostic potential. For example, in patients with IgAN, the urine levels of miR-29b and miR-29c are significantly lower  while th6.n = 33) achieved complete remission (CR) at the end of follow-up. However, there was no significant difference in urine sediment miRNA levels between the CR group and the non-CR group. Liang et al. [The most promising use of miRNA levels in urine is to predict the prognosis of diseases. At present, there has been great progress in research related to the use of miRNAs to predict the prognosis of IgAN. However, there are still some problems: for example, small sample size; too short follow-up time; lack of Cox survival analysis; and lack of ‘hard end points’, which are usually determined as double Scr levels compared with a renal puncture, or ESRD or eGFR decreased by 50%. Wang et al.  showed tg et al.  found no7.In summary, there has been great progress in the research of miRNAs in IgAN since 2010, including their impact on the pathogenesis and progression of IgAN, their use as biomarkers to determine the severity of renal damage in IgAN, and their diagnostic and prognostic value. However, there are still some problems that need to be solved in future studies.First, the pathogenesis and progression regulated by miRNA should be further illustrated. As for the pathogenesis, here, we summarized the majority of the articles published since 2010 and found that most of the studies focused on the mechanism by which miRNAs cause the production of gd-IgA1 and the imbalance of immune regulation. However, the excessive production of pathogenic IgA1, insufficient IgA clearance, and deposition of IgA in the mesangial region are also major pathogenesis factors of IgAN. For example, miR-133a, miR-133b, and miR-185 seem to be associated with IgA1 deposition, and miR-17-5p might be associated with mesangial proliferation and endocytic trafficking. However, these miRNAs have only been screened by high-throughput sequencing and are expressed at low levels in IgAN , so furtSecond, the credibility and specificity of results should be improved. First, due to the small sample sizes as well as the lack of validation cohort and other glomerular disease controls, the current studies in IgAN should be further confirmed. In addition, because miRNAs in specific lymphocytes subgroups are difficult to analyze, PBMCs are currently used in the study of miRNAs. Future studies should isolate specific lymphocytes to minimize confounding factors. At the same time, studies on the effect of miRNA modulators and other RNA‑targeted agents need more development.Third, strong analytical approaches should be developed to urinary miRNAs research. Urinary miRNAs have become a research hot spot because of noninvasive and convenient collection and analysis. Nevertheless, optimization and standardization of miRNA extraction and quantification from urinary sediment are challenging. Commonly used methods include ultracentrifugation, through the addition of macromolecular crowding reagents, such as polyethylene glycol, or paramagnetic particles. Although these methods can obtain more pure miRNAs, they require a larger amount of fluid and are difficult to carry out in clinical practice . In addiIn addition, miRNA has great potential in targeted therapy. First, one miRNA can act on multiple targets through different pathways, thereby affecting multiple pathogenesis or progression mechanisms of IgAN; second, miRNAs are small, with known and conservative sequences, and they are easy to manufacture; third, the treatment method is simple, including local or gastrointestinal injection, and the tissue can fully absorb miRNAs . However8.Overall, the role of miRNAs in IgAN has been more fully elucidated. The research has gradually shifted from the preliminary exploration stage to more detailed studies, including the identification of downstream targets of miRNAs, the precise location of miRNAs, and the study of combinations of miRNAs for improving the diagnostic potential. Urine miRNAs have become a focus of research due to their intrinsic advantages. However, the research of urinary miRNAs needs further improvement, especially in the field of diagnosis and prognosis prediction, which requires multicenter studies. The role of miRNAs in IgAN also provides a basis for their pharmacological research. More attention should be paid to the role of miRNA modulators and inhibitors in the treatment of IgAN in the future.


The recycling of electronic waste (e-waste) contaminates ecosystems with metals, though a compilation of data from across sites worldwide is lacking, without which evidence-based comparisons and conclusions cannot be realized. As such, here, a systematic review of the literature was conducted to identify peer-reviewed studies concerning e-waste sites (published between 2005 and 2017) that reported on the concentration of heavy metals  in soil, water and sediment. From 3063 papers identified, 59 studies from 11 countries meeting predefined criteria were included. Reported metal concentrations were summarized, and a narrative synthesis was performed. This review summarized 8286 measurements of the aforementioned metals in soils (5836), water (1347) and sediment (1103). More than 70% of the studies were conducted in Asia. In nearly all cases, the average metal concentrations in a particular medium from a given site were above guideline values; suggesting soils, water and sediment at, or near, e-waste recycling sites are contaminated. Across all media, concentrations of Pb were generally highest, followed by Cr, As, Cd and Hg. The synthesized information demonstrates that e-waste sites worldwide are contaminated with metals, that geographic data gaps exist, that the quality of most studies can be improved and that action is needed to help reduce such levels to protect human health and the environment. The generation of electronic waste (e-waste) has rapidly emerged to become of growing concern worldwide ,2. For eActivities within the entire e-waste sector are notorious for contaminating ecosystems with a range of potentially toxic elements , as docuDespite the growing literature on ecosystem contamination at e-waste sites, there is a lack of a worldwide review on the subject matter from which we can synthesize global understanding, perform comparative studies , identify data gaps and ultimately draw evidence-based conclusions and make recommendations. Notably, a recent review by the WHO and the United States National Institute of Environmental Health Sciences—U.S. NIEHS —called oA systematic review method was developed based on guidance from the United States Office of Health Assessment and Translation . A literThe scientific papers were reviewed in a two-step process : first, From each included paper, data were collected on the study design , measurement , the type of heavy metal  and the environmental media , and the results were measured as both a central tendency value (geometric mean or median or mean) and a high-end value .The different units of measurement for metals from the studies included in this analysis were harmonized. All units were converted to mg/kg for soil and sediment and mg/L for water. This allowed us to easily make comparisons of heavy metal concentrations according to the studies, types of sampling area, countries and continents.First, the extracted data were analyzed using Microsoft Excel 2013 software. Statistical analyses were done to synthesize the data according to the variables. Second, a narrative synthesis was done on all included studies, and key points on each of the items studied were reported.The initial search of titles/abstracts resulted in 3063 published articles, of which 2856 were excluded, because they did not meet the predefined criteria , water  and sediment (dust and river). Of the five target metals, only Pb was common to all studies and measured in each .Regarding the instruments used to detect the heavy metals, about one-third (33.8%) of the studies used inductively coupled plasma mass spectrometry, while the rest used atomic absorption spectroscopy (22.1%), inductively coupled plasma atomic emission spectroscopy (16.2%), inductively coupled plasma optical emission spectrometry (14.7%) and atomic fluorescence spectrometry (8.82%).The median values of the concentrations of heavy metals in the soil by country are summarized in In this group, 14 studies from three countries were identified, in which measurements of As were taken from 595 soil samples. The pooled central median concentration of As in soil was 9.55 mg/kg see  interqu. The higComparing the values of each study with the United States Environmental Protection Agency (USEPA) guidelines , it can In this group, 36 studies from six countries were identified. Combined, these studies analyzed 1625 soil samples in total. The pooled central median concentration of Cd in soil was 1.11 mg/kg  IQR: 0.. The higAs presented in In this group, 32 studies from five countries were identified. Combined, these studies analyzed 1310 soil samples in total. The pooled central median concentration of Cr in soil was 34.79 mg/kg see  IQR: 18. The higAccording to In this group, 42 studies from 10 countries were identified. Combined, these studies analyzed a total of 1607 soil samples. The combined central median concentration of Pb in soil was 96.46 mg/kg see  IQR: 46. The higBy comparing the soil Pb upper values reported in the literature and USEPA guidelines, many of them are above the accepted limit. These non-standard values have been found in Uruguay , Ghana ,40,52,53In this group, 42 studies from 10 countries were identified. Combined, these studies analyzed a total of 699 soil samples. The pooled central median concentration of Hg in soil was 0.34 mg/kg see  IQR: 0.. It shouThe comparison between the upper values of Hg in soil reported in the literature and the USEPA guidelines shows that several concentrations are above the guidelines . These nBy synthesizing the information on all heavy metals in soil, we note in this systematic review a predominance of studies conducted in Asia, especially in China, on the contamination of soils by heavy metals from e-waste recycling. The imbalance of the scientific data on the topic does not allow for a global perspective, such that a more or less universal decision may be made or conclusion drawn. It is therefore important to conduct studies in other developing regions so that the analysis is truly global.In addition, studies on soil contamination by heavy metals are more numerous than studies on other aspects of environmental contamination (water and sediment). This situation could be explained, first, by the position of the soil in relation to recycling activities and the ease with which a scientist can determine the heavy metals in the soil and attribute the concentrations directly to e-waste. Indeed, e-waste is recycled on soil and this direct contact obviously explains the concentrations detected in the soil ,68. On tThe median values of the concentrations of heavy metals  in water by country are summarized in In this group, six studies from five countries were identified. Combined, these studies analyzed 241 water samples in total. The pooled central median concentration of arsenic in water was 0.0064 mg/L see  IQR: 0.. The higComparing the upper values of As in water with WHO guidelines , it can In this group, 10 studies from five countries were identified. Combined, these studies analyzed 452 water samples. The combined central median concentration of Cd in water was 0.00049 mg/L see  IQR: 0.. The higComparing the upper values of Cd in water with the WHO guidelines, it can be seen that some concentrations are above the recommended limit see . These lIn this group, eight studies were identified in six countries. Combined, these studies analyzed 235 water samples. The pooled central median concentration of Cr in water was 0.0022 mg/L see  IQR: 0.. The higThe comparison between the upper values reported in the literature and the WHO guidelines shows that several reported Cr concentrations in water are above the guidelines see . ExceedaIn this group, 10 studies from six countries were identified. Combined, these studies analyzed 287 water samples. The combined central median concentration of Pb in water was 0.0063 mg/L see  IQR: 0.. The higAs shown in Regarding water contamination by mercury, four studies from three countries were identified. Combined, these studies analyzed 132 water samples. The pooled central median concentration of Hg in water was 0.0005 mg/L see  IQR: 0.. China , followeUpper values of Hg in water compared with WHO guidelines show that, in China, there are concentrations above the recommended limit . After sThe median values of heavy metal concentrations  in sediment by country are summarized in Only three studies—all conducted in China—were found on the contamination of sediment by As. The studies analyzed a total of 107 sediment samples. The median central pooled concentration of As in sediment was 11.3 mg/kg see  IQR: 8.. The higIt is important to note that all values reported in the literature on As in sediment ,70,81 arTwelve studies, conducted in two countries (China and Vietnam), were found on the contamination of sediment by Cd, with 11 of them conducted in China. These studies analyzed 347 sediment samples in all. The combined central median concentration of Cd in sediment was 2.15 mg/kg see  IQR: 1.. The higBy comparing the upper values of Cd in sediment with the USEPA guidelines, all of the studies reported concentrations above the recommended threshold see . It shouOnly three studies, all conducted in China, showed Cr contamination in sediment. Combined, these studies analyzed 171 sediment samples. The combined central median concentration of Cr in the sediment was 58 mg/kg see  IQR: 39. AnalysiAs presented in Thirteen studies, conducted in two countries (China and Vietnam), were found on the contamination of sediment by Pb, of which 12 were conducted in China. Combined, these studies analyzed 371 sediment samples. The pooled central median concentration of lead in sediment was 233.5 mg/kg see  IQR: 65. The higBy comparing the upper values of Pb in sediment with the USEPA guidelines, all the studies reported concentrations above the recommended limit see . It shouOnly three studies, all conducted in China, reported on Hg contamination in sediments. Combined, these studies analyzed 107 sediment samples. The median central pooled concentration of Hg in the sediment was 0.49 mg/kg see  IQR: 0.. The higIn synthesizing information on heavy metal pollution in sediments, we noticed that almost all these studies were conducted in China. There is therefore a need for research in other parts of the world for a global analysis of the situation.This systematic review analyzed peer-reviewed studies published between the years 2005 and 2017 that reported on As, Cd, Cr, Hg and Pb levels in soil, water and sediment collected from areas that recycle e-waste. In general, there are five broad conclusions of this work. First, across all studies, the concentrations of metals in a given medium are generally higher than international standards. Second, the risks associated with such exposures for both human health and the environment are not well characterized, and, as such, further studies are needed. Third, there are geographical data gaps, as most studies were from Asia (notably China). As e-waste recycling occurs in many countries worldwide, there is a need to increase research in other geographical areas like Africa, Oceania, Europe, America and even in Asian countries other than China. This will allow a clearer comparison between contamination within developing countries  and that of developed countries . Here, we only focused on papers published in English and French, and we acknowledge that studies published in different languages were missing. Fourth, we note that many studies did not include key variables . A future study of this kind could design a risk of bias score to identify (and better consider) higher quality studies. Fifth, the findings here raise concern about metal contamination at e-waste sites worldwide, and thus it is imperative for actions  to be taken at these sites to help reduce exposure (and thus risk).


Background: The effects of different intake patterns of meal protein on muscle mass have not been clarified. We cross-sectionally and longitudinally examined the effect of different timing of protein intake on sarcopenia-related factors in older adults.Methods: This cross-sectional study 1 included 219  elderly subjects aged ≥65 years. Subjects who consumed more protein at breakfast than at dinner were grouped into the morning group , and those who consumed more protein at dinner than at breakfast were grouped into the evening group . In cross-sectional study 2-1 , the subjects were classified into four groups according to the number of meals with sufficient protein intake. In cross-sectional studies 2-2  and 2-3 , the subjects were classified into eight groups and three groups according to whether they had consumed sufficient protein at three meals; sarcopenia-related factors were compared. The intervention study was a placebo-controlled, double-blind, randomized controlled trial that included 40 elderly women with low daily breakfast protein intake. The subjects were divided into four groups: morning protein and placebo intake groups and evening protein and placebo intake groups. Each group consumed the test food (containing 10 g milk protein) or placebo in the morning or evening for 12 weeks. Blood indices and physical function were assessed before and after the intervention.Results: Comparing all subjects, MG showed significantly higher handgrip strength than did EG (P < 0.05). The higher ratio of morning protein intake relative to the total protein intake, the better the muscle mass  and handgrip strength . The intervention study showed an increase in muscle mass with the intake of milk protein in the morning rather than in the evening (P < 0.05).Conclusions: Protein intake at breakfast might have relatively stronger effects on skeletal muscle mass than at lunch and dinner. As we age, skeletal muscle mass decreases, causing a decline in muscle strength and physical function , a condiMuscle hypertrophy occurs when the rate of muscle protein synthesis (MPS) exceeds that of muscle protein breakdown (MPB), while muscle atrophy occurs when the rate of MPS falls below that of MPB. Since MPS is stimulated by dietary protein, protein intake is important for maintaining and increasing muscle mass . In addiRecently, it has been suggested that factors such as the quality and distribution of daily protein intake are more relevant to muscle synthesis than the amount of daily protein intake. In fact, previous studies have shown that consuming enough protein in all three meals is more effective in maintaining and improving muscle mass, strength, and physical function . FurtherMany studies regarding protein intake and sarcopenia-related factors have been conducted on healthy subjects, and few studies have been conducted on obese people, and those requiring support . InsulinN = 60) . The subjects were healthy, obese, or required support; the study was conducted from August 2017 to February 2019 in Tokyo and Hokkaido (Japan). Subjects who required support in this study were those able to live on their own but needing partial assistance in their daily activities and have been certified by the nursing care insurance system in Japan. Some of the data used in this study were collected earlier for a previous study on the effects of morning or evening protein intake on the physical functions of the elderly (N = 60) .Subjects without regular exercise habits were included in this study. Regular exercise habit was defined as continuous physical activity for at least 30 min per session, at least three times per week, as defined by a previous study . SubjectAll subjects were fully briefed on the outline and safety of the study, and written consent to participate was obtained. The study protocol conformed to the Helsinki Declaration and was approved by the ethics committee for humans at Waseda University .In cross-sectional study 1, we examined the effect of different timings of protein intake on sarcopenia-related factors in all subjects. All subjects were divided into two groups: those who consumed more protein at breakfast than at dinner were grouped into the morning group (MG) and those who consumed more protein at dinner than at breakfast were grouped into the evening group (EG) .In cross-sectional study 2, 125 healthy or obese female subjects  were examined for the effects of different patterns of protein intake  on sarcopenia-related factors. In the cross-sectional study 2-1, the subjects were classified into four groups according to the number of meals with sufficient protein intake : 0 mealsBW was measured to the nearest 0.1 kg using a digital balance  and height was measured to the nearest 0.1 cm using a wall-mounted stadiometer . Body mass index (BMI) was calculated as weight in kilograms divided by the square of height in meters.Muscle mass was measured by direct segmental multi-frequency (20 kHz to 100 kHz) bioimpedance analysis . The skeletal muscle index (SMI) was calculated as the skeletal muscle mass (kg) divided by the square of height (m). Muscle strength was measured using a digital hand dynamometer . The handgrip strength of the dominant hand was measured twice while standing, and the mean of these measurements was used for analysis. Gait speed test was also evaluated. The subjects walked a 5 m straight course at a normal speed. The walking time for the mid 3m of the course was measured using a digital gait speed measuring instrument , and the gait speed (m/s) was calculated by dividing the distance in meters by the time in seconds.All participants were asked to wear a triaxial accelerometer  for a week. They always wore the accelerometer each day from morning until night, except during shower and bedtimes. In this study, we selected 4 weekdays and one holiday in which the wearer wore the device for at least 10 h (600 min) and averaged the data to calculate the daily physical activity. We used moderate-to-vigorous physical activity (MVPA) and the number of steps required for evaluation. All minute recordings that were ≥3 METs  were classified as MVPA .To determine the chronotype of the subjects (morningness to eveningness), a lifestyle survey was conducted using the Morningness-Eveningness Questionnaire (MEQ) . The scoThe Food Frequency Questionnaire (FFQ) was used to assess the dietary and nutritional intake of the subjects. It consists of questions on 29 food groups and 10 cooking methods. Most FFQs for Japanese are highly effective in estimating nutrients . AverageForty healthy elderly women aged ≥65 years  who consented to participate in the present study and whose daily breakfast protein intake did not meet 0.4 g/kg BW were included in the intervention study. This study included elderly women without regular exercise habits and the inclusion criteria were as follows: (1) no antioxidant, anti-obesity, or anti-diabetes supplements use; (2) no medical diagnosis of diabetes, dyslipidemia, or sleep apnea syndrome; (3) no hypertension . Therefore, it was only intended for subjects who had been confirmed to have no medication use, disease history, or smoking habits at the initial recruitment stage.This study was conducted in Tokyo (Japan) from August 2017 to February 2019. The participants were those who had no special lifestyle changes during the intervention period and did not have a regular exercise habit.https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000032737 as UMIN000028612.This study was approved by the Ethics Committee of Waseda University  and was conducted in accordance with the guidelines established in the Declaration of Helsinki. The human trial of the present study was registered at n = 10), morning placebo group , evening protein group , and evening placebo group   . The ranMeiji Co., Ltd provided both the test food (containing milk protein) and the control food (placebo) used in the present study. We asked Meiji Co., Ltd, the organization that provided the test foods, to have the participants and the person in charge of the experiment pack the test foods in such a way that they could not be identified, and then mail them to each subject. Disclosure regarding the test foods was made after the experiment was completed. As summarized in Anthropometry, physical activity levels, chronotype, and energy intake were assessed before and after the intervention using the same methods as in the cross-sectional studies. In addition to the items investigated in the cross-sectional study, the subjects participating in the intervention study underwent measurements of appendicular skeletal muscle mass and appendicular skeletal muscle index (ASMI), physical fitness tests , and “Sit to Stand” Test), taken before and after the intervention.ASMI was calculated as appendicular skeletal muscle mass (kg) divided by the square of height (m). A one-leg stand test was conducted to evaluate the balance ability of the participants. The participants were instructed to stand on one leg on a flat surface for as long as possible. The arms were held by the body with the eyes opened. If the participant was able to stand on one leg for more than 120 s, the measurement was stopped at 120 s. The measurement was performed twice, and a better record was used for the analysis. The sit-to-stand test was performed five times to assess lower extremity muscle strength. When measuring the time taken to change from a sitting to a standing position and vice versa, participants were instructed to stand up from sitting five times as quickly as possible without using their arms for support. The total duration was recorded in seconds. The TUG test was used to assess the mobility and balance of the subjects. The time (s) it took for the subject to stand up from a sitting position in a chair, walk to 3 m, and then return to the original chair position was measured.Venous blood samples were collected before and after the intervention. The participants were required to refrain from any strenuous exercise for at least a day before the collection of the blood sample and fast for at least 12 h overnight. The participants' fasting blood was collected at 10–11 am the following day. After collection, blood for serum analysis was allowed to stand for 30 min at room temperature, whereas blood for plasma analysis was centrifuged at 3,500 rpm for 10 min. After centrifugation, serum and plasma samples were extracted from the respective blood collection tubes and stored at −80°C until the day of the assay. Plasma insulin, glucose, and serum growth hormone (GH) were analyzed by Kotobiken Medical Laboratories, Inc. .*Power, version 3.1.9.2, Universitat Kiel, Germany). The normal or non-normal distributions of the data were analyzed using the Shapiro–Wilk test. In cross-sectional study 1, the mean values between the MG and EG groups were compared, and data that were normative and equally distributed were evaluated using the unpaired t-test. Data that were not confirmed to be normative or equally distributed were evaluated using Mann-Whitney's U test. In cross-sectional studies 2 and 3, data with normality and equal variance were evaluated using one-way analysis of variance (ANOVA), while data without normality or equal variance were evaluated using the Kruskal-Wallis test. Pearson's product-moment correlation coefficient was used to examine the relationship between the rate of protein intake in each meal and physical function.The Predictive Analytics Software for Windows  was used for data analysis. The total sample size was calculated to be able to detect a medium effect. Total sample size of 128  and 48 (Intervention study) were required to have ~80% power to detect large effects at a significance level of 0.05   .There were no significant differences in energy intake and total protein intake between the groups .n = 219; MG = 69, EG = 150), MG showed significantly higher handgrip strength than did EG (P < 0.05). Correcting handgrip strength for each subject's weight reduced the significance of the MG's higher handgrip strength (P = 0.054). In all healthy subjects , SMI and handgrip strength of the MG were significantly higher than those of the EG , and the MG tended to have higher muscle mass than the EG (P = 0.071). In contrast, there were no statistically significant differences between groups among all obese subjects  and all those requiring assistance .Comparing all subjects  showed significantly higher values or a trend toward higher values for SMI, handgrip strength, and handgrip strength (weight-corrected) in the MG than in the EG . In addition, in women with obesity , handgrip strength and handgrip strength (weight-corrected) were significantly higher in the MG than in the EG  , there were no statistically significant differences in sarcopenia-related factors between the groups. On the other hand, healthy female subjects (< 0.001) .P < 0.05, P < 0.05, P < 0.01, respectively) and handgrip strength (weight-corrected)    . In term= 0.076) .Protein intake patterns were classified into eight groups, according to whether the protein intake during the three meals was sufficient or not, and the subjects belonging to each intake pattern were divided into eight groups for comparison .P < 0.05, respectively; 1 meal group vs. 2 meals LD group; P < 0.01). In addition, handgrip strength (weight-corrected) was significantly higher or tended to be higher in the 3 meals group than in the 0 meal group, 1 meal D group, 2 meals BL group, or 2 meals LD group  (The results of the comparison of sarcopenia-related factors by protein intake patterns are shown in = 0.053) .Handgrip strength (weight-corrected) was lower in the group that consumed sufficient protein at both breakfast and lunch than in the group that consumed sufficient protein at only one meal in the morning. If we consider the importance of protein intake in the morning, we can assume that the comparison of the two groups would yield similar results. However, the results of this study differ from our hypotheses.To examine the effects of protein intake at breakfast, lunch, and dinner in more detail, we compared sarcopenia-related factors in three groups that had sufficient protein intake at only one meal. There were no significant differences in physical characteristics or energy intake between the groups .P = 0.080 and P < 0.001, respectively) (P < 0.001)   was higher in the 1 meal B group than in the 1 meal L and 1 meal D groups (ctively) . Additio< 0.001) . Furtherctively) . HoweverThere were no significant differences between characteristics of participants, and pre-intervention energy intake in each group .P = 0.066, ASMM, and ASMI; P < 0.05, respectively) (P = 0.059), SMI , ASMI . In the EPRO group, ASMI showed a decreasing trend after the intervention compared with before the intervention .The results of the comparison of the rate of change of sarcopenia-related factors by intervention are shown in ctively) . In addiP < 0.01, respectively) (P = 0.059), handgrip strength (weight-corrected) .In contrast, the rate of change in the EPLA group was significantly lower than that in the MPLA group in handgrip strength and handgrip strength (weight-corrected) (ctively) . In addiThe present study was a cross-sectional and interventional investigation of the effects of different protein intake patterns on sarcopenia-related factors. The main results showed that adequate protein intake in the morning is important for maintaining muscle mass and strength, with the effect being more pronounced in women. In the intervention study, only morning milk protein intake over 12 weeks resulted in increased muscle mass. These results suggest that morning protein intake is also effective in improving muscle mass and strength.Sarcopenia-related factors, such as muscle mass, grip strength, and physical function, may be influenced by the MEQ scores and physical activity. Morningness has been shown to have higher daily physical activity than eveningness  and incrn = 145; MG: n = 54, EG: n = 91) divided by their BW  and grip strength (weight-corrected), and the faster the walking speed. These results are in agreement with those of previous studies . Since pIn cross-sectional study 2-2, we examined the effects of eight different patterns of protein intake timing, for the three meals, on sarcopenia-related factors. In cross-sectional study 2-3, we examined the effects of different timings of breakfast, lunch, and dinner on sarcopenia-related factors in people who consume enough protein in only one meal. The results showed that adequate protein intake at only one breakfast meal was more important for maintaining muscle strength than at only one lunch meal or one dinner meal. Furthermore, it was suggested that the effect of sufficient protein intake at only one breakfast meal on muscle function was equivalent to that of sufficient protein intake at all three meals.Atrogin-1 and MuRF-1, genes involved in muscle degradation, is high from the late active phase to the early inactive phase (corresponding to nighttime in humans)  , 22. The humans) , 23. The humans) . TherefoThis cross-sectional study showed that high protein intake in the morning maintained higher muscle mass and strength in healthy and obese elderly women. However, the same results were not obtained for men as for women. There are two possible reasons for this finding.First, it is possible that women are more dependent on dietary protein for muscle synthesis than men. In a previous study, it was shown that the rate of muscle mass loss was lower with higher daily protein intake in elderly women, but there was no association between daily protein intake and muscle mass in elderly men . FurtherMyoD, a gene involved in muscle differentiation, has a diurnal rhythm controlled by clock genes and is greatly affected by diet  compared to the test food. In previous studies, breakfast carbohydrate intake was reported to improve exercise performance . TherefoIn contrast, there was no statistically significant difference between MPRO and EPRO. However, there was a slight increase in the rate of change of handgrip strength before and after the intervention only in EPRO. In general, sports performance, such as muscle strength and flexibility, is associated with diurnal variation in body temperature, which has been reported to be greatest in the evening . HoweverIn a 12-week intervention study, differences in the timing of milk protein intake did not affect blood indices  . InsulinThe lack of changes in these blood indices in the present study suggests that the intake of milk protein at different intake timings did not affect these blood indices. In addition, the increase in appendicular skeletal muscle mass in the MPRO group did not improve insulin resistance or the hormonal environment. Therefore, it is possible that the 12-week period of milk protein intake was too short, and that a longer intervention should be conducted in the future. In addition, the blood samples in this intervention study were taken in the fasting state, and we did not compare the blood indices in the morning and evening after protein intake before and after the intervention. Considering that skeletal muscle protein synthesis in the elderly is resistant to the anabolic effects of insulin and that this is an important factor in the development of sarcopenia , it is nThis study had several limitations. The study was conducted on elderly subjects. However, elderly people are less sensitive to the stimulation of muscle protein synthesis by amino acids than younger people . Since lCross-sectional study 2-2 showed that handgrip strength (weight-corrected) was lower in the group that consumed protein only at two meals, in the morning and at lunch, than in the group that consumed enough protein only at one meal in the morning. If it is important to consume protein in the morning, it is expected that muscle strength would show similar values when the group consumed enough protein at only one meal and when the group consumed enough protein at two meals: breakfast and lunch. This may be due to the small number of participants, as there were only six participants who consumed enough protein in two meals: breakfast and lunch. Therefore, there is a need to increase the number of elderly people with inadequate protein intake patterns in the future for a more detailed study.Previous studies have not reached a consensus on the differences between men and women in muscle protein synthesis pathways, such as mTOR activity, due to diet and exercise, and much remains unclear , 42. In Calcium was a component of the test food. Several studies have reported no association between calcium intake and muscle mass or function –45. HoweIn conclusion, the current study suggests that adequate protein intake in the morning may be effective in maintaining and increasing muscle mass and strength, and this effect is particularly pronounced in older women. Furthermore, the results demonstrated that morning milk protein supplementation may lead to increased muscle mass in older women with inadequate morning protein intake.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by Ethics Committee for Humans at Waseda University. The patients/participants provided their written informed consent to participate in this study.H-KK, HC, and SS: conceptualization. HC and H-KK: data curation. H-KK and HC: formal analysis. SS, SH, and MS: funding acquisition. H-KK, HC, MF, JO, MO, and TN: investigation. H-KK, HC, and SS: methodology. H-KK and SS: project administration. SS and H-KK: resources. SS: supervision. H-KK and HC: visualization. H-KK, HC, MT, and SS: writing—original draft. TN, MT, and SS: writing—review and editing. All authors read and approved the final manuscript.This work was supported by the Japan Society for the Promotion of Science (KAKENHI Grant Number 19H01089 to SS), JSTMirai Program Grant Number JMPJM120D5, Japan, and by Meiji Co., Ltd. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.SH and MS were employed by company Meiji Co., Ltd. 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.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.


CLCN5 gene c. 941C > T mutation (p.S314L), and was finally diagnosed as Dent disease 1. The clinical manifestations of Dent disease are complex and diverse. For patients with atypical clinical manifestations or unsatisfactory therapeutic effects, genetic testing is recommended.Dent disease is a rare genetic disease characterized by low-molecular-weight proteinuria. Dent disease with Bartter-like syndrome is rare and can easily be misdiagnosed and mistreated. Herein, we report a case of Dent disease 1 with Bartter-like syndrome as the initial manifestation. The patient was admitted to The Second Xiangya Hospital of Central South University due to polydipsia, polyuria, and weakness of both lower limbs at 2 years of age. Laboratory tests showed that serum sodium, potassium and chlorine levels were low, while serum creatinine levels were normal. The calcium level in the urine was normal. The patient was initially diagnosed with Bartter syndrome, and despite medical interventions, he eventually developed chronic kidney disease stage 4 at 13 years of age. To determine the cause, the patient was recommended to undergo genetic testing, which showed a  Dent disease is an X-linked recessive renal tubular disorder characterized by low-molecular-weight proteinuria, with or without hypercalciuria, renal calcinosis, and progressive renal loss of renal function . In addiHere, we report a case of Dent disease 1 with Bartter-like syndrome as the initial presentation.The patient was a third child of unrelated parents and was born in February 2003. He had two sisters, both of whom were in good health. However, his grandmother has a history of uremia. At 2 years of age, the patient was admitted to The Second Xiangya Hospital of Central South University due to polydipsia, polyuria, and weakness of lower extremities. The 24-h urine output was about 4,000 ml, and the blood pressure was normal (90/50 mmHg). Laboratory tests showed normal serum creatinine level (57.8 umol/l), while low levels of serum sodium (110.4 mmol/l), potassium (2.02 mmol/l), chlorine (83.5 mmol/l) and phosphorus (0.45 mmol/l) were reported . Serum cSymptoms such as polydipsia and polyuria were significantly improved after treatment. The urine protein levels fluctuated from + to 2+, and serum potassium level was maintained at a normal low level. In order to control urinary protein, the patients were treated with prednisone and mycophenolate mofetil in 2015. However, despite medical interventions, the patient developed chronic kidney disease stage 4 at 13 years of age. To determine the pathological condition of the kidney, a renal biopsy was performed in 2016. Light microscopy of renal tissue showing focal segmental glomerulosclerosis and renal interstitial fibrosis. Electron microscopy of renal tissue showing mild glomerular lesion, no parabulbar organs, renal tubular epithelial edema and interstitial fibrous hyperplasia. Ultrasonography of our patient's in 2020 showed diffuse parenchymal lesions of both kidneys and multiple cysts in both kidneys.CLCN5 gene c. 941C > T mutation (p.S314L), with the mother being a heterozygous carrier at this site. No mutation was detected in the pathogenic gene of Bartter syndrome. The patient was finally diagnosed with Dent disease 1.Although the patient was initially diagnosed with Bartter syndrome, the symptoms were not typical. First, there was no obvious metabolic alkalosis and the patient had long-standing proteinuria. Second, most patients with Bartter syndrome have normal renal function and good prognosis , while oCLCN5 gene encoding voltage-gated chloride channel protein 5 (ClC-5), while the mutation point of Dent disease 2 is located in the OCRL gene encoding an inositol polyphosphate 5-phosphatase, which is also the pathogenic gene of Lowe syndrome  thiazide diuretics can significantly reduce urinary calcium levels, however, there are also some side effects, such as severe dehydration and hypokalemia . There iAbout 30% to 80% of patients with Dent disease develop chronic kidney disease at the age of 30–50 . While tIn conclusion, for patients with proteinuria whose clinical manifestations are not typical and therapeutic effects are not ideal, genetic testing and evaluating the dosage of low molecular weight urinary proteins are recommended to reduce unnecessary harm to patients.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.Written consent was obtained from the patient's family for the publication of the case report.QC was the first-year resident and wrote the manuscript. YC was the attending physicians that participated in the care of the patient. LX and JL collected the patient's data. XW analyzed and interpreted the patient's data. 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.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.


Multiple sclerosis (MS) is a challenging and disabling condition, predominantly affecting individuals in early adulthood. MS affects the physical, cognitive, and mental health of persons suffering from the disease as well as having a great impact on their financial status and quality of life. However, there is a lack of systematic approach toward assessing the socioeconomic consequences of MS. Our objective was to systematically review analytical observational studies investigating the socioeconomic consequences in persons with MS with different levels of physical disability and cognitive function. We conducted a systematic review on socioeconomic consequences of MS with a focus on employment-, income-, work ability-, and relationship-related outcomes in persons with MS with special focus on disability and cognition. Additionally, the educational characteristics were examined. From 4,957 studies identified, 214 were assessed for eligibility and a total of 19 studies were included in this qualitative assessment; 21 different outcomes were identified. All identified studies reported higher unemployment, higher early retirement, and higher risk of unemployment in relation to higher physical disability. Also, cognitive function was found to be a predictor of employment (unemployment). The studies pointed out significant correlations between greater disability and lower earnings and higher income from benefits. A study found the same correlation in relation to cognitive function. The studies reported higher work disability in relation to higher physical disability and lower cognitive function. In conclusion, this systematic review summarizes the pronounced differences in various socioeconomic outcomes between patients with MS with regards to their physical disability and cognitive function. In addition, we identified a lack of studies with longitudinal design in this field that can provide more robust estimates with covariate adjustments, such as disease modifying treatments. Approximately 2.8 million people worldwide are affected with multiple sclerosis (MS)—a chronic demyelinating and neurodegenerative disease of the central nervous system with increasing prevalence , 2. MS pWithin the MS population, the spectrum of disability ranges from essentially unaffected to highly disabled. The most common measure utilized to assess physical disability is the Expanded Disability Status Scale (EDSS) , which iCognitive decline is recognized as a prevalent and debilitating symptom of multiple sclerosis . MeasuraPreviously, we summarized the pronounced differences between patients with MS and the general population, e.g., 15–30% lower employment, lower earnings and higher social benefits, higher absenteeism and presenteeism proportions, and higher work disability  among persons with MS . Howeverhttps://www.crd.york.ac.uk/prospero/), ID: CRD42020182085. Published studies on socioeconomic consequences of MS were systematically searched in Medline (Ovid), Embase, and Web of Science (Clarivate). A combination of relevant keywords to construct the search strategy, such as MS, socioeconomic outcomes, employment, income, earnings, benefits, disability pension, sickness absence, sick leave, and marital status, was used  statement . The stuhttps://rayyan.qcri.org/welcome) was used to facilitate the review process. Consensus between the two reviewers was used to resolve any disagreement.One author (AK) conducted the first screening of potentially relevant records based on titles and abstracts, and two authors (AK and VDK) independently performed the final selection of included studies based on full text evaluation against the eligibility criteria. Rayyan, a web and mobile app for systematic reviews ;Study design: analytical observational studies  , excludiInitially 4,957 studies were identified  and 4,78Three reviewers  independently assessed the quality of the included studies focusing on such study characteristics as study design , data sources (registries and databases prioritized over surveys and interviews), timeline, and the size of the study population. Accordingly, on the basis of the aforementioned study characteristics, each study was evaluated by points, whereby this is reflected in the final grading . Consensus was used to resolve any disagreement. The quality assessment was performed ensuring that at least one of the reviewers is not among the co-authors .Our aim was to broadly review the studies with regards to the socioeconomic outcomes analyzed, thus we applied a comprehensive search strategy to include all possible operationalized definitions. In total, 21 different outcomes were identified. We grouped the outcomes into the categories of employment-, income-, work ability-, and relationship-related outcomes, also mapping the reported indicators for each of the included study . AdditioA total of 19 studies were selected for inclusion into this systematic review of socioeconomic consequences of MS in relation to physical disability and cognitive function. Of them, 18 studies provided data from their respective countries, and one study was multi-center with the results from 16 European countries. The majority of studies (12 of 17) were conducted in Europe ; four studies—in North America (three in USA and one in Canada); one-study in Hong Kong and one in New Zealand.With respect to study design, three were cohort studies and 16—cross-sectional studies; four studies analyzed data from the registries, whereas 14 studies included data from surveys, questionnaires, or interviews . The selected studies are summarized in the We identified 12 studies that investigated the employment-related outcomes: nine in relation to physical disability  and threIn addition, three studies explored early retirement due to disease  pointing to a higher proportion among those with higher physical disability level, e.g., 75% among those with EDSS 7–9.5 in the United Kingdom , and 69.ORs) for employment/unemployment. With regards to unemployment, in New Zealand adjusted OR for unemployment was 2.05  for those with EDSS 3–6, and 9.32  for those with EDSS > 6, when compared with those with EDSS <3  for those with EDSS >3  for those with EDSS > 6 when compared with those with EDSS 0–3; and OR for employment in Hong Kong was 0.071  for those with EDSS >5.5 , while the risk ratio for receiving benefits was 1.93 .In total, five cross-sectional studies investigated income-related outcomes; four of them with regards to physical disability , and oneSimilarly, the other two studies reported an increasing proportion of persons with MS on benefits with increasing physical disability: from 40% receiving disability related income at EDSS 0–4.5 to 91% at EDSS 7–9.5 in the United Kingdom  and fromTo summarize, the studies pointed out significant correlations between greater disability and lower earnings and higher income from benefits.CI, 1.29–1.49) and 0.81 , respectively, when compared with the persons in the lowest quartile.With regards to the cognitive function and income among persons with MS, a Swedish study  thoroughCI, 1.72–3.39) and 2.61 , respectively, at EDSS 7.9–5 when compared with those with EDSS 0–3.5. Whereas, Sundstrom et al.  and 150 , respectively, at EDSS >6 when compared with those with EDSS 0–3.5. Another study in the United States , 3229, 3d States  investigCI, 1.42–2.10). At 3-year follow-up this estimate was similar . In addition, another Swedish study   .Information on the formal education level was available and extracted from the three included studies , 9 out oAs expected, when comparing persons with MS with the highest cognitive function in the fourth quartile (QIV) to those with the lowest cognitive function in the first quartile (QI), a smaller proportion had a lower educational level: 2.5 vs. 15.8%, respectively ; and 42.In this systematic review of the socioeconomic consequences of MS, we summarized findings of differences between persons with MS with regards to the physical disability and cognitive function in terms of employment, income, work ability, family status, and education. All identified studies reported higher unemployment, higher early retirement, and higher odds for unemployment in relation to higher physical disability. In addition, cognitive function was found to be a predictor of employment (unemployment). The studies pointed out significant correlations between greater disability and lower earnings and higher income from benefits. Besides, one identified study showed the similar results with regard to the cognitive functions. The studies reported higher work disability in relation to higher physical disability and lower cognitive function.Our results are in line with other studies that reported similar findings with regards to physical disability. For example, Findling et al.  reportedIn addition, Campbell et al.  and Lau This is in line with a study that showed employment status to be associated with the Processing Speed Test (adaptation of SDMT) , whereasOR for sick leave, IRR for work disability) instead of proportions.Among the strengths of our study is that we assessed a wide spectrum of socioeconomic outcomes. As listed in Due to this wide spectrum, it was not possible to assess the extracted information from the studies in a quantitative manner. In addition, the majority of the studies were cross-sectional in design. It is important to underscore that due to well-known limitations of cross-sectional designs, the correlations revealed in the studies may not necessarily be causative , may protect against cognitive decline, just as cognitive decline may contribute to unemployment in persons with MS). Given the chronic and progressive nature of MS, more studies with longitudinal approach are needed for more robust measures. Additionally, we were specifically looking into physical disability as assessed by EDSS and cognition as assessed by SDMT, however, there are many more various assessments and evaluations used in the clinical practice. Furthermore, the generalizability of the studies may be limited to countries with a similarly functioning labor market and welfare system. One additional aspect that can be explored further is comorbidity, as a study in Denmark found that both psychiatric and somatic comorbidity implied an increased risk of a low income 10 years after MS onset . A studyBy reviewing and summarizing the studies investigating the socioeconomic consequences, we illustrate how such outcomes can be used to study MS. The high correlation between EDSS and both earnings and benefits indicate that these could be used as proxies for disability in registry studies investigating factors of importance for MS progression . CognitiIn conclusion, this systematic review summarizes the pronounced differences in various socioeconomic outcomes between persons with MS in regard to their physical disability and cognitive function. In addition, we identified lack of studies with longitudinal design in this field that can provide more robust estimates with covariate adjustments, such as the disease modifying treatments.The original contributions presented in the study are included in the article/AK and JH conceived and planned the study. AK, VD, and JH defined the search strategy. AK conducted the first screening of potentially relevant records based on titles and abstracts. AK and VD independently performed the final selection of included studies based on full text evaluation. AK, VD, and SB independently assessed the quality of the included studies. AK drafted the manuscript. VD, SB, and JH reviewed and edited the manuscript. All authors contributed to the article and approved the submitted version.The study was financially supported by Biogen. Biogen courtesy reviewed the manuscript and provided feedback to the authors. The authors had full editorial control and provided approval to final content.AK is also employed by Takeda Pharma AB. VD has received financial support from Stockholm County Council; Biogen ; Novartis ; Merc . SB has received speaker's fee and had travel and conference expenses paid by Biogen. JH received honoraria for serving on advisory boards for Biogen and Novartis and speakers fees from Biogen, MerckSerono, BayerSchering, Teva, and SanofiGenzyme. He has served as P.I. for projects sponsored by, or received unrestricted research support from Biogen, SanofiGenzyme, MerckSerono, TEVA, Novartis, and BayerSchering. His MS research is funded by the Swedish Research Council and the Swedish Brain Foundation. The authors declare that none of the funders were involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.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.


Purpose: There is uncertainty as to which anticoagulant should be used in non-valvular atrial fibrillation (AF) with valvular heart disease. This systematic review and meta-analysis aimed to assess the efficacy and safety of direct-acting oral anticoagulants (DOACs) compared with warfarin in patients with non-valvular AF with valvular heart disease.Methods: We performed a comprehensive literature search using PubMed, Scopus, Embase, and Clinicaltrials.gov from the inception of databases up until August 2, 2021, and the search was updated and finalized on October 17, 2021. The intervention group was DOACs and the control group was warfarin. The primary outcome was systemic embolism and stroke (SSE), and the secondary outcome was major bleeding and intracranial hemorrhage. The pooled effect estimate was reported as the hazard ratio (HR) and odds ratio (OR).Results: There were 21,185 patients from seven studies included in this systematic review and meta-analysis. Stroke and systemic embolism were lower in patients receiving DOACs  compared with warfarin. The subgroup analysis on RCTs showed the significant reduction of SSE in the DOACs group . There was no significant difference in terms of major bleeding . Intracranial hemorrhage  were lower in the DOAC group.Conclusion: This meta-analysis indicates that DOACs were associated with a lower risk of SSE and intracranial hemorrhage compared with patients receiving warfarin. There was no significant difference between the two groups in terms of major bleeding. One of the most important complications of atrial fibrillation (AF) is a systemic embolism, mainly stroke. The risk can be mitigated by lifelong anticoagulation; however, anticoagulation predisposes patients to bleeding. Thus, long-term efficacy and safety are important to balance the risk and benefit of anticoagulation . Due to Recent studies compared the use of DOACs vs. warfarin in patients with non-valvular AF with valvular heart disease, aiming to resolve this issue. This systematic review and meta-analysis aimed to assess the efficacy and safety of DOACs compared to warfarin in patients with non-valvular AF with valvular heart disease.This systematic review follows the reporting guideline of the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA).We performed a comprehensive literature search using PubMed, Scopus, Embase, and Clinicaltrials.gov using the keywords “(rivaroxaban OR Xarelto OR dabigatran OR apixaban OR edoxaban) AND (warfarin OR vitamin K antagonist or coumadin) AND  AND ” from the inception of databases up until August 2, 2021, and the search was updated and finalized on October 17, 2021. Two independent authors screened the title and abstracts for eligibility based on the inclusion and exclusion criteria. Discrepancies that arose were resolved by discussion.The population was patients with non-valvular AF with valvular heart disease which is defined as the presence of AF in the absence of moderate-to-severe mitral stenosis or a mechanical heart valve, with concomitant aortic stenosis/regurgitation, tricuspid valve stenosis/regurgitation, pulmonic stenosis/regurgitation, mitral regurgitation, mitral valve prolapse, bioprosthetic valve, or valve repair. The intervention group was patients receiving DOACs and the control group was patients receiving warfarin. The primary outcome was systemic embolism and stroke (SSE), defined as systemic embolism and stroke as a result of cardiac embolism. The secondary outcome was major bleeding and intracranial hemorrhage.Studies that met the following criteria were included: (1) observational studies or randomized controlled trials evaluating patients with non-valvular AF and valvular heart disease, (2) comparing DOACs and warfarin, and (3) primary and/or secondary outcomes.Studies that met at least one of the following criteria were excluded: (1) non-research letters, (2) abstract-only publication, (3) reviews, and (4) commentaries or editorial. There was no language restriction imposed.Data extraction from the included studies was performed by two independent authors. The first author, study design, sample size, valvular involvement, age, sex, hypertension, diabetes, coronary artery disease, paroxysmal AF, CHADS2-VASc, HAS-BLED, and the primary and secondary outcomes were the data of interest. Discrepancies that arose were resolved by discussion.The Newcastle Ottawa Scale (NOS) for cohort studies was used to assess the observational studies and the Cochrane risk of bias assessment tool was used to assess the randomized controlled trials . The NOSThe primary outcome was SSE, defined as systemic embolism and stroke as a result of the cardiac embolism. The secondary outcome was major bleeding and intracranial hemorrhage. The pooled effect estimate was reported as hazard ratio (HR) and odds ratio (OR).P-values were considered statistically significant if they were below 0.05. The Cochran's Q-test and I2 statistics were used to assess heterogeneity; I2 values above 50% or/and p-value below 0.10 indicated statistically significant heterogeneity. The Funnel-plot analysis and Egger's test were used to assess publication bias and small-study effects. Review Manager 5.4 and STATA 16.0 were used to perform the meta-analysis.The HR and dichotomous data containing events per total of intervention and control group were extracted from each study. The log HR and standard error were then calculated and pooled using the random-effects inverse-variance method. The Mantel-Haenszel method was used to calculate the ORs using the random-effects model regardless of heterogeneity for dichotomous values. There were 21,185 patients from seven studies included in this systematic review and meta-analysis  5–11). . 11). DiThere were four studies by Breithardt et al., Briasoulis et al., Guimarães et al., and Strange et al. that compared rivaroxaban to warfarin. Two studies compared dabigatran to warfarin, namely Briasoulis et al. and Ezekowitz et al. There was one study by Avezum et al. that compared apixaban to warfarin. There were two observational studies (one propensity-score matched) and five randomized controlled trials. Out of five randomized controlled trials, one was open-label and four were double-blinded. The baseline characteristics of the included studies can be seen in p < 0.001; I2: 5%, p = 0.39] compared to warfarin , p = 0.35; I2: 63%, p = 0.07] , warfarin . The sub = 0.07] .p = 0.18; I2: 69%, p = 0.002] , p = 0.68; I2: 75%, p = 0.02].There was no significant difference in terms of major bleeding  . Intracr= 0.001]  were lowp = 0.420) for the pooled effect estimate of the primary outcome. The risk of bias is based on the Cochrane RoB tool can be seen in The funnel plot was asymmetrical  and the This meta-analysis indicates that DOACs were associated with a lower risk of SSE and intracranial hemorrhage compared to patients receiving warfarin. There was no significant difference between the two groups in terms of major bleeding. Thus, either DOAC or warfarin may be used depending on the patient's profile.Warfarin has been long known to reduce the risk of ischemic stroke in patients with atrial fibrillation. However, frequent monitoring and dose adjustment are needed and might be inconvenient and not suitable for the patient . RecentlThe underlying valvular pathology might also contribute to the disturbance of hemostasis. The change in platelet indices and turbulent flow contribute to the activation of the coagulation cascade –17. The While DOACs offer convenience, more predictable dynamics, and relatively less interaction with other drugs that the patient might be taking in comparison to VKA, the choice of using DOAC or VKA has to be tailored to each of the patients since the outcome of DOACs and VKA might differ depending on the patient's clinical profile and underlying valvular heart disease. The patient's kidney and liver baseline status might also be taken into consideration before prescribing DOAC or VKA. DOACs might offer slightly better outcomes related to thromboembolism and bleeding in comparison to warfarin , 21. MeaThe limitation of this meta-analysis is that only two studies were randomized controlled trials. The number of studies is too small to perform adequately powered meta-regression analysis, thus we cannot analyze whether a certain type of valvular heart disease or prosthetic valve will correspond to a better outcome with a certain anticoagulant. Due to inadequate data to perform subsequent analysis for specific types of valve disease, we cannot explore whether the types of valvular heart disease are the cause of heterogeneity in this study. In order to extensively analyze this aspect, more studies are needed and the meta-analysis of individual participant data is required. The weight among the studies included in this meta-analysis was not equal.This meta-analysis indicates that DOACs were associated with a lower risk of SSE and intracranial hemorrhage compared to patients receiving warfarin in patients with non-valvular AF with valvular heart disease. There was no significant difference between the two groups in terms of major bleeding. Thus, either DOAC or warfarin may be used depending on the patient's profile.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.JM: conceptualization, investigation, writing—review and editing, and supervision. RP: conceptualization, methodology, software, data curation, formal analysis, investigation, validation, writing—original draft, and writing—review and editing. WR: data curation, investigation, and writing—original draft. AW: investigation and writing—original draft. MA: investigation and writing—review and editing. 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.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.


Although previous studies have explored relationships between psychological abuse and social support, the pathways from psychological abuse to social support are still unclear, particularly in Chinese adolescents. This cross-sectional study attempts to delineate the prevalence of psychological abuse and explore the relationships between psychological abuse, social support, and self-esteem under the Chinese cultural context. Data were obtained from 417 Chinese adolescents aged 15–18 years old. All of them completed the Child Psychological Abuse and Neglect Scale, Rosenberg Self-Esteem Scale (SES), and Multidimensional Scale of Perceived Social Support (MSPSS). Results indicated that the prevalence of psychological abuse in Chinese adolescents was 25.66%, and psychological abuse was negatively associated with self-esteem and social support, respectively. Self-esteem partially mediated the relationships between psychological abuse and social support. Findings highlight the importance of improving self-esteem in survivors of psychological abuse for decreasing the negative effects on social support. Additionally, the significance and limitations of the results were discussed. Child abuse and neglect of all kinds have been an important worldwide public health issue for its high prevalence and negative outcomes e.g., . PsycholSocial support is a crucial factor for coping with stress in daily life, and high social support is a protective factor for later development. Some previous studies have explored the relationships between psychological abuse and social support e.g., , but thePsychological abuse, one subtype of child abuse and neglect, has been explored for several decades. Its prevalence has been an important topic for studies . Some stChina, as an ancient Eastern country, has a different culture from Western countries. This difference may contribute to different prevalence of psychological abuse. Some previous Chinese studies delineated the prevalence of psychological abuse. Hence, the results were inconsistent  delineate the prevalence of psychological abuse, (2) verify the relationships between psychological abuse and social support, and (3) explore the role of self-esteem in the relationships between psychological abuse and social support. Thus, we hypothesize that (1) the prevalence of psychological abuse in Chinese adolescents is higher than in Western countries, and that Chinese boys are more likely to get high scores on psychological abuse; (2) psychological abuse is negatively associated with social support; and (3) self-esteem mediates the relationships between psychological abuse and social support.n = 201). The mean age was 16.76 years (SD = 0.83), with a range of 15–18 years. Twenty-six-point-fourteen percent of them (n = 109) were an only child in the family. Regarding family income, 11.99% of participants were from families with monthly income below ¥1,000 ($149.07), with 39.09% falling between ¥1,001 ($149.21) and ¥3,000 ($447.21), 31.65% falling between ¥3,001 ($447.36) and ¥5,000 ($745.35), and 17.27% falling above ¥5,000.We recruited 450 students from two high schools in Jiangsu Province, China to attend the current study. We removed 33 questionnaires with more than 15% missing data. After this exclusion, a final total of 417 participants were included in the current study. Of those participants, 48.20% of them were girls  was given as compensation.My parents call my names when I did not expect it,” “My parents didn’t answer my questions”) using a 5-point scale (from 0 = very conformity to 4 = very inconformity) and ratings were averaged for a total score. High scores indicate high levels of psychological abuse and neglect. The CPANS has been used in some studies in Chinese adolescents , developed by lescents . The psyI think I have many good qualities) on a 4-point scale (from 1 = very conformity to 4 = very inconformity) and ratings were averaged to form a total score. High scores indicate high levels of self-esteem. The SES has been used in some studies among Chinese adolescents , developed by ts e.g., , and thets e.g., . Hence, my family can give me emotional help and support when I need) using a 7-point scale (from 1 = very strongly disagree to 7 = very strongly agree). The MSPSS has shown good reliability and validity under Chinese culture context in previous studies  = 1.79, p < 0.001, 95%CI = ]. Boys  reported higher psychological abuse than girls . Psychological abuse was negatively associated with self-esteem  and social support , and social support was positively associated with self-esteem . Descriptive statistics and correlations are presented in The prevalence of psychological abuse was 25.66% (107/417). Results of the independent-sample p < 0.001). The models also showed a good fit to the data  and social support , while self-esteem was positively associated with social support . Results of a bias-corrected percentile method showed that the 95% confidence intervals (CI) of indirect effects was  and that the 95% CI of direct effect was . Self-esteem partially mediated the relationships between psychological abuse and social support in Chinese adolescents. In this mediation model, the rate of total mediation effect to total effect was 28.57% (0.10/0.35).The bootstrapping method was used to estimate the mediating effects. In this mediation model , psycholThe present study delineated the prevalence of psychological abuse and explored the pathways from psychological abuse to social support under the Chinese culture, which may broaden the scopes of psychological abuse in Chinese samples. Results showed that the prevalence of psychological abuse was 25.66%, and boys got significantly higher scores on psychological abuse than girls. Moreover, psychological abuse was negatively associated with social support and self-esteem. Furthermore, self-esteem partially mediated the relationships between psychological abuse and social support in Chinese adolescents.Results showed that the prevalence of psychological abuse was higher than in high-income countries . This waMoreover, the results showed that male adolescents were more likely to get high scores on psychological abuse than female adolescents, which is in line with our hypothesis and with some previous studies . InconsiThese findings suggest that psychological abuse may be an important issue among Chinese adolescents. Therefore, governments and communities should provide some information about positive parenting. For example, free reports about positive parenting strategies  for parents may be provided to decrease the prevalence of psychological abuse.Meanwhile, the results showed that, consistent with previous studies, psychological abuse was negatively associated with self-esteem and social support . AccordiFurthermore, results showed that self-esteem plays a partially mediating role in the relationships between psychological abuse and social support, which is in line with our hypothesis. Individuals exposed to psychological abuse may only have a few interpersonal skills, which may cause a lack of support from others . In addiThese findings suggest that the levels of self-esteem may change the pathway from psychological abuse to social support. Governments and communities should provide some strategies for survivors of psychological abuse to overcome the influence of psychological abuse. For example, schoolteachers should pay much more attention to survivors of psychological abuse and give them positive feedbacks to improve their self-evaluations and self-esteem.Several limitations should be acknowledged in this study. Firstly, there are several types of self-esteem. The present study only discussed explicit self-esteem and therefore cannot give a whole view of the relationships between psychological abuse and self-esteem. Future studies need to verify the relationships between psychological abuse and other types of self-esteem. Secondly, adolescents may be psychologically immature or overconfident about their self-evaluation and esteem e.g., , which mThe present study delineated the prevalence of psychological abuse and explored the pathways from psychological abuse to social support under the Chinese culture context. Results showed that the prevalence of psychological abuse was 25.66% and that boys got significantly higher scores on psychological abuse than girls. Moreover, psychological abuse was negatively associated with social support and self-esteem. Self-esteem also partially mediated the relationships between psychological abuse and social support. These findings underscore the importance of increasing levels of self-esteem in interventions designed to improve that of psychologically abused adolescents’.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by the Zhejiang Normal University. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.CC designed the study, wrote and revised the manuscript, and guided the data analysis. SJ collected the data and did part of the data analysis, and wrote part of the manuscript. JJ collected the data and did part of the data analysis. 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.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 plasma AG had a satisfactory predictive ability for in-hospital mortality among AIS patients (areas under the receiver operating characteristic curve: 0.631). The plasma AG is an independent risk factor that can satisfactorily predict the in-hospital mortality among AIS patients.We aimed to investigate the association between the plasma anion gap (AG) and in-hospital mortality among patients with acute ischemic stroke (AIS). In total, 1236 AIS patients were enrolled using the Medical Information Mart for Intensive Care Database IV. Primary outcome was in-hospital mortality. The patients were divided into four groups according to AG category. The mean age and Charlson comorbidity index increased as the AG category increased. The fourth AG category was most related to the in-hospital mortality (hazards ratio (HR), 95% confidence interval (CI): 2.77, 1.60–4.71), even after adjusting for possible confounding variables . Moreover, intensive care unit mortality ( According to the report of the Global Burden of Disease Study 2017, stroke is the second leading cause of death and disability worldwide. The increased burden of stroke puts tremendous pressure on patients, their families, and society  − . Corrected AG was calculated using the equation of Figge–Jabor–Kazda–Fencl: corrected AG = observed AG + 0.25 ×  . The priCategorical variables were represented as numbers (percentages) and were compared using the Chi-square and Fisher exact tests. Continuous variables were described as means (standard deviation) and were compared using the Kruskal–Wallis test or one-way analysis of variance.We measured the linearity assessment of the AG value with the ICU and in-hospital mortality of patients with ischemic stroke with a restricted cubic splines model. The restricted cubic spline curve and univariate Cox-proportional hazards regression of the ICU and in-hospital mortality showed approximate linear regression . The patUnivariate and multivariate Cox hazards model analyses were performed to identify the association between the AG and ICU and in-hospital mortality. In model 1, the covariates were adjusted only for those that were unequal in the baseline characteristics. Model 2 included the adjusted variables, including model 1, and the clinically relevant factors such as vital signs and laboratory data. The results were expressed as the hazards ratio (HR) with a 95% confidence interval (CI). The risk factors for multivariate adjustment were selected as potential covariates for a poor outcome after ischemic stroke on the basis of prior knowledge. The logistic regression of the incidence of intracerebral hemorrhage was applied with the adjustments of models 1 and 2. The receiver operating characteristic (ROC) analysis was further drawn to evaluate the ability of the SIRS score, SOFA score, and AG to predict in-hospital mortality.p-values of less than 0.05 were used to denote statistical significance between two or more groups. Statistical analyses were performed using the MedCalc Statistical Software version 20.011 , Statistical Package for the Social Sciences , and R Version 4.0.1 (R Core Team (2020), R Foundation for Statistical Computing, Vienna, Austria).All comparisons were planned, the tests were two-sided, and A total of 257,366 medical records were reviewed, and 50,048 patients were admitted to the ICU. We excluded 378 patients receiving tissue plasminogen activator or endovascular mechanical thrombectomy and 48 patients without the value of anion gap. In total, 1236 patients with ischemic stroke were included in the study . Table 1p < 0.001). In model 1, the highest AG was associated with an increased risk of in-hospital mortality after adjusting for age, sex, vital signs, and comorbidities . In model 2, after adjustments for model 1 and the additional clinically relevant factors, a highest AG remained significantly associated with an increase in in-hospital mortality rates . We had corrected the influence of hypoalbuminemia among critically ill patients for the AG, and a positive trend was also noted ICU mortality  was calculated. The AUC was 0.631 (95% CI: 0.603–0.658) for the AG, 0.644 (95% CI: 0.616–0.670) for the SIRS score, and 0.628 (95% CI: 0.600–0.655) for the SOFA score A. The prThis study is to clearly reveal the potential linear trend between the plasma AG and in-hospital mortalities. This large retrospective cohort study of critically ill patients with acute ischemic stroke has demonstrated that patients with an elevated plasma AG are more likely to have poor clinical outcomes and a higher risk of in-hospital mortality, even after adjustments for traditional cerebrovascular risk factors. Although the plasma AG may improve the discrimination and reclassification of patients at risk, the predictive ability of AG regarding the risk of in-hospital mortality is only satisfactory, even in the model that corrected the influence of hypoalbuminemia. However, an inexpensive clinical indicator can be readily used by physicians to evaluate the prognosis among stroke patients.Stroke remains one of the leading causes of death and disability worldwide, and there are presently no appropriate prognostic biomarkers for physicians early in the course of the disease. Recently, several studies have focused on the clinical value of the plasma AG, which is obtained from the concentration of plasma sodium, chloride, and bicarbonate, to predict the risk in critically ill patients. In a retrospective study that analyzed 6868 hospitalized patients, Lolekha et al.  showed tData regarding the association between the plasma AG and ischemic stroke are scarce; however, some evidence shows that it is, at least, partially causal . An incrBlood gas analysis, as an alternative means to evaluate acid–base disturbances, might also predict prognosis in critically ill patients; however, blood gas analysis can be influenced by a compensatory respiratory alkalosis. The plasma AG is relatively independent of acute respiratory changes and a sensitive tool of metabolic derangement . FurtherIn a meta-analysis, Glasmacher et al.  includedThe main strength of our study was being a large and diverse population study design using real-world data. However, the results should be elucidated in the context of the following limitations. First, this was a retrospective study, and the diagnosis of ischemic stroke was according to the administrative diagnosis codes. Although the first sequence of diagnosis was used in this study, there remained the possibility of misclassifications that could cause false associations. Second, hypoalbuminemia was commonly seen in critically ill patients, which might result in the underestimation of the AG. Thus, we used the equation of Figge to correct the AG, and the results showed a similar trend for the in-hospital mortality. Third, because of the nature of the MIMIC database, we lacked some potential variables such as the National Institute of Health Stroke Scale and the subtypes of ischemic stroke (TOAST classification). Therefore, we used other severity scoring systems such as the SIRS and SOFA scores as well as the simplified acute physiology score III to assess the severity of stroke. No long-term follow-up events were provided from the MIMIC-IV database, so the functional outcomes and poststroke disposition of patients were unknown. Finally, the study might have selection bias, as it was a single-institution study. Some stroke patients might not be referred from other hospitals because of a narrow window time for reperfusion therapy after symptom onset of ischemic stroke and the evolution of stroke severity. These high-risk patients might not have been enrolled in our study. Furthermore, the patients with a low severity of ischemic stroke might be admitted to the general ward and not involved in our analysis. Hence, to investigate the external generalizability, further studies are necessary.The AG was an independent risk factor for in-hospital mortality and was associated with adverse clinical outcomes among ischemic stroke patients. According to our results, an AG of ≥17 mmol/L had a satisfactory ability to predict a poor prognosis. However, to confirm the AG’s role as a clinical indicator for the prognosis of ischemic stroke patients, more prospective case-control studies are warranted.