Bone is crucial for supporting the body, protecting other organs, providing minerals, and secreting hormone to regulate other organ’s function. Bone disorders result in pain and disability, severely affecting human health, reducing the quality of life and increasing costs to society. With the rapid increase in the aging population worldwide, bone disorders have become one major disease. As a result, efficacious therapies of bone disorders have become the focus of attention worldwide. Mesenchymal stem cells (MSCs) have been widely explored as a new therapeutic method for numerous diseases. Recent evidence suggests that the therapeutic effects of MSCs are mainly mediated by their extracellular vesicles (EV). MSCs-derived extracellular vesicles (MSCs-EV) is indicated as a novel cell-free alternative to cell therapy with MSCs in regenerative medicine. Here, we review the current knowledge of EV and highlight the application studies of MSCs-EV in bone disorders by focusing on osteoarthritis (OA), rheumatoid arthritis (RA), osteoporosis (OP), and bone fracture. Moreover, we discuss the key issues and perspectives of MSCs-EV as a clinical therapeutic strategy for bone diseases. Bone, one most important supportive structure of human body, plays important roles in supporting body, protecting other organs, providing minerals and secreting hormone to regulate other organs. Bone disorders have a serious impact on human health and have become common diseases among the elderly. Therefore, appropriate and effective treatment of bone diseases is one of the greatest concerns in the world today.Mesenchymal stem cells (MSCs) are multipotent fibroblast-like cells with the potential for self-renewal and multilineage differentiation. Moreover, MSCs possess the ability to migrate to the damaged sites, where they secret anti-inflammatory factors and growth factors to promote wound healing. Thus, MSCs have become a desirable cell source in regenerative medicine and immune therapy. MSCs transplant treatment (MSCT) is considered to be a promising therapy for a variety of human diseases and has drawn increasing attention. However, the direct use of MSCs for treating diseases faces many challenges, including genetic instability , loss ofRecent evidence suggest that MSCs exert their therapeutic capabilities primarily through paracrine secretion of particles, rather than a cellular manner . The secHere, we review the current knowledge of extracellular vesicles (EV) and MSCs-derived extracellular vesicles (MSCs-EV), and highlight the application studies of MSCs-EV for treatment of bone disorders by focusing on osteoarthritis (OA), rheumatoid arthritis (RA), osteoporosis (OP), and bone fracture. Furthermore, we discuss the key issues of MSCs-EV for clinical application.Exosomes are a type of EV and the term “exosome” was first adopted by There is a different classification of EV proposed by different literature, ranging from two to six major different EV types . HoweverAs particles naturally secreted from the cell, EV has been identified as vital mediators of paracrine communication  and demoDifferent type of EV is generated through different way and contains different cargos, which depends on the cell types and the physiological conditions. The biogenesis of exosomes is well-studied, which involves the exocytosis of multivesicular endosomes . GeneralAt present, the well-known mechanism of exosome generation is driven by the endosomal sorting complex required for transport (ESCRT), which consists of approximately 30 proteins that form four complexes  with associated proteins including vacuolar protein sorting-associated protein 4 (VPS4), vesicle trafficking 1 (VTA-1), and apoptosis-linked gene 2 (ALG-2)-interacting protein X (Alix) . They gi1 and Vesiclepedia2.Extracellular vesicles contain markers from the parent cells and therefore their subtypes can be identified and characterized. Specific markers in exosomes are mainly located at the membrane, including the tetraspanin family , major histocompatibility complex (MHC), and lipid raft such as Flotillin-1 . Moreoveg. Ultracentrifugation is suitable for large sample volumes, but not for small volumes because it is time-consuming, labor-intensive and requires expensive equipment  exposed on the EV surface. This approach is particularly useful when the protein expressed on the EV surface lacks a soluble counterpart  memnterpart ; (c) tranterpart ; (d) aconterpart ; and (f)nterpart .Characterization of EV is essential for determining their biochemical properties and biological functions. The characterization mainly includes the evaluation of the size, structure, surface biochemical markers, concentration and contents of EV. There are numerous approaches for characterizing different biochemical properties of EV. To detect EV biochemical markers, western blotting, flow cytometry, microfluidic-based technique and nanoparticle-tracking analyses (NTA) are normally used. EV components, including proteins, mRNA, miRNA, and lipid subsets can be detected by conventional test method such as western blotting, PCR and flow cytometry. As technology advances, high throughput transcriptomic studies have identified a wide range of mRNA and miRNA data sets based on microarray and next-generation sequencing (NGS) analyses leading to a comprehensive data classification. For detecting size and structure of EV, NTA, Tunable-resistive pulse sensing (TRPS), Dynamic-light scattering (DLS), Photon-correlation spectroscopy (PCS), Atomic-force microscopy (AFM), Transmission electron microscopy (TEM), Raman spectroscopy and Flow cytometry are used. Meanwhile, NTA and TRPS can be used to detect concentration.in vitro.MSCs, also known as mesenchymal stromal cells (MSCs), are multipotent fibroblast-like cells with the potential for self-renewal and multilineage differentiation . The MesMSCs reside in almost all post-natal organs and tissues such as bone marrow, adipose, liver, lung, spleen, and muscle . MSCs haWith the above characteristics, MSCs are commonly used in cell therapy for regenerative medicine and immunotherapy . MSCT haRecently, numerous studies demonstrate the therapeutic effect of MSCs is primarily mediated by the paracrine secretion of cytokines, growth factors and EV . MSCs-EVOver the years, of a wide array of bioactive molecules, MSCs secretions such as growth factors, cytokines and chemokines have been proved to play vital biological roles. Among these secretory products, none of them, by itself, can fully decipher the mechanism of MSCs . In 2009Previous studies have shown that the function of MSCs-EV may vary depending on the source of the MSCs, thus affecting the biological effects of MSCs-EV . Thus, MOsteoarthritis is the most common chronic joint disease around the world, with an incidence of 10–20% in the population over 50 years old. As the population ages and obesity increases, the incidence of OA is expected to double within the next 30 years . It has There is still currently no effective treatment for OA. Most treatments are applied to manage pain, stiffness and swelling to improve joint mobility, and joint replacement is the only option for treating the entire joint dysfunction. Although the current physiotherapy or pharmacological therapy can temporarily relieve the clinical symptoms, it is difficult to fully restore joint function and also has a high risk of instability and infection .The potential of MSCs to treat OA has been extensively studied . Recent Inflammation is an important factor in the onset and progression of OA . In OA p+ and CD8+ T cell subsets -exosomes (size of 104 ± 19 nm) and MV (size of 279 ± 94 nm) show great potential in anti-inflammatory and preventing degeneration processes in OA . Exosome subsets . In addi subsets . These f subsets . MSCs-ex subsets . CosenzaThe main pathology of early stage OA is the degeneration of chondrocytes, resulting in damage to articular cartilage. Metabolic and structural changes in articular cartilage play a major role in the initiation and progression of OA. MSCs-EV exert important therapeutic effect on OA by protecting cartilage from degradation and promoting cartilage regeneration, which is now the focus of clinical therapy.The efficacy of hESC-MSCs-exosomes  on cartilage repair was firstly reported in 2016 . After tSeveral key cargo components of MSCs-EV have shown important roles in mediating the therapeutic effects of MSCs-EV. MiRNAs, a large cargo of MSCs-EV , are ideIn addition to miRNA, a few lncRNAs have been found as main components of EV and to function as novel biomarkers and therapeutic targets for various diseases . ExosomaAs mitochondrial dysfunction is one important cause of OA  and MSCsArthritis is a chronic autoimmune disease involving joints. It is characterized by persistent inflammation of joints. In RA, auto-reactive T cells and B cells are activated because of defective immune regulation. These cells proliferate and differentiate into pathological T cells and plasma B cells, which produce auto-reactive antibodies, eventually leading to inflammation and degradation of joints . As mentin vitro, and alleviated arthritis in CIA mice in vivo. These findings indicate that EV facilitate the direct intracellular transfer of miRNAs and represent a potential therapeutic strategy for RA (Collagen-induced arthritis (CIA) is one of the most accepted animal models of RA for its capacity to simulate RA inflammatory symptoms clinically and biologically. y for RA .At present, only a few studies have reported the therapeutic effect of MSCs-EV on RA and the mechanism is unclear. As MSCs-EV play roles in immunoregulation and cartilage protection and regeneration, this may partially contribute to the therapeutic effect of MSCs-EV on RA. More research is necessary to prove the effects of MSCs-EV in treating RA.Osteoporosis is an age-related systemic bone disease characterized by reduced bone mass, destroyed bone microstructure, weakened bone strength, which causes increased bone brittleness and fracture risk. As one major disease worldwide, osteoporosis seriously affects people’s health and increases society’s financial burden. Therefore, efficient therapy of osteoporosis is one main concern of the world.MSCs-EV have been indicated as a novel therapeutic method for osteoporosis. Present studies demonstrate that MSCs-EV alleviate osteoporosis by activating several signaling pathways. Wnt/β-catenin signaling is a key pathway for bone development and homeostasis . The actCOL I, ALP, and VEGF, and promoted bone formation in vivo  rescues the fracture healing speed in CD9–/– mice and increases that in the wild-type mice, indicating the potential therapeutic role of MSCs-exosomes in fracture healing  have been found to promote bone regeneration by enhancing angiogenesis. MSCs-exosomes increased hMSC migration, induced mineral deposition and enhanced the differentiation potential of hMSCs into osteoblasts. In addition, MSCs-exosomes enhanced the expression of osteogenesis-related and angiogenesis-related genes, such as  in vivo . The CD9 healing . In addi healing . Further healing . They de healing . In a se healing . In a la healing . Compare healing . These fin vitro and in animal models , macular holes (NCT03437759) and acute ischemic stroke (NCT03384433)in vitro and in vivo studies reveal the efficacy of MSCs-EV in treating OA, RA, OP, and bone fracture. MSCs-EV may alleviate the pain, promote overall joint repair and regeneration in OA by suppressing inflammation, promoting cartilage repair and regeneration, and restoring joint homeostasis. They also show immunomodulatory function in RA by regulating the function of T lymphocytes and B lymphocytes and inhibiting angiogenesis via downregulating MMP14 and VEGF, exerting therapeutic effects on joint destruction of RA. Moreover, MSCs-EV improve the osteoporosis by promoting cell proliferation, osteogenic differentiation, and reducing cell senescence of BM-MSCs or osteoblast. Furthermore, the therapeutic effect of MSCs-EV is also observed in bone fracture healing. MSCs-EV orchestrate the process of osteogenesis and angiogenesis to enhance fracture healing. Overall, the present findings suggest MSCs-EV as a new cell-free therapeutic method for bone disorders.MSCs-EV, lipid-bilayer spheroids, are characterized by possessing immunomodulatory and regenerative properties, similar to their producing cells. As MSCs-EV mediate both intercellular communication and the interactions with the cellular microenvironments, they have become fascinating to be a novel cell-free therapeutic strategy for treating diseases, including bone disorders. The currently The findings at current stage are very encouraging; however, further research is still needed to make MSCs-EV a routine clinical treatment for bone disease. There are several critical issues to consider, including: (1) The optimal source of MSCs. Since there are many sources of MSCs  and MSCs-EV produced by different cell source contain different cargos, it is important to determine the optimal source of MSCs, which may be bioengineered for producing MSCs-EV or their specific cargos according to specific requirements. (2) Standard methods for large-scale production and isolation of MSCs-EV. Because the culture condition affects the MSCs-EV production, the production methods of MSCs-EV should be optimized and controllable for large-scale and specific type of MSCs-EV production. Moreover, there is an urgent need to develop standardized methods for the isolation and purification of MSCs-EV, although establishing a universal isolation method is unlikely due to the complexity of MSC-EV. The isolation methods should not disrupt the structure and functions of MSCs-EV. (3) Methods for rapid and accurate quantification and characterization of MSCs-EV, which are critical for MSCs-EV clinical application. (4) Safe and effective approaches to deliver MSCs-EV to the body or to target sites for treatment. (5) The pharmacokinetics  of MSCs-EV in the body. (6) Safe and optimal dosage of MSCs-EV for treating different bone diseases. MSCs-exosomes execute synergetic biological functions through combinatorial effects together with their large diverse proteomic and RNA cargo . It has SLiu, XX, and SLia drafted the manuscript. ZC and YZ revised the manuscript. SLiu designed the figure. AQ and LH revised and approved the manuscript. All the 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.


The survey examined parent-reported impacts of COVID-19 on lifestyle , as well as current family food acquisition and eating behaviors . Descriptive statistics were calculated, incorporating sampling weights based on sociodemographics. In terms of COVID-19 impacts, parents reported increases in working from home, decreased work hours, and increased child care and instruction, with most children attending school or receiving care at home. Parents reported increased home cooking and online grocery shopping; only 33% reported increased take-out or delivery from restaurants. About half of parents reported that their child dined at restaurants, 62% reported getting take-out, and 57% reported delivery from restaurants at least 2–3 times per month. About half viewed dining at restaurants as safe, while take-out and delivery were seen as safe by around three-quarters. Approximately two-thirds reported recent food insecurity. These nationally-representative results illustrate possible longer-lasting shifts in family life, with the potential to impact health and well-being. Sociodemographic differences and research and policy implications are discussed.Evidence of short-term impacts of the coronavirus disease 2019 (COVID-19) pandemic on family life is emerging. Continued research can shed light on potential longer-term impacts. An online survey of U.S. parents with 4- to 8-year-old children ( The coronavirus disease 2019 (COVID-19) pandemic caused sudden and drastic lifestyle changes across the globe. In the United States (U.S.), protection measures were implemented beginning in March 2020 to halt the spread of the virus, closing restaurants, businesses, schools, and child-care facilities around the country and sending more than 50 million children back to their homes to finish the school year . FamilieRecently published survey data suggest that the early months of the pandemic brought changes in many energy-balance-related behaviors. In the initial months of the pandemic, there were reported increases in sedentary behavior and less time spent on physical activity for both adults and children ,8,9. ThiPrior to the start of the pandemic, U.S. children had a notably poor diet quality, consumed few nutrient-dense foods such as whole grains, fruits, and vegetables, and frequently ate restaurant foods ,18. U.S.Taken together, emerging evidence suggests that the drastic lifestyle changes of the pandemic’s early months brought changes in energy-balance-related behaviors for children and families. However, little is known about whether these changes have persisted more than six months into the pandemic. A description of current behaviors can elucidate the extent to which COVID-19 may have longer-lasting impacts on families’ energy-balance-related behaviors and health. Therefore, in Fall 2020, we examined the following among a nationally representative sample of U.S. parents with at least one 4- to 8-year-old child: (1) parent-reported impacts of COVID-19 on various aspects of daily life, including food acquisition, physical activity, child care, and employment; and (2) families’ current food acquisition and eating behaviors, including preparation of meals at home, children’s consumption of restaurant foods in-person and via take-out and delivery, and factors affecting restaurant meal choices. n = 1000). Participants were recruited using the Harris Poll Online opt-in panel (https://theharrispoll.com/), which includes millions of respondents who have agreed to participate in survey research. To be eligible, individuals needed to be English-speaking, at least 18 years of age, a parent/caregiver (referred to herein as parents) with at least one 4- to 8-year-old child, and have internet access. Possible participants were sent a password-protected email invitation to participate in the survey. Invitations to participate in this study were sent to a stratified random sample identified as U.S. residents 18 years of age or older with at least one 4- to 8-year-old child in the household . Other survey items were adapted or created for this study as described herein. Overall, the main modification to existing items was to specify that responses should reflect experiences during the past two months where appropriate. Other minor modifications to existing items are described below.Parents reported their age, gender, height, weight, marital status, highest level of education, household income, employment status, race/ethnicity, and whether the household received any government benefits , which provides nutritional assistance to supplement food budgets, or Medicaid, which assists low-income individuals with health costs). Parents also reported characteristics of their 4-to-8-year-old child, including age, gender, race/ethnicity, and eligibility for free or reduced-price school meals. Additionally, they indicated who in the household was the most familiar with the child’s daily activities . A brief validated 2-item screen was administered to identify households at risk for food insecurity , specifyp < 0.0001).Parents were also asked a series of questions developed by the research team about the extent of current COVID-19 related protection measures in their town/city, including if mask wearing was mandated and whether there were restaurant-related restrictions. Children’s schooling and care in the last week  was also assessed. Parental stress during the previous month was measured using the short version of the validated Perceived Stress Scale (PSS-4) . ParticiParent-reported changes in daily life and energy-balance-related behaviors were assessed using questions adapted from The Epidemic–Pandemic Impacts Inventory (EPII), establishing who in the household was affected by changes related to care of, instruction of, and quality time with children, and care for other family members . ParentsParents were asked how frequently meals were prepared at home during the past two months with response options including 0–1 times per week, 2–3 times, 4–5 times, and more than 5 times per week . RestaurThree additional restaurant-related items were developed for the present study. Parents reported what was typically ordered for the child when ordering restaurant food for take-out or delivery: their own kid’s meal, their own adult meal, shared food with other family members, or other. Parents also ranked their top five reasons for deciding to order restaurant food for take-out or delivery and the top five reasons affecting their choice of restaurant from a list of options .Frequencies  and means and standard errors (for continuous variables) were calculated for demographic/contextual variables. Items from the PSS-4 were reverse-scored as appropriate and then summed, resulting in a composite score ranging from 0–16, with higher scores indicating higher stress. Frequencies  and means and standard errors (for continuous variables) were calculated to describe: (1) parent-reported impacts of COVID-19 on various aspects of daily life and energy-balance-related behaviors, including employment, child care and instruction, physical activity, screen time, grocery shopping, cooking, and ordering take-out or delivery; as well as (2) families’ current food acquisition and eating behaviors. These included: frequency of preparation of meals at home, children’s consumption of restaurant foods , perceived safety of restaurant foods, who chose children’s restaurant meals and types of meals chosen, and factors affecting children’s meal choices and restaurant choices. Analysis of factors affecting children’s meal choices were restricted to parents who reported playing a role in deciding the child’s meal order (determining it themselves or with the child), as those not playing any role in the decision would not be expected to know which factors contributed to the decision. p < 0.05. All analyses incorporated sampling weights, so that results were representative of U.S. parents with 4- to 8-year-old children. Sampling weights were based on parent age, sex, race and ethnicity, education, income, region, marital status, household size, and number of children under 18 years. Data were analyzed using SAS 9.4 .Given the potential for differential impacts of COVID-19, we also explored whether current food acquisition behaviors differed by sociodemographics. We tested models that considered parent age, sex, race/ethnicity, education, and family income as predictors of: the frequency of home cooking, dining out, take-out, and delivery, as well as the perceived safety of each mode of restaurant use. Linear regression models were used unless distributions of residuals violated normality assumptions, in which case outcomes were dichotomized, with logistic regression used to predict meaningful outcomes . Backwards deletion was used to arrive at final models, retaining independent variables that predicted outcomes at A majority of responding parents were married or living with their partner (83%), with a median of 2 children in the household. Most parents (95%) reported being a primary caregiver of the target child, indicated by reporting that they were the parent or guardian in the household who is the most familiar with the child’s daily activities, or that they and another parent or guardian were equally familiar. Despite variability in family income, reported food insecurity was very common among families over the past two months. More than two-thirds (69%) of parents met the criteria for food insecurity by reporting that they had often or sometimes felt that they might run out of food and not have money to purchase more (66%); or that it was often or sometimes true that the food they had purchased hadn’t lasted and they didn’t have money to purchase more (56%). In terms of current COVID-related protection measures, a majority of parents reported that masks were mandated in the city or town where they resided (90%), and that in most cases, at least some closures had been reversed, with very few (38%) or some (44%) businesses closed at the time of survey administration. About half of parents reported that restaurants were open for both indoor and outdoor dining at a reduced capacity, while approximately one-third (29%) reported restaurants in their town or city could only offer take-out or delivery. In many cases, changes to children’s schooling persisted: parents reported that 47% of children were attending school virtually, and 31% were being homeschooled, while 21% attended in-person elementary school, and 19% received care outside the home . Parents reported an average stress level of 7.2 (standard error of the mean (SEM) = 0.14) on the PSS-4′s 0–16 scale. Additional demographic and contextual variables are reported in Parents reported changes to employment as a result of the COVID-19 pandemic, including that one-third (38%) moved to working remotely (from home) while 14% lost their job permanently. One-third (30%) of parents also indicated that their job put them at an increased risk for getting COVID-19. Parent-reported impacts on employment appear in Parent-reported impacts of COVID-19 on energy-balance-related behaviors—physical activity, screen time, grocery shopping, cooking, and ordering take-out and delivery—appear in Recent food acquisition and eating behaviors are reported in p < 0.01). Being a female parent also predicted a lower frequency of the child consuming food at restaurants , as did lower income . Parent education was the only significant predictor of children’s frequency of take-out consumption in the tested multivariable models, such that parents with lower education levels reported less take-out . Lower parent education was also linked with less restaurant delivery , as were lower income  and non-Hispanic Asian race . Race and ethnicity was the main predictor of variability in the reported safety of restaurant use: using dummy-coded indicators of race/ethnicity, Hispanic , non-Hispanic Black , and non-Hispanic Asian  respondents were all less likely to view in-person dining as safe, as were respondents with lower education . Hispanic respondents were less likely than respondents in other race/ethnicity categories to report that restaurant delivery was safe as well . Other demographic factors were unrelated to perceived restaurant safety.In terms of individual differences in current food acquisition behaviors, parent gender was the only significant predictor of cooking at home in the tested multivariable models, with female parents cooking at home more than other respondents  and/or varying lived experiences as different demographic groups may occupy different spaces . Generally, a larger percentage of parents in the present study viewed take-out and delivery as safe, compared to dining-in, highlighting a need for more research on individual differences, as well as on these understudied modes of restaurant dining in the future. Convenience and taste were the primary reported reasons for take-out and delivery choices, and taste and nutrition were highly ranked reasons for child meal choices from restaurants overall. Surprisingly, cost was not one of the higher-ranked choices for children’s meal choices. Research prior to COVID-19 has shown that for many low-income families, cost is a dominant factor in meal selection, even after the decision to eat out is reached , while iLimitations of the present study include the use of a self-report measure, which can be subject to social desirability bias. Minor modifications to some existing survey items were made to fit with the aims of the present study . Furthermore, the short versions of some survey instruments were used . While demonstrations of the validity of these short forms are present in the literature, the long-form versions of these measures generally have superior psychometrics. In the present study, the PSS-4 had a relatively low Cronbach’s alpha, as observed in some prior research , suggestContinued surveillance can elucidate lasting shifts in behavior as a result of the pandemic and guide interventions to be safe, feasible, and relevant in the future. Nationally representative studies allow for generalizable conclusions, and examination of individual differences can facilitate targeted research and policy efforts to promote health and provide support to those most impacted. Research and policy efforts to address food insecurity are also of paramount importance.Key goals of the present study were to describe parent-reported impacts of COVID-19 and current family food acquisition and eating behaviors more than six months into the pandemic. Results suggest continuing impacts of COVID-19 in many areas  and a potential move toward normalcy in other areas  among some families, with some evidence of sociodemographic differences. Most parents reported that their child was consuming food from restaurants at least 2–3 times per month, with lower use of restaurants and lower reported perceived safety among some sociodemographic groups. These observations have implications for future research as the pandemic progresses, as well as intervention and policy efforts as scientists and policymakers consider the best ways to improve health and well-being among families in the COVID-19 era.


Results: The PIBW and BMI-for-age z-score improved during the first 6 months . The CIR (p = 0.015) and PIR (p = 0.004) increased during the study period. The baseline BMI and PIBW of the previous nasogastric tube feeding group were better than those of the oral feeding group . The BMI-for-age z-score, PIBW, CIR, and PIR improved in the hypertonic group . Conclusion: PEG tube feeding and active nutritional intervention improved the nutritional status of neurologically impaired children immediately after PEG insertion. The nutritional requirements might vary by the muscle tonicity.Aim: To evaluate the long-term effects of nutritional improvement following percutaneous endoscopic gastrostomy (PEG) tube feeding stratified by previous feeding method and to assess the impact of underlying muscle tone on the outcomes of the nutritional intervention. Methods: Neurologically impaired children who underwent PEG tube insertion and nutritional intervention provided by a pediatric nutritional support team were enrolled. We measured anthropometric variables, laboratory parameters, and nutritional intake at baseline, 6 months after PEG insertion, and the last visit. We evaluated the percent ideal body weight (PIBW), body mass index (BMI)-for-age  With advances in medical treatments, the survival of neurologically impaired children has increased. However, along with improved life expectancy, feeding problems are on the rise . OropharPercutaneous endoscopic gastrostomy (PEG) has long enabled enteral nutrition in children who are unable to meet their nutritional needs orally . Since mNutritional intervention is important, particularly in children with moderate to severe protein-calorie malnutrition. The pediatric nutritional support team (PNST) is a multidisciplinary team consisting of physicians, including pediatric gastroenterologists, neonatologists, surgeons, dieticians, pharmacists, and nurses. A pediatric gastroenterologist coordinates the team as a leader, and the PNST evaluates the nutritional status of every patient who needs enteral or parenteral nutrition and/or any patient who needs special nutritional support under consultation and suggests future nutritional plans to attending doctors. Since there are few studies on the nutritional effect of PEG tube feeding on such patients, we sought to evaluate the ability of PEG tube feeding to improve nutritional status and assessed the efficacy of the regular nutritional intervention by PNST. We compared the nutritional status, including improvement in the anthropometric variables, in the oral feeding group and nasogastric (NG) tube feeding group according to the previous feeding method and muscle tonicity (hypertonic or hypotonic).This longitudinal retrospective cohort study was conducted at Korea University Guro Hospital (KUGH) and investigated the nutritional outcomes of PEG tube feeding in neurologically impaired children. The changes in the anthropometric parameters and nutritional status were measured before and after PEG feeding tube insertion. The KUGH Institutional Review Board approved this study (2019GR0354), and the requirement for informed consent was waived, due to the retrospective nature of the study.Pediatric patients with neurological impairments who underwent PEG tube insertion between 2012 and 2018 at KUGH were eligible to participate. The exclusion criteria were (1) age > 20 years, and (2) a short follow-up period (<6 months). Each patient underwent at least three tests before PEG tube insertion, including a videofluoroscopy swallowing study, 24 h multichannel intraluminal impedance pH monitoring, and esophagogastroduodenoscopy (EGD), to assess the indications for PEG, in which a feeding tube was inserted using a pull-through or push-through technique.We analyzed the formatted medical records of the PNST at three time points: Immediately before PEG tube insertion (baseline), six months after PEG tube insertion (six months), and at the last hospital visit (last). The PNST evaluated the anthropometric parameters (height and weight) and laboratory tests  to check the nutritional status and general condition of the patients at every visit. The PNST calculated the patients’ nutritional requirements  and recommended an optimal nutritional plan if it was deemed insufficient. The PNST also recorded the following nutritional information: Anthropometric data, previously ingested food types, feeding route , the volume of food ingested daily, ingested calories and protein, laboratory tests, and recommended type and volume of the formula.In real practice, the PNST routinely monitored all children in the intensive care unit, those who were receiving enteral nutrition or total parenteral nutrition, and those who were referred by their physicians. The PNST members gathered at least once a week and performed additional monitoring of patients if needed. The pediatric neurologists requested the PEG tube insertion or the PNST suggested tube insertion after the evaluation.z-scores of height-for-age, weight-for-age, body mass index (BMI)-for-age (≥24 months of age), and weight-for-height (<24 months of age) using the 2017 Korea National Growth Charts [The ulnar length was measured to predict the patients’ height . Bodyweih Charts . The groh Charts  were useIn addition to gross motor function evaluation, the modified Ashworth scale (MAS) was used to evaluate the patients’ muscle tone .z-score divided by the World Health Organization growth standard as follows: Above 3, obese; above 2, overweight (overnutrition); above −2, normal; between −2 and −3, wasted ; and below −3, severely wasted  [z-score, the nutritional status of children under 24 months old was assessed as wasted (weight-for-height z-score below −2), normal (between −2 and 2), or overweight (over 2) [Malnutrition was assessed according to the range of BMI-for-age trition) . Waterlotrition)  was usedtrition) : Underwe(over 2) .z-score below −2 as the malnutrition group. The PNST recommended the amount of feeding formula based on the Schofield equation [The PNST evaluated the current nutritional status and calculated the nutritional requirements based on anthropometric variables and laboratory test results. The nutrition level was divided into four stages by severity: Obese, well-nourished , moderately malnourished (wasted), and severely malnourished (severely wasted) . The nutequation  and the equation .U test. p-values < 0.05 were considered statistically significant. Analyses were performed using SPSS 24.0 for Windows .The differences in data were examined using the Wilcoxon signed-rank test, and the differences between the oral feeding group and the NG tube feeding group were evaluated using the Mann–Whitney Thirty patients underwent PEG tube insertion during the study period, of whom 12 were excluded for the following reasons: Five children from secondary hospitals who came to our hospital for PEG insertion before returning to the secondary hospital following the procedure and seven children aged > 20 years from the baseline. z-score of the 2017 Korea National Growth Chart [z-score, and they maintained their well-nourished status during the study period.According to the BMI-for-age th Chart , all 16 p = 0.009), PIBW , and height-for-age z-score  improved significantly at the 6-month and last visits ) and then to 85.7% at the last visit . The protein intake increased from 50.1% to 84.0% ) at the 6-month visit and then to 90.0%  at the last visit.Both caloric and protein intake increased significantly after PEG tube insertion . The calz-score, BMI-for-age percentile, and PIBW of the NG tube feeding group were significantly better than those of the oral feeding group  at baseline and 6-month visit. The median BMI z-score of the oral feeding group was −4.55 , that of the BMI percentile was 4.64 , and that of the PIBW was 65.19 . The median BMI z-score of the NG tube feeding group was −1.13 , that of the BMI percentile was 30.93 , and that of the PIBW was 91.6   .The baseline median CIR of the oral feeding group was 43.55 , while that of the NG tube feeding group was 62.5 . The baseline median PIR of the oral feeding group was 50.12 , while that of the NG tube feeding group was 55.68 . There were no significant differences in baseline nutrition between the two groups.p = 0.01 for CIR; 95% CI: 15.67–70.01, p = 0.02 for PIR). The increase in nutritional intake in the oral feeding group was better than that in the NG tube feeding group   .p = 0.02; during the study period: 95% CI: −0.18–24.45, p = 0.05) and PIR  were continuously improved during the study period. The BMI-for-age z-score of the hypertonic type group was also increased at the 6-month visit . There were statistically significant increases in BMI-for-age percentile , height-for-age z-score , and CIR between the 6-month visit and the last visit . In the hypotonic group, all anthropometric parameters, except height-for-age percentile and height-for-age z-score, and nutritional data improved without statistical significance.We compared the parameters according to the patients’ muscle tonicity (hypertonic vs. hypotonic). Nutritional support, including enteral feeding, helps solve the nutritional deficiencies of neurologically impaired children. The body composition parameters, including anthropometric variables, muscle mass, bone density, and fat deposition of these patients are reduced ,25,26; tIBW or optimal bodyweight  can be uA previous study reported that the anthropometric parameters of children with CP aged 5 months to 17 years were improved 6 and 12 months after PEG tube insertion without serious complications , while az-score, and PIBW were improved, and the PIBW reached almost 100% at the 6-month follow-up visit. However, the changes in anthropometric parameters were minimal after six months. This finding implies that most of the catch-up growth was achieved in the first six months; thus, we should focus on nutritional care during this period since it appears to be important for the overall outcomes. One child became obese after the intervention period; it can be assumed that this is because individualized nutrition guidelines for different disease entities have not yet been developed. Therefore, continuous nutritional support is important to maintain the patients’ nutritional status.To the best of our knowledge, this is the first study with a follow-up period of longer than 12 months  to evaluate the anthropometric and nutritional effects after PEG tube insertion. We found that children achieved most of the catch-up growth and nutritional correction in the six months following PEG tube insertion. Weight-for-age, BMI-for-age z-score, and PIBW of the NG tube feeding group were better than those of the oral feeding group. The oral feeding group increased caloric intake during the first six months after PEG tube insertion. Nutritional intake of the NG tube feeding group was increased without statistical significance; thus, we assume that children with NG tube feeding would not be affected by switching to a PEG tube. This result implies that PEG tube feeding is superior to NG tube feeding to provide stable nutritional support. Moreover, NG tube feeding can cause complications, such as gastrointestinal bleeding and aspiration. Indeed, seven of our 10 patients with NG tubes experienced bleeding ulcers, while the remaining three had aspiration problems prior to PEG insertion. We can assume that these complications prevented their caregivers from actively feeding the patients.The baseline BMI-for-age percentile, An Asian cultural background makes parents reluctant to subject their children to invasive procedures, such as NG tube placement, and a considerable number of parents in our study had refused PEG tube insertion for a long time. This repulsive emotion has a tendency to worsen malnutrition and delay the treatment of the underlying disease. In our study, two children under 24 months were maintained a normal or overweight status; this may be due to the short duration of diseases and earlier intervention and suggests that earlier nutritional intervention can prevent malnutrition. Considering previous studies demonstrating the improved quality of life of caregivers ,42,43 anz-score and PIBW in the hypertonic group improved significantly after PEG tube insertion, but did not improve in the hypotonic group despite similar increases in nutritional intake. Since the number of hypotonic children was small, we could not demonstrate statistical significance. To the best of our knowledge, this is the first study to show different nutritional improvement according to the muscle tonicity after PEG tube feeding. A previous study on hemiplegic CP of asymmetric growth between the affected and unaffected sides [Another interesting result was that the BMI for-age ed sides  reporteded sides . Hypertoed sides , making In comparison with that after the nutritional evaluation using growth curves for CP, the poor nutritional status was overly exaggerated when our patients were assessed against the 2017 Korea National Growth Charts ,16, whicThe laboratory findings did not provide significant nutritional information during the study period, which demonstrated that the assessment of macronutrients using laboratory tests would not support the nutritional status of children with neurologic impairments. The ESPGHAN recommends micronutrient assessment  . VitaminThis study had several limitations. It was a retrospective study with a small number of patients. In the future, a large-scale study, including more detailed micronutrient data , are needed to fully validate our findings.When a child’s nutritional intake is insufficient, PEG tube insertion should be actively encouraged to ensure adequate nutritional support, even if he or she can eat orally. This must be explained to caregivers and physicians alike. Regular intervention by the PNST is important to ensure adequate nutritional support for children. In the future, the development of a growth chart for neurologically impaired children according to the degree of rigidity is required to ensure adequate nutritional support for this population. The findings of the current study might contribute to establishing individualized nutritional plans for children with neurological disabilities.


Multi-modality image fusion provides more comprehensive and sophisticated information in modern medical diagnosis, remote sensing, video surveillance, etc. Traditional multi-scale transform (MST) based image fusion solutions have difficulties in the selection of decomposition level, and the contrast loss in fused image. At the same time, traditional sparse-representation based image fusion methods suffer the weak representation ability of fixed dictionary. In order to overcome these deficiencies of MST- and SR-based methods, this paper proposes an image fusion framework which integrates nonsubsampled contour transformation (NSCT) into sparse representation (SR). In this fusion framework, NSCT is applied to source images decomposition for obtaining corresponding low- and high-pass coefficients. It fuses low- and high-pass coefficients by using SR and Sum Modified-laplacian (SML) respectively. NSCT inversely transforms the fused coefficients to obtain the final fused image. In this framework, a principal component analysis (PCA) is implemented in dictionary training to reduce the dimension of learned dictionary and computation costs. A novel high-pass fusion rule based on SML is applied to suppress pseudo-Gibbs phenomena around singularities of fused image. Compared to three mainstream image fusion solutions, the proposed solution achieves better performance on structural similarity and detail preservation in fused images. Image fusion generates a composite image via integrating the complementary information from multiple source images in the same scene. The input source images in an image fusion system can be acquired either from various kinds of imaging sensors or from one sensor with different optical parameter settings. So the fused image as output is more fit for human visual perception and machine processing than any single source image. Image fusion techniques have been widely used in computer vision, surveillance, medical imaging, remote sensing, and so on .Pixel-level fusion algorithms are mainly categorized as spatial domain and transform domain based solutions . SpatialBased on quad-tree structure and morphology, I. De proposed a novel image fusion algorithm . M. BaghPyramid-based image fusion algorithm is widely used in the transform-domain method. The Laplacian pyramid was used in the multi-scale decomposition of the image, and after that the corresponding scales were merged to form the fused image . Du presCompared to conventional pyramid-based algorithms, wavelet-based transform methods not only contain more temporal and frequency features, and multi-resolution properties, but also achieve good performance in fused results. Mallat first applied wavelet-based transform to image fusion . In receAs a novel theory of image representation, sparse representation (SR) addresses the natural sparsity of signal, according to the physiological characteristics in the human visual system. SR is a transform-based approach, which is widely used in image classification ,18, imagAn SR-based fusion framework was proposed and a corresponding dictionary for SR was established by discrete cosine transform (DCT). Based on group sparse-representation, Li introduced the de-noising method into medical image fusion . HoweverThe source image can be described by combining the sparse linearity in sparse representation of atoms selected in an over-complete dictionary. The salient information of source images can be represented by only few non-zero elements in sparse coefficients, because the obtained weighted coefficients are sparse. Based on a joint patch clustering, an efficient dictionary learning method was proposed for multi-modality image fusion . Only a However, conventional SR-based image fusion methods have the following defects. (1) The fine details of original images such as textures and edges are often smoothed. The reconstructed result is not close to the input signal because all fine details may not be sufficiently represented by dictionary. (2) The consistence of gray in fused image may be caused by the Max-L1 rule, when the original image is captured by different imaging methods. In the past few years, many approaches, such as SR-based and MST-based methods, have been proposed to improve the fusion performance. An image fusion framework that integrates the complementary advantages of MST and SR (MST-SR) was proposed for multi-modality image fusion . It overIt decomposes source images into high- and low-pass bands, and applies inverse NSCT to the merged coefficients to obtain fused image. With multi-scale, multi-direction and shift-invariant features, NSCT can suppress pseudo-Gibbs phenomena effectively.It uses PCA-based dictionary learning in the fusion of low-frequency coefficients. It reduces the dimension of learned dictionary and computation time. At the same time, it effectively improves the detailed performance and accuracy of the fused image.It utilizes MAX-SML to fuse high-frequency coefficients. It selects the coefficient with a large SML value as the fusion coefficient. It not only suppresses pseudo-Gibbs phenomena around singularities of the fused image, but also improves the visual quality.The key contributions of this paper can be elaborated as the following three points:The rest of this paper is organized as follows: Based on NSCT multi-scale transformation, the proposed NSS fusion framework is shown in NSCT Decomposition: It performs a given NSCT on two original images Low-pass and High-pass Decomposition:Low-pass Decomposition: It iterates vector generation and sparse representation process for all source image patches High-pass Decomposition: It merges high-frequency component NSCT Reconstruction: It does NSCT inversely on There are three main steps of the proposed solution; they are as follows:Based on contourlet transform (CT), it proposes nonsubsampled contourlet transform (NSCT) with time shift invariance and direction selectivity. Compared to conventional MST fusion methods, each sub-band image decomposed by NSCT has the same size as the source image, which is easier to use for image fusion.CT employs Laplacian Pyramid (LP) and Directional Filter Bank (DFB) in multi-scale and direction decomposition respectively. Based on Nonsubsampled Pyramids Filter Bank (NSPFB) and Nonsubsampled Directional Filter Bank (NSDFB), the proposed NSCT shown in NSPFB is a two-channel Nonsubsampled Filter Bank (NFB), which is used by NSCT. It removes up- and down-samplers from LP, and then does upsampling accordingly. For multi-scale property, it does not need additional filter design.j-stage support region low pass filter is j-level cascading NSPFB are given by Equation NSDFB used by NSCT is a shift-invariant version of the dual-channel critical sampling DFB in CT. Therefore, the two-dimensional frequency plane is divided into a directional wedge by the results in tree structured filter banks.D is a quincunx matrix i.e.,The upper sampling fan filters The equivalent filter in each channel (z)k=0,1,,3 can beAs shown in ling law ,33 as a ling law ,34.The main difficulty of image reconstruction and fusion techniques is choosing an over-complete dictionary based on sparse representation. Over-complete dictionaries use DCT and wavelet in most cases. A fixed dictionary is easy to be achieved; however, its performance is somewhat limited in terms of data and application types. Aharon  developep principal components to form a sub-dictionary as follows:p eigenvectors, i.e., atom. The eigenvalues of jth eigenvector p. If An over-complete dictionary constructed by clustering all local neighbor patches is shown in This combination dictionary onary in  because T patches denoted as i, rearrange For each position Calculate the sparse coefficient vectors orithm byαAi=argmiMerge The fused result of All the original image patches in A sparse-representation based fusion approach is applied to each low-pass NSCT band. The fusion scheme contains the following steps:i, j) in the 1-scale k-direction.NSDFB decomposes each high-frequency component P and Q denote the window of size Calculate the Modified Laplacian (ML) and SML of the high-frequency coefficients i, j) in the 1-scale k-direction.Merge Iterate the above (2) and (3) process for all the high-frequency coefficients in high-frequency component In this paper, the high frequency coefficients are fused using the MAX-SML rule. Select the coefficient with a large SML value as the fusion coefficient. Suppress pseudo-Gibbs phenomena around singularities of fused image. The fusion scheme contains the following steps:The final fused image http://www.med.harvard.edu/aanlib/home.html. Infrared-visible and gray-level multi-focus image pairs were collected by Liu QTE [QIE [QY [QCB , and VIF[QY [QCB .QTE ,39 and QQTE [QIE ,40 evaluE [QAB/F  and QP [AB/F [QP ,42 are uP [QAB/F  is a graAB/F [QP ,42 is anAB/F [QP  and QY [ [QP [QY ,40 are mMI  measuresQY ,40 evaluQY [QCB ,44 and VQY [QCB  evaluateQCB [QCB ,44 is huQCB [QCB  is definIn this subsection, four popular fusion methods are applied to demonstrate the advantages of proposed image fusion framework (NSS). The rest of the popular fusion methods include Kim’s multi-modal image fusion proposed by Minjae Kim , the novIn this experiment, we set the NSCT filters mainly based on the optimal setting obtained by Liu . We use The dictionary used in sparse model is learned by PCA method.In modern medical diagnosis, various types of medical images provide great help in the accurate diagnosis of diseases. Common medical image techniques include X-Ray, Computed Tomograpy (CT), Magnetic Resonance (MR), and Positron Emission Tomograph (PET), etc. There are significant differences in the attention of different modal medical images of human organs and tissues, because of the different imaging mechanisms. Single-type image often fails to provide comprehensive and sufficient information for disease diagnosis. Clinically, doctors generally need to synthesize multiple different types of medical images from the same position to diagnose patient’s condition, which often brings great inconvenience and affects the accuracy of diagnosis. As a solution to these issues, the multi-modal medical image fusion is successfully applied to medical diagnosis. As a key advantage, multi-modal medical image fusion combines the information from different modalities of medical images and presents the combined one in a fused image.Since the optical system has a limited range of focus, getting a full-focus image in one scene is difficult to achieve. When an object is within the focus range, a clear image can be captured. But the out-of-focus objects suffer from blurs in various degrees. At present, the resolution of the optical lens is continuously improving. However, the overall impact of limited focusing range on imaging still exists. However, a fully focused image in one scene can be obtained by multi-focus image fusion. The multi-focus fusion techniques can effectively overcome the limited focus range of the optical system ,27. MultAs illustrated in In the reconnaissance shooting task, visible light cameras and infrared imaging devices are used to acquire the object images. Infrared thermography uses thermal radiation technique to convert infrared wavelengths beyond the human eye observation wavelength into visible information mapped into the image. However, the obtained images have poor contrast and cannot extract enough details. Images obtained by visible light camera have high resolution and enough detailed information of texture and edge. However, the imaging quality is easily affected by natural conditions. Since the differences and limitations between visible light and infrared images , relyingTwo infrared-visible image fusion examples are displayed in As illustrated in Based on the above experiments, the effectiveness of the proposed NSS image fusion framework is verified via the subjective visual effects and objective evaluation indicators.This paper talks about multi-source image fusion, which covers multi-modal medical, multi-focus, and visible-infrared image fusion. An image fusion framework (NSS), based on NSCT and SR, is proposed to solve the contrast loss, the difficulties in the selection of decomposing level, the defects of representation ability, and other weaknesses in conventional MST and SR-based fusion algorithms. In this fusion framework, low-frequency coefficients are fused via the SR-based scheme which uses PCA dictionary learning, and the high-frequency coefficients are fused via the Sum Modified-laplacian (SML) rule. The fused image is obtained by performing inverse transform of NSCT on fusion coefficients. Compared with conventional MST fusion methods, the NSS framework can obtain more informative fused images. The NSS framework can also improve the detailed performance and accuracy of the fused image by using PCA dictionary learning in comparison with conventional SR-based methods. It eliminates the gray-scale discontinuity, while effectively preventing smooth fine details by sliding window technology. Experiment results prove that the NSS fusion approach sufficiently integrates the advantages of NSCT and SR. Compared with three mainstream fusion methods, the NSS method can achieve superior performance in fused results. Particularly, the NSS method owns the advantages of simple implementation, high efficiency and good performance. It owns the great application prospect in infrared-visible image fusion. Furthermore, the proposed fusion framework also has great potential in the visible-infrared image fusion. In the future, we will improve the computational efficiency and enhance the image fusion performance. Particularly, the NSS fusion framework will be continuously optimized for visible-infrared image fusion.


This study examined the socioeconomic costs of dementia based on the utilization of healthcare and long-term care services in South Korea. Using 2016 data from two national insurance databases and a survey study, persons with dementia were categorized into six groups based on healthcare and long-term care services used: long-term care insurance users with home- and community-based services , nursing home services , and combined services ; and long-term care insurance non-users cared for by family at home , living alone , and admitted to long-term-care hospitals . Their direct and indirect costs were estimated. The total socioeconomic cost of dementia was an estimated US$10.9 billion for 457,524 participants in 2016 . Among the six groups, the annual per-person socioeconomic cost of dementia was lowest for long-term care insurance users who received home- and community-based services . It was highest for long-term care insurance non-users admitted to long-term care hospitals . Effective strategies are necessary to promote long-term care insurance with home- and community-based services to enable persons with dementia to remain in their communities as long as possible while receiving cost-efficient, quality care. Older adults living with dementia accounted for 10% 705,473) of the total older adult population (65 years or older) in South Korea in 2018, and this proportion is anticipated to rise to 16%  in 2050  paid by NHI and US$1350 [27.1%] paid by a patient).Direct non-medical cost per person was highest in LTCI users receiving nursing home services  and lowest in those receiving home- and community-based services (US$6915) among the three LTCI user groups. In LTCI users receiving nursing home services, non-medical costs paid by LTCI amounted to US$9456 (63.7%), while the costs paid by a patient amounted to US$5390 (36.3%).The 2016 total indirect cost per person was estimated to be US$10,340, with 75.7% for family caregiver productivity loss and 24.3% for general indirect cost see . LTCI noGeneral indirect cost  per person was similar between LTCI users receiving home- and community-based services (US$3715) and LTCI non-users cared for by family (US$3706). For LTCI users receiving nursing home services and LTCI non-users admitted to LTC hospitals, general indirect cost was estimated to be zero because that cost was included in their hospitalization or nursing home fees.Caregiver productivity loss per person with dementia was more than four times higher in LTCI non-users cared for by family  and those living alone  than in LTCI users receiving home- and community-based services (US$3175). LTCI users receiving nursing home services also exhibited caregiver productivity loss of US$2918 owing to their need to be accompanied to hospitals and outpatient clinics for medical services. Conversely, caregiver productivity loss was assumed to be zero for LTCI non-users admitted to LTC hospitals. Since persons with dementia in LTC hospitals stayed there for a longer period and could receive medical services on site, we assumed that their family members did not need to take leave of absence from work.This study examined the socioeconomic costs of dementia in South Korea by comparing six groups of persons with dementia based on the utilization of healthcare and LTC services. In 2016, the total socioeconomic cost of dementia was estimated to be US$10.9 billion for 457,524 persons with dementia, which represents US$23,877 per person. Among six groups of persons with dementia, the annual socioeconomic cost of dementia per person was lowest in LTCI users who received home- and community-based services US$21,390.58) and highest in LTCI non-users admitted to LTC hospitals . These findings support the South Korean government’s promotion of LTCI with home- and community-based services Frequent or long-term hospitalization places a major financial burden on the government, persons with dementia, and their families ,26. In oOur findings support that an LTC-related social security system, like LTCI, helps reduce the financial burden of caring for these individuals. In particular, LTCI’s home- and community-based services were the least costly care modality among the six groups of persons with dementia. This finding is consistent with existing evidence . Furtherhours of informal support provided to the person with dementia in an average day in respect of each type of support: ADL, instrumental ADL, and supervision”  and lowest in LTCI users who received home- and community-based services . However, these costs were much higher than those for LTCI users receiving nursing home services and LTCI non-users admitted to LTC hospitals. These findings suggest that LTCI with home- and community-based services partly relieves family caregivers’ burden, but this care modality still requires systematic support for informal caregiving.To improve LTCI with home- and community-based services, the South Korean government launched an integrated home- and community-based service, which employs a case management approach, in August 2019 . Before This study has some limitations. First, although the severity of dementia and number of comorbidities are associated with an increase in socioeconomic costs of dementia ,39, we dBased on our findings, LTCI with home- and community-based services was the least costly dementia care approach among the six healthcare and LTC service types. Future research needs to consider dementia stages, comorbidities, family members’ health, and unpaid caregiving to estimate more comprehensively the socioeconomic costs of dementia. Moreover, studies that develop evidence-based, innovative strategies  and examine their cost-effectiveness are necessary to promote LTCI with home- and community-based services and provide practical and systematic support to family caregivers. These efforts may eventually enable persons with dementia to remain in their communities for as long as possible while receiving quality care.


Comparisons of effectiveness of bariatric surgery (BS) procedures encompass weight loss, metabolic/clinical outcomes, and improvements or worsening of comorbidities. Post-operative physical activity (PA) and diet influence such outcomes but are frequently not included in comparisons of effectiveness. We assessed the value and necessity of including post-operative PA/diet data when comparing effectiveness of BS. Including post-operative PA/diet data has significant benefits for BS and patients. The paper proposes an explicit preferred reporting system . Including post-operative PA/diet data could result in more accurate appraisals of effectiveness of BS procedures. This could translate into better ‘individualized’ BS by achieving a better ‘fit’ between patient and procedure. Comparisons of short-, medium-, or long-term effectiveness and outcomes of various bariatric surgery (BS) procedures, and comparisons of effectiveness and outcomes of BS vs no surgery usually encompass a range of variables. Important outcomes include safety  or other relevant indicators  –7. In adThe current review explored four related questions: (1) Do post-op PA/diet need to be accounted for in comparisons of effectiveness of different BS procedures?; (2) If yes, are post-op PA/diet currently included in comparisons of effectiveness?; (3) How could post-op PA/diet be included in comparisons of effectiveness?; and, (4) What are the preferred reporting methods for explicitly elucidating whether post-op PA/diet data were collected and/or included in comparisons of effectiveness, and their emergent findings?We searched electronic databases including PubMed, MEDLINE, Embase, CINAHL, Web of Science, Scopus, and Google scholar for published articles of comparisons of outcomes of various BS procedures or comparisons of outcomes of BS procedures with medical management relevant to answering these research questions.We used the keywords “bariatric surgery” [in Title/Abstract]. The medical subject headings (MeSH) terms used were bariatric surgery [All Fields] AND  Original studies.Language: (2) Published articles in English language.Time Period: (3) Original studies published from 01 January 1990 through 28th February 2020.Interventions: (4) Published articles that assessed bariatric surgery.Participants: (5) Published articles enrolling patients of any age, gender, and ethnicity anywhere in the world.Studies that did not include outcomes or comparisons.The review assessed whether post-op PA/diet was associated with WL after BS; examples of non-inclusion of post-op PA/diet in comparisons of effectiveness; reasons why post-op PA/diet need to be included in comparisons of effectiveness; whether post-op PA/diet is used as ‘process’ or as ‘outcome’ variables in comparisons of effectiveness; and, examples of tools that collect data on post-op PA/diet among bariatric patients and their related challenges.Based on the emergent findings, the review proposed a way forward for a preferred reporting of post-op PA/diet in comparisons of effectiveness of BS procedures.Evidence suggests that post-op PA is associated with WL after BS. For patients who underwent primary Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG), change in leisure activity at 24 months was positively associated with %TWL at 24 months, where patients with higher improvements in leisure activity had better WL . LikewisDespite all the above, there is a dearth of data on the effects of exercise on WL and WL maintenance after BS . AlthougBinging and grazing eating patterns after BS are associated with poor outcomes . Post-BSThe post-op quality of diet is also important, as various BS procedures might be associated with different post-op diet preferences. A year after surgery, RYGBP patients ate significantly less carbohydrates and more lipids and had higher daily cholesterol intake than the SG patients . In/direThe above evidence proposes that it could be appropriate to include post-op PA/diet data in the analyses of comparisons of effectiveness between various BS procedures, or in comparisons of effectiveness of BS vs no surgery. Long-term dietary control and PA can help patients achieve optimal WL . Hence, Yet, the majority of studies seem not to collect or include data on these two important variables (PA and diet) that can potentially influence the gauging of effectiveness. This is regardless whether such studies are short-, medium-, or long-term comparisons of effectiveness between “variants” of one BS procedure, e.g., regular biliopancreatic limb RYGB vs. long biliopancreatic limb RYGB ; betweenSome studies acknowledged the lack of control for post-op PA/diet in their analyses of comparative effectiveness of various BS procedures. A comparison of the effects of RYGB vs SG on body mass composition explicitly acknowledged its limitations which included the inability to evaluate accurate protein and macronutrient consumption or differences in PA patterns, highlighting that “while all their patients undergo similar dietary education with emphasis on daily exercise, this was not strictly controlled for” p. 454 .Other studies undertook case-matched analysis. A comparison of laparoscopic very, very long limb revisional vs primary RYGB-matched patients by gender, age, preoperative/pre-revisional BMI, and diabetes . UnfortuStill, others seem to have collected the requisite data. A comparison of effectiveness of RYGB vs SG vs SG with jejunal bypass collected daily diet and leisure-time exercise data by telephone interviews . HoweverVery few exceptions illustrate the importance of inclusion of post-op PA and diet in the analyses. Research of WR in RYGB vs SG patients with symptoms of post-BS hypoglycemia (PBSH) was concerned about the potential confounding effect of nutritional adherence on WR . Hence, per se . As an alternative, post-op PA can be used as process variables, i.e., mobilized to help verify that observed differences in BS outcomes are due to the BS itself and not actually influenced by differences in patients’ PA/diet .When PA/diet data are available, a related point is the manner in which such data is employed. Post-op PA and diet data is frequently used as outcomes For instance, a study collected information that could implicitly have some requisite data. A comparison of SG vs one-anastomosis gastric bypass (OAGB) measured quality of life in both groups using the Moorehead-Ardelt quality of life questionnaire II that assessed, among other things, approach to PA and interest in food , 38. HowNotwithstanding, relationships between post-op PA/diet on the one hand and the anthropometric WL and biochemical/clinical outcomes of BS on the other exhibit inconsistencies. After BS, individuals who increased their PA tended to lose more weight than those who maintained or decreased their PA, but the WL differences were not significant . LikewisEqually, post-BS, patients who achieved optimal WL consumed dessert more frequently than those with suboptimal WL . InteresOther considerations exist. For instance, RYGB and SG decreased the hedonic evaluation of high-fat food stimuli, but this did not translate into decreased preferences for high-fat food . Post-BSPost-op adherence to exercise and diet are difficult to evaluate –56. ManyIn terms of post-op diet of BS patients, many self-report tools assess consumed food quality and tolerance, and food records of foods and beverages consumed accompanied by a picture album of food-portion sizes might enhance accuracy , 65, 66.Adherence is generally evaluated via verbal/written self-reports employing cutoffs (adherent vs non-adherent)  and suffPost-op PA or diet could act as confounders or effect modifiers. However, one will not know whether PA and/or diet is a confounder, effect modifier, or neither unless data about these variables are collected and appraisals are undertaken. Figure A confounder is an ‘extra’ variable that the researcher did not account for; a variable, other than the independent variable of interest , which may affect the dependent variable  , 79. ConAn effect modifier is to identify whether the effect of a treatment (type of BS) is different in groups of patients with different characteristics (PA/ diet) . Effect Bariatric researchers almost always include patients’ age and sex as potential confounders when comparing the effectiveness of various BS procedures. Yet, it is not clear why patients’ post-op PA and dietary practices are not considered in such analyses. There have been calls for the comprehensive measurement of outcomes in BS . HoweverAccurate assessments of post-op PA and dietary practices are not easy and will require extra efforts from patients and research teams alike, but should preferentially be attempted and included in analyses of comparisons of effectiveness of BS procedures. In refining the evidence base, Table per se do not essentially bring about positive long-term effects [Patients’ variability in post-BS WL could be to some extent, due to differences in adherence to dietary and PA recommendations, given that physiological changes acquired through surgery  effects , 87. HenIn addition, knowledge of whether (and extent to which) effectiveness of a given BS procedure might vary across different groups of patients with different PA/diet characteristics will be key to assist surgeons in assessing patients who could more likely benefit from a given BS procedure. Patients’ comorbidities and potential risks are included in the choice of the appropriate BS , and potThe inclusion of post-op PA and diet in analyses of comparisons of BS outcomes and reporting such inclusion  as highlighted in the preferred reporting above could provide fresh evidence about the role of these two variables in assessments of effectiveness. Should their roles be important, the emergent knowledge on the ‘net’ gains of effectiveness of BS procedures and the magnitude of influence of post-op PA and diet could advance the field. New understandings could broaden the preoperative counseling of patients to include more evidence-based perspectives of post-op PA. These could include pre-op subjective/objective appraisals of a patient’s potential motivation and ability for post-op PA, particularly that motivation is the best predictor of adherence to exercise, and that preoperative PA and planning before RYGB predicted post-op PA , 88–90. Adherence to dietary and PA guidelines is associated with greater WL after surgery , but lit


Multidrug-resistant tuberculosis (MDR-TB) are unsatisfied to treat, pressing more effective and innovative treatment regimens. New efficient regimens for MDR-TB have obtained high treatment success rates. However, those regimens without drug susceptibility testing (DST) are also likely to contribute to the emergence of resistance. Precision treatments guided by DST might optimize the patients’ treatment outcome individually and minimize resistance amplification.TB-TRUST is a phase III, multicenter, open-label, randomized controlled clinical trial of non-inferiority comparing the treatment success rate between the World Health Organization (WHO) shorter regimen and the refined ultra-short regimen for fluoroquinolones and second-line injectable drugs susceptible rifampicin-resistant TB. The control arm uses the WHO injectable-containing shorter regimen for 36–44 weeks depending on time of sputum smear conversion. The investigational arm uses a refined ultra-short regimen guided by molecular DST to pyrazinamide via whole-genome sequencing (WGS) to optimize the treatment of pyrazinamide-susceptible patients with levofloxacin, linezolid, cycloserine and pyrazinamide for 24–32 weeks and pyrazinamide-resistant with levofloxacin, linezolid, cycloserine and clofazimine for 36–44 weeks. The primary outcome is the treatment success rate without relapse at 84 weeks after treatment initiation. Secondary outcomes include the time of sputum culture conversion and occurrence of adverse events. Assuming α = 0.025 level of significance (one-sided test), a power of 80%, a < 10% difference in treatment success rate between control arm and investigational (80% vs. 82%), and a 5% lost follow-up rate, the number of participants per arm to show non-inferiority was calculated as 177.Rapid molecular testing distinguishes patients who are eligible for shorter regimen with fluoroquinolone and the WGS-guided results shorten the treatment to 6 months for pyrazinamide susceptible patients. It’s foreseeable that not only novel developed medicines, but also traditional powerful medicines with the susceptibility confirmed by DST are the key factors to ensure the effect of anti-MDR-TB drugs. As a DST-guided precision treatment, TB-TRUST are expected to optimize therapy outcome in more patients who cannot afford the expensive new medicines and minimize and even avoid resistance amplification with the rational use of anti-TB drugs.NCT03867136. Registered on March 7, 2019.ClinicalTrial.gov, The online version contains supplementary material available at 10.1186/s12879-021-05870-w. As an ancient infectious disease, tuberculosis (TB) has gained new worldwide attention due to the emergence of drug resistance. About 20% of the TB strains have developed resistance to at least one anti-TB drug. In 2019, there were approximately 465,000 incident cases of rifampicin-resistant TB (RR-TB), of which 78% had multidrug-resistant TB (MDR-TB) [MDR-TB is heavily challenging to treat, pressing more powerful and novel treatment regimens. Treatment for MDR-TB is largely carried out through standardized, empirical combination regimens. However, precision treatment guided by detailed DST results in improved individual outcomes . StandarTreatment of MDR-TB remains challenging, with lengthy treatment durations and complex drug regimens. In 2010, Van et al. reported he Bangladesh regimen of 9-month consisting of seven drugs for MDR-TB treatment, resulting in a treatment success rate of 87.9%, marking the success of the short-term treatment for MDR-TB . SubsequIn our early study, we showed that introducing molecular DST to pyrazinamide successfully improved the treatment outcome with the relapse-free success rate of 82.4% for pyrazinamide-susceptible cases and shortened the regimen to 12 months without any additional agents . HoweverRapid testing of resistance to fluoroquinolones and SLIDs is of great significance for recognizing MDR-TB patients who are eligible and recommended in shorter regimens. Xpert® MTB/XDR  leverages the new 10-colour homogeneous detection within the GeneXpert system, which enables the detection of multiple mutations across several genes with detecting resistance to isoniazid, ethionamide, fluoroquinolones, amikacin, kanamycin and capreomycin. Xpert® MTB/XDR testing can quickly select fluoroquinolones and SLIDs susceptible patients taking the most appropriate and precise shorter regimen [pncA [Mycobacterium tuberculosis (MTB). Whole-genome sequencing (WGS) is a viable and financially feasible tool for timely and comprehensive diagnosis of drug resistance, and our early study has proved it a promising approach to predict resistance to pyrazinamide with satisfactory accuracy, sensitivity and specificity of over 85.0% [Pyrazinamide resistance is associated with full-length mutations in pncA , 12, whier 85.0% . Our cener 85.0% –17, is aTB-TRUST is designed based on the trend of shorter and full oral treatment programs under DST guidance. Based on the molecular susceptibility testing platforms of Xpert® MTB/XDR and WGS, a randomized controlled study is carried out. This study innovatively detects fluoroquinolone and SLIDs resistance to select opportune rifampicin-resistant/multidrug-resistant tuberculosis (RR/MDR-TB) patients and optimizes the regimen according to result of pyrazinamide resistance, comparing with the WHO shorter regimen as a standardized and non-DST guided control arm. This protocol describes the background, design and rationale of the TB-TRUST trial.This is a phase III, multicenter, open-label, randomized controlled clinical trial of non-inferiority with two arms, recruiting RR/MDR-TB patients susceptible to fluoroquinolones and SLIDs detected by Xpert® MTB/XDR. Recruited participants will be randomly divided into the ultra-short regimen as investigational arm and the WHO shorter regimen as control with a ratio of 1:1. Figure The ultra-short regimen consists of two periods. During the first 4–8 weeks, patients are waiting for the result of pyrazinamide DST and receive five agents including levofloxacin, linezolid, cycloserine, pyrazinamide and clofazimine. The result of molecular DST to pyrazinamide will be determined by two technical staff in the central laboratory of Huashan Hospital, Fudan University according to the established criteria that were reported previously in elsewhere , 19, refThe control regimen is WHO injectable-containing shorter regimen with two phases of treatment for 36–44 weeks. The first is the intensive phase of 16 weeks (extended up a maximum of 20 or 24 weeks in case of lack of smear conversion by 16 or 20 weeks), containing moxifloxacin, amikacin, prothionamide, pyrazinamide, high-dose isoniazid, ethambutol and clofazimine. The followed one is a continuation phase for 20 weeks with the following agents: moxifloxacin, pyrazinamide, ethambutol and clofazimine. Table This trail is under the guidance of the China National Tuberculosis Defense Association, led by Huashan Hospital, Fudan University, Zhejiang Province Center for Disease Control and Prevention and Chinese Center for Disease Control and Prevention. The recruiting-cooperative units are 15 hospitals in nine provinces in China, namely Henan Infectious Disease Hospital, Xinjiang Uygur Autonomous Region Chest Hospital, Shenzhen Third People’s Hospital, Hangzhou Red Cross Hospital, Ningbo Huamei Hospital of Chinese Academy of Sciences , Enze Hospital of Enze Medical Center (Group) in Taizhou, Zhejiang, the Affiliated Hospital of Shaoxing College of Arts and Sciences , Guiyang Public Health Treatment Center, Wenzhou Central Hospital, Jiangxi Chest Hospital, Hunan Chest Hospital, Huaihua First People’s Hospital, Shanxi Tuberculosis Prevention and Treatment Institute, Xuzhou Infection Disease Hospital, Yunan Infectious Diseases Hospital. A specialized auditing team will make the quality control of the cooperative units half a year.In addition to participate in this clinical trial voluntarily, the main eligibility criterion is smear-positive pulmonary RR/MDR-TB susceptible to fluoroquinolones and SLIDs identified by the Xpert® MTB/XDR platform. Patients will be excluded if they were in critical condition or with aspartate transaminase or alanine aminotransferase greater than five times the upper limit of normal, or blood creatinine greater than 1.5 times the upper limit of normal or HIV testing positive, considering the safety in the regimen. If patients are simultaneously applying the drugs that affect the efficacy of or contraindicated with this study drugs, they will be also excluded. Besides, pregnant or breastfeeding women are also excluded. Table RR/MDR-TB patients identified by Xpert® MTB/RIF assay  are screening to ascertain whether they satisfy the other eligibility criteria for enrolment. The follow-up content of this trial during the first screening including medical history collection, personal information collection, signed informed consent, physical examination, clinical evaluation, height and weight measuring, hearing examination, sputum smear, sputum culture, liver function, AIDS testing, blood sugar, blood potassium, electrocardiogram, chest radiography, urine routine, peripheral neuropathy brief examining with the use of a Brief Peripheral Neuropathy rating scale and ophthalmologic examination, including assessment of visual acuity and color vision. After screening procedures finished, potentially eligible patients are performed by Xpert® MTB/XDR to detect the resistance of fluoroquinolone and SLIDs, those without evidence of resistance to fluoroquinolone and SLIDs are recruited into this trial.The Patients who meet the eligibility criteria will be registered online and managed by an authorized doctor in every branch centers. And then participants will be assigned to the study arm based on an 1:1 randomization ratio. The randomization is performed through the online central randomization system stratified by the study sites , and the treatment plan is notified to the branch centers by the central laboratory of Huashan Hospital, Fudan University.After screening and baseline assessment, follow-up visits were conducted every 2 week in the first 8 weeks, and then every 4 weeks until the end of treatment, and every 12 weeks at the period of post-treatment until 84 weeks after treatment initiation. During the follow-up, physical examination, clinical assessment, weight measurement, sputum smear, sputum culture, blood and urine routine, liver function, renal function, electrocardiogram, brief peripheral neuropathy screen, ophthalmologic examination and some other tests will be evaluated. Detailed schedule of patient monitoring exams and laboratory tests will be shown in the This sample size was calculated using the PASS 11 system . Assuming α = 0.025 level of significance (one-sided test), a power of 80% and a non-inferiority margin of 10% between the control and investigational arms (80% versus 82% favorable outcome), the number of participants needed per arm to show non-inferiority of the investigational regimen was calculated as 168. Considering the 5% lost follow-up rate, 177 patients were required for each are, so the total sample size of the two arms was considered to be 354.Clinic staff in the cooperative hospitals or centers will use the specialized website and data collection forms for study management to record data. All data access in websites will be controlled by unique usernames and passwords and staff will have access restricted to the functionality and data that are appropriate for their role in the study. Central Coordinating Office (CCO) staff will be responsible for provision of the relevant website and case report forms. CCO will check the eligibility of patients and follow-up data integrity regularly. After patients complete the trial, CCO will lock the file for further generation of data extracts for analysis. Only three main investigators of Huashan Hospital, Fudan University can have access to the final trial dataset and report the results of the trial via publication.The grading system for AE has been established. To provide the advice to complicated event management, we build a highly experienced clinician team which includes a pulmonologist, an infectious diseases expert, a nephrologist, a psychiatrist, a cardiologist, a hepotologist, a hematologist, a rheumatologist, and an experienced nurse. Severe AE will be reported to the center within 24 h and discussed by the committee. AE and the adjustment or withdraw of drugs will be recorded and checked by CCO.M.tuberuclosis strains from each patients enrolled in this study were sent to the National Tuberculosis Reference Laboratory of Chinese Center for Disease Control and Prevention in accordance with international transportation guidelines. A total of twelve anti-tuberculosis drugs susceptibility, including ofloxacin, moxifloxacin, rifampin, amikacin, rifabutin, para-aminosalicylic acid, ethionamide, isoniazid, kanamycin, ethambutol, streptomycin, and cycloserine were measured with the use of the Sensitire MYCOTB MIC Plate (MYCOTB) on one 96-wells plate.Baseline The primary objective is to compare the treatment success rate without relapse between the WHO injectable-containing shorter regimen group and the refined ultra-short regimen group at 84 weeks after treatment initiation. Treatment outcomes will be classified into favorable outcome which means successful treatment and unfavorable outcome. Table mITT) and per protocol (PP) approaches with a primary consideration for mITT results. For the primary outcome analysis, the upper bound of the 95% confidence interval of the difference in proportion of favorable outcome between the WHO shorter regimen and the refined ultra-short regimen must be less than 10% (the margin of non-inferiority) in both the mITT and the PP populations for the ultra-short regimen to be declared non-inferior to the WHO shorter regimen group.The results of this trial for efficacy outcomes will be analyzed based on both modified intention-to-treat  and treatment interruption due to adverse events will be collected and documented, and the proportion per type of AEs in the two regimens will be compared using the chi-square test or Fisher’s exact test.Participants’ personal information will be limited to only information necessary for outcome evaluation of study regimen with laws on privacy protection and guaranteeing of confidentiality. Paper documents containing participants’ data will be locked in a specialized office in cooperative hospitals. Digital documents will be stored in password-protected files on website. Access to study documents will be restricted to authorized personnel only.China accounted for 14% of the global total MDR/RR-TB in 2019, while treatment of RR/MDR-TB success rate only reached to 57% globally [Exploration of initiatives for MDR-TB started decades ago, but only increased in size and scope in the past few years. In 2020, WHO consolidated guidelines on TB (Module 4) revised current policy recommendations on treatment strategy for drug-resistant TB (DR-TB) [At present, a number of studies of shorter regimen for MDR-TB including MDR-END , endTB  and so oOur early study  providesThe 2018 WHO guidelines for DR-TB  proposedTB-TRUST study has few limitations. As a full-oral shorter regimen, without introducing bedaquiline is regrettably. Bedaquiline-containing regimens have achieved high conversion and success rates of MDR- and XDR-TB trials in published studies , 26, 27 Additional file 1.


The colonization of Extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-PE) in bloodstream infections (BSIs) has been increased dramatically worldwide, and it was associated with worse clinical outcomes in patients with malignancy. We performed the meta-analysis to investigate the prognosis and risk factors in BSIs caused by ESBL-PE in oncological patients.PubMed, EMBASE, and Cochrane Library were searched for related studies. All-cause mortality was considered as the primary outcome. Subgroup analyses, meta-regression analyses, and sensitivity analysis were used to investigate heterogeneity and reliability in results.P < 0.001), with a significant between-study heterogeneity . Subgroup analyses showed that children  and hematological malignancy  were associated with a higher mortality. Severe sepsis/ septic shock, pneumonia, and ICU admission were the most common predictors of mortality.6,729 patients from 25 studies were eligible. Six studies enrolled oncological patients with BSIs caused by ESBL-PE only, while 19 studies both enrolled ESBL-PE and non-ESBL-PE infections. The results showed that BSIs caused by ESBL-PE in patients with malignancy was associated with higher mortality than non-ESBL-PE infections (RR = 2.21, 95% CI: 1.60–3.06, Our study identified that BSIs caused by ESBL-PE in patients with malignancy were associated with worse clinical outcomes compared with non-ESBL-PE infections. Furthermore, children and hematological malignancy were associated with higher mortality. Severe sepsis/ septic shock, pneumonia, and ICU admission were the most common predictors of mortality. In recent years, the incidence of bloodstream infections (BSIs) caused by Extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-PE) has been increasing over time all over the world . There iPatients with malignancy are more vulnerable to developing severe infection, including those caused by ESBL-PE since they are more likely to be immunocompromised due to chemotherapy, radiotherapy, surgery, invasive procedures, malnutrition, and malignancy itself , 5. As aPrevious meta-analyses have investigated the prevalence of BSIs caused by ESBL-PE in patients with malignancy , 8. HoweOur meta-analysis was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines . We condStudies were considered as eligible based on the following criteria:  populatiTwo investigators (AM Jiang and N Liu) independently extracted the data using a standardized approach. Any disagreement in the study selection and data extraction phases was resolved through discussion with the third investigator (R Zhao). The following data information was retrieved from each article: first author’s name, year of publication, country, study population, infection type of BSIs, the total number of screened subjects, the total number of ESBL-PE caused BSIs, the total number of BSIs caused death and ESBL-PE BSIs caused death, and ESBL detection method. The data was extracted from texts or tables in articles. Newcastle Ottawa Quality Assessment Scale (NOS) was used in our research to assess the quality of selected studies . The sca3 [Neutropenia was defined as an absolute neutrophil count of < 500 neutrophils/mm3 .Empirical antibiotics treatment was considered inappropriate once the antibiotics could not suppress the activity of the isolated pathogens according to the results of antimicrobial susceptibility tests during the first 24 h after the blood culture was obtained .The all-cause mortality at the end of the study and the predictors in BSIs due to ESBL-PE in patients with malignancy were the primary outcomes in the study .I2 statistic test. When the heterogeneity was statistically significant (P < 0.05 and I2 > 50%), a random-effects model was applied to obtain the pooled RRs; otherwise, a fixed-effects model was performed. Subgroup analyses and meta-regression analyses were conducted to explore the sources of heterogeneity. We also performed a sensitivity analysis to evaluate the quality and stability of results by omitting one study in each turn. Begg’s test and Egger’s test were used to assess the publication bias. Statistical tests were two-tailed at the significance level of P < 0.05. All analyses were used with STATA V.14.0 .The RRs and 95% CIs for mortality were calculated to assess the outcomes of BSIs caused by ESBL-PE in oncological patients. All results were depicted as forest plots. Heterogeneity was assessed using Cochran’s Q test and the Our literature search identified 1,260 studies. After excluding repeated records and the initial screening based on titles and abstracts, 25 articles were eligible in this study. Of these, six studies enrolled oncological patients with BSIs caused by ESBL-PE only, while 19 studies both enrolled ESBL-PE and non-ESBL-PE infections. Of the 25 studies, there were eight prospective cohort studies, 14 retrospective cohort studies, and three case–control studies. All included studies were published between 2009 and 2019, and there were six studies published in 2019, accounting for 24%. There were 15 studies conducted in Asia, seven studies conducted in Europe, and three studies were conducted in North America. The detailed flow chart of the study selection process was described in Fig. P < 0.001) .In all the studies, the time of death records was not similar. The majority of studies used 30-day mortality to evaluate the clinical outcomes of BSIs caused by ESBL-PE in patients with malignancy, –29 only P = 0.014), and the RR of mortality in studies from Asia  was lower compared with Europe and North America, with no evidence of heterogeneity . The detailed information was in Table Subgroup analyses in all selected studies were conducted by study design, region, study population, malignancy type, FN, ESBL detection methods, and NOS score. Most of the subgroups  were consistent with the overall trend and showed statistically significant increases, except for the subgroup without FN, and the subgroup with NOS score < 6. The subgroup analyses suggested that study region was identified as potential sources of the heterogeneity  . Consistent with our findings, Trecarichi EM et al. reported that ESBL-PE caused BSIs in patients with malignancy was associated with high mortality compared with non-ESBL-PE infections [In this meta-analysis, we included 19 studies that both enrolled oncological patients with ESBL-PE and non-ESBL-PE infections, and the results showed that the mortality in BSIs caused by ESBL-PE among patients with malignancy was higher compared with non-ESBL-PE infections  . SimilarTo our knowledge, this is the first study that evaluated the clinical outcomes and risk factors in BSIs caused by ESBL-PE among patients with malignancy using Meta-analysis. However, our study has several limitations. First, all of the included articles were observational studies and published in English. Besides, high-estimated heterogeneity was observed, which is probably related to different design, study region, and study population. Moreover, some studies included oncological patients with FN, but the data was not available for subgroup analysis. Therefore, the clinical outcomes of BSIs caused by ESBL-PE in these patients should be further validated since these patients are more vulnerable to severe infections. To sum up, clinical conclusions need to be comprehensive assessment in combination with other indicators, and more sample sizes and studies need to be added to verify our results.In summary, our study provided a systematic analysis for the prognosis and risk factors of BSIs due to ESBL-PE in oncological patients. Our findings suggested that BSIs caused by ESBL-PE in patients with malignancy were associated with worse clinical outcomes compared with non-ESBL-PE infections. Furthermore, children and hematological malignancy were associated with higher mortality. We also identified that severe sepsis/ septic shock, pneumonia, and ICU admission were the most common predictors of mortality. Large-scale and prospective studies are warranted to verify the results of our study.Additional file 1: Table S1. Quality assessment conducted according to the NOS for all included studies. Figure S1. Forest plots of mortality in BSIs due to ESBL-PE among patients with malignancy by different subgroups. (a) study design; (b) region; (c) population; (d) malignancy type (e) FN; (f) ESBL detection methods; (g) NOS score. Figure S2. Sensitivity analysis of mortality in BSIs due to ESBL-PE among patients with malignancy. Figure S3. Tests for publication bias. a Begg's funnel plot with pseudo 95% confidence limits; b Egger's publication bias plot.