Anaerostipes caccae, Eubacterium hallii, and Bifidobacterium bifidum in AD individuals, with Akkermansia muciniphila, Roseburia intestinalis, Haemophilus parainfluenzae, and Rothia mucilaginosa in controls. Meanwhile, functional profiles showed that the pathway of lipid metabolism had a higher proportion in the AD group, and the pathway of xenobiotics biodegradation was abundant in controls. Among urinary organic acids, adipic acid, 3-hydroxyglutaric acid, tartaric acid, homovanillic acid, 2-hydroxyphenylacetic acid, aconitic acid, and 2-hydroxyhippuric acid were richer in the AD group. However, only adipic acid remained significant in the multivariate analysis . In the correlation analysis, Roseburia intestinalis had a negative correlation with aconitic acid , and the latter was positively correlated with adipic acid . Besides, the pathway of xenobiotics biodegradation seems to inversely correlate with adipic acid . The gut microbiota plays an important role in the development of AD in autistic children, and more well-designed studies are warranted to explore the underlying mechanism.Autism is a kind of biologically based neurodevelopmental condition, and the coexistence of atopic dermatitis (AD) is not uncommon. Given that the gut microbiota plays an important role in the development of both diseases, we aimed to explore the differences of gut microbiota and their correlations with urinary organic acids between autistic children with and without AD. We enrolled 61 autistic children including 36 with AD and 25 without AD. The gut microbiota was sequenced by metagenomic shotgun sequencing, and the diversity, compositions, and functional pathways were analyzed further. Urinary organic acids were assayed by gas chromatography–mass spectrometry, and univariate/multivariate analyses were applied. Spearman correlation analysis was conducted to explore their relationships. In our study, AD individuals had more prominent gastrointestinal disorders. The alpha diversity of the gut microbiota was lower in the AD group. LEfSe analysis showed a higher abundance of  Autism spectrum disorder (ASD) is a kind of neurodevelopmental condition and troubles a lot of children in the world, with a prevalence up to 1%–2% . ASD is Enterococcus, Escherichia coli, Bacteroides, and Bifidobacterium and higher abundance of Lactobacillus compared to controls ; and ③ the score of Autism Behavior Checklist (ABC) or Childhood Autism Rating Scale (CARS) more than 30 to avoid the potential influence of Attention Deficit Hyperactivity Disorder and other neuropsychiatric diseases. In our study, atopic dermatitis was diagnosed by a professional dermatologist in our hospital according to the criteria of the UK proposed by Williams HC in 1994 . MoreoveA series of questionnaire surveys were conducted to fully assess the severity of autism, including ABC, CARS, Clinical Language State Questionnaire (CLSQ), and The Autism Treatment Evaluation Checklist (ATEC). CLSQ involves two aspects—expression (CLSQ-I) and cognition (CLSQ-II)—and a lower score indicates more severe language impairment. ATEC consists of four subscales, and a higher score is in consistency with the increasing severity of autistic symptoms.In case of bias, we omitted the item “insensitive to pain” in ATEC, considering that it was hard to be described precisely by children themselves or their caregivers. Meanwhile, these following items potentially relevant to gastrointestinal (GI) problems were added based on clinical experience and scored from 0 to 3 (0 means absence): “feces containing undigested food or smelling sour”, “hiccup/acid regurgitation/abdominal distension”, “extremely happy of unknown reason”, “jump/run back and forth”, and “difficulty in concentrating”.Before fecal collection, participants were required not to take any dosage of antibiotics in a month and any probiotics in 2 weeks. Also, fruits and tomatoes were prohibited in 24 h before urine collection. A fresh fecal sample and the first clean midstream specimen of urine in the morning were collected. All samples were stored in dry ice within 3 min since collected.We extracted DNA from fecal samples according to the protocol of the MO-BIO PowerSoil DNA Isolation Mini Kit . Gel electrophoresis was applied for sample quality inspection and quality level judgement. Moreover, the sequencing library construction and template preparation were based on the NEBNext Ultra DNA Library Prep Kit . Each sample was marked by a barcode, and equal quantities of barcoded libraries were used for sequencing. All extracted DNA samples were stored at -80°C, and the final sequencing libraries also received quality and quantity assessment before Illumina sequencing. NGS analysis was performed on an Illumina instrument according to the manufacturer’s instructions . Illumina HiSeq 2500 and HiSeq X Ten sequencing systems  were applied for paired-end 150-bp sequencing. In order to appreciate the diversity and to sample a sufficient number of microbial genes, generating at least 4 Gb of data per sample was recommended in our study.MetaPhlAn (version 1.7.7)  was usedThe urine samples were analyzed by gas chromatography–mass spectrometry, following the instructions described in the study . All anat-test or Mann–Whitney U test. Categorical variables were analyzed by chi-square test or Fisher’s exact test. For urinary organic acids, those with a P value less than 0.05 in univariate analysis were further enrolled in multivariate binary logistic regression analysis using the method of forward stepwise. Then, the Spearman correlation test was applied to explore the correlation among gut microbiota, their functional pathways, and urinary organic acids. Statistical analyses were performed in SPSS 24.0.0.0 and R software (version 4.0.0), and a two-tailed P value less than 0.05 was considered statistically significant.Continuous variables were expressed as mean and standard deviation or median and quartile if appropriate and further analyzed by Student’s A total of 61 children were enrolled in our study between 2015 and 2018, including 36 children in the AD group and 25 children in the control group. The basic characteristics of both groups are shown in Considering the verbal limitation in children, we newly added five items in our study, which could be the indicators of potential GI problems to some extent. According to ), while there was no significant difference in terms of Pielou’s evenness, Shannon Diversity Index, and Simpson’s Diversity Index . Additionally, principal coordinate analysis (PCoA) could not make a distinction between individuals in the AD group and those in the control group . Herein, we only presented those items with statistical significance based on the univariate test Table 2.Roseburia intestinalis, enriched in those without atopic dermatitis, had a negative correlation with aconitic acid . As for the functional pathways and urinary organic acids, however, we did not observe any statistically significant correlation. The pathway of xenobiotics biodegradation and metabolism seems to inversely correlate with adipic acid (r = -0.42), yet with a P value of 0.18. Among urinary organic acids, aconitic acid was positively correlated with adipic acid . Besides, there were positive correlations among urinary organic acids with a correlation coefficient of about 0.5. This could directly explain why the difference in results existed between logistic regression and univariate analysis for urinary organic acids. We also conducted correlation analysis between other taxa at genus or species level identified in metagenomic sequencing and those aforementioned urinary organic acid, as shown in The Spearman correlation test was applied to further explore the correlation among gut microbiota; functional pathways  with those urinary organic acids were significant in univariate analysis Figure 4The coexistence of atopic dermatitis in autism is far from rare, which bothers those children and further lowers their life quality. This is the first study exploring the alterations of gut microbiota and urinary organic acids in autistic children with AD compared with those without AD. We found that there was no significant difference in sex, age, and disease evaluation between both groups, which was reasonable to carry out further analysis.As expected, in our study, autistic children with AD had more prominent GI symptoms than their control counterparts. GI symptoms showed greater prevalence in patients with ASD compared to those without ASD . As for B. bifidum showed an enrichment in autistic children with AD (0.31% vs. 0.05%). For children with ASD, Xu et al. summarized that the relative abundance of Bifidobacterium was lower compared to controls  , which was irrelevant to feeding methods  . At spec species . However methods . Further methods . Similar methods . Additiopatients . TherefoLachnospiraceae in both groups, among which A. caccae and E. hallii predominated in AD individuals, with R. intestinalis in controls . All these microbes were involved in the production of short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate . According to previous studies, compared to healthy children, atopic children showed a significant decrease in or even deletion of A. muciniphila . Both two species are usually regarded as opportunistic pathogens, which could lead to a variety of diseases, such as pneumonia, endocarditis, and bacteremia . Adipic acid was produced from the omega-oxidation pathway of fatty acids, a process which was normally an alternative to the beta-oxidation pathway in mitochondria . This pafunction , finallyfunction . The disBesides, as We acknowledge that our study has several limitations. Firstly, it was a single-center study and the sample size was limited. Secondly, in this study, we only enrolled autistic children with AD and without AD, lacking those healthy or only with AD as controls. It is impossible for us to exclude the potential effect of autism as a confounder. Thirdly, due to the limitation of technology, we just took urinary organic acids into consideration, not including fecal or blood samples, which may affect the final result to some extent. Apart from the complex network among gut microbiota and their interactions with the host, this may explain why we did not observe evident correlations between urinary organic acids and gut microbiota. Lastly but very importantly, we just limited the usage of antibiotics and probiotics before sample collection, while the diets of enrolled children were not obtained and analyzed, which would introduce deviation in the final results. The question of causality of the alteration of the gut microbiota and the development of AD remains an egg or chicken problem. All of these will make our study preliminary and exploratory. Large-scale and well-designed studies in the future are needed.Altogether, lots of studies have shed light on the role of the gut microbiota in the pathogenesis of disease. Herein, we identified significant differences of gut microbiota and urinary organic acids between autistic children with and without AD, and the underlying mechanism on AD occurrence in autism needs further investigation. A more comprehensive understanding of the relationship between gut microbiota and AD in autistic children will be beneficial for clinicians to manage those children in the prevention and treatment of AD better.The data presented in the study are deposited in the National Center for Biotechnology Information (NCBI) Bioproject repository, accession number PRJNA845014.The studies involving human participants were reviewed and approved by the Peking Union Medical College Hospital Ethics Committee. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.All authors contributed to the study conception and design. Material preparation and data collection were performed by XY, X-jX, X-fZ, and XZ. Data analysis and interpretation were performed by R-pH, Y-yH, GT, Y-fJ, and J-dL. The first draft of the manuscript was written by R-pH, Y-yH, and X-jX, and all authors commented on previous versions of the manuscript. All authors contributed to the article and approved the submitted version.This work was supported by the Autism Special Fund from the Peking Union Medical Foundation, the CAMS Innovation Fund for Medical Science (CIFMS) (2017-I2M-3-017), and the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2019XK320030). The study sponsors had no involvement in the study design, the collection, analysis, and interpretation of data, the writing of the report, and the decision to submit the paper for publication.Authors J-dL and GT were employed by the company Geneis (Beijing) Co., Ltd.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Alzheimer's disease is a global health concern, and with no present cure, prevention is critical. Exposure to adverse childhood experiences may increase the risk of developing Alzheimer's disease. This systematic review was conducted to synthesize the evidence on the associations between adverse childhood experiences (<18 years) and the risk of Alzheimer's disease in adulthood.A search strategy was developed and conducted to identify articles investigating the associations between exposure to adverse childhood experiences and the onset of Alzheimer's disease by searching key databases . Two reviewers independently determined the eligibility of studies according to pre-determined criteria, and assessed the methodological quality using the US National Heart, Lung and Blood Institute 14-item checklist for observational cohort and cross-sectional studies, respectively. Due to limited studies, a descriptive synthesis was performed. The protocol for this review is published in BMJ Open and registered with PROSPERO (CRD42020191439).Our search yielded 781 articles, of which three  met the predetermined eligibility criteria. The methodological quality assessment yielded an overall mean score of 78.9% (range 66.6 – 84.6%). All studies found adverse childhood experiences were associated with an increased risk of Alzheimer's disease. However, there was a limited number of available studies to inform the synthesis.Adverse childhood experiences appear to be associated with an increased risk of Alzheimer's disease, although, further research is needed.The protocol for this review is registered with PROSPERO (CRD42020191439) and published with BMJ Open (Corney et al.,  Alzheimer's disease (AD) is an incurable neurodegenerative disorder and the most common form of dementia, affecting approximately 70% of people with the disease, and has a high personal and societal impact , presenelin-1 and presenelin-2 in chromosomes 21, 14 and 1, and in late-onset AD, apolipoprotein E series, especially APOE4, is the major genetic risk , which refers to sources of trauma or stress occurring under the age of 18. ACEs include emotional, physical and sexual abuse, emotional and physical neglect, and exposure to household challenges, such as domestic violence, substance abuse, mental illness, criminal behavior and parental loss   and the risk of AD in adulthood. Given the multi-factorial nature of AD, a better understanding of how adverse events throughout early life influence AD may help provide strategies to combat the growing burden of AD.(CRD42020191439). This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) .The exposure included any ACE before 18 years of age, defined by emotional/physical/sexual abuse, emotional/physical neglect, and household challenges, such as exposure to domestic/family/intimate violence, substance abuse, mental illness, criminal behavior and parental loss  , Diagnostic and Statistical Manual of Mental Disorders (DSM), National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA criteria), and/or National Institute on Aging–Alzheimer's Association (NIA-AA workgroup criteria).Studies were excluded if they were randomized controlled trials in design or published in a language other than English.via the EBSCOhost platform, a secondary search was performed on the 23rd of March 2022 to identify any new studies. Limitations were applied, restricting studies published in a language other than English. Gray literature was searched using an adapted search in Google. In addition, hand-searching the reference lists of included studies was performed to identify any further studies. A complete search strategy for each database is presented in 3.In consultation with an academic librarian, a search strategy was developed combining elements of the Population, Exposure, Comparator, and Outcomes (PECO) inclusion criteria, and translated for each research database  . One revTwo reviewers (K.B.C. and E.C.W.) independently screened the titles/abstracts and reviewed full texts according to a predetermined screening checklist based through covidence data extraction and agreed 100% on selection. One reviewer (K.B.C.) screened the reference lists of eligible studies to locate any further articles.A data extraction form was developed in Covidence and reviewed by K.B.C and E.C.W in addition to the supervising author L.J.W. Next, pertinent data were extracted by K.B.C and E.C.W independently, including: citation/study details ; study approach ; participant/population information ; exposure information ; comparator information; outcomes ; and key results.p value], as well as hazards ratio and Wald statistic .The effect measures for this review included odds ratio  and paternal death occurring when participants were aged 0–4 years [OR 2.2 (p = 0.009)]. Norton et al. (p = 0.055), and no association among persons aged 70–74 years, 75–79 years, and 80 years or older. Norton et al. , with the prevalence more than doubling with maternal death during subject's adolescence [OR 2.266 (p = 0.001)] (11–17 years). However, no association was found between maternal death and AD in subjects aged 0–4 years and 5–10 years. Whereas, an association between paternal death and AD was reported in subjects aged 0–4 years [OR 2.228 (p = 0.009)], but not for subjects aged 5–10 years and 11–17 years. Additionally, Norton et al. (p = 0.017)] and paternal age  at the participants birth were associated with a higher risk of AD. However, when tested for their association with AD net of maternal and paternal death, both maternal age and paternal age at the participants birth were no longer associated with AD. However, the associations between maternal death during the participants adolescence  and paternal death before age 5  with AD remained robust after adjustment for parental ages at participants' birth.Differences in age were observed in two studies . When separate models were run for each of the four age groups, a trend was found for the association between familial deaths during childhood and AD risk for persons aged 65–69 years , whereas no association was found among persons aged 70–74 years, 75–79 years, and 80 years or older.Furthermore, Norton et al.  reportedThis systematic review identified and evaluated existing research investigating the association between ACEs and AD. AD risk was reported to be higher for those with ACEs overall and for specific age groups and sex among these studies. However, it appears this topic remains substantially understudied, and the findings from this synthesis should be interpreted with caution.While limited evidence was found, the identified literature suggests ACEs are associated with increases in AD risk. Suitably, there are a number of mechanisms which could explain these findings. Recent studies have noted age and sex differences can modify stress responses to ACEs, with these differences interacting with biological development, and therefore increasing the susceptibility to AD  mentioned above, however future research could consider other adversities such as maltreatment and/or trauma and their associations with AD risk. Sixth, the relationship between ACEs and AD may vary by age, sex, number and/or type, however, the identified eligible studies only evaluated some of these relationships, and thus, future research should incorporate these factors.A strength of all studies was employing an internationally recognized clinical diagnostic tool as their instrument of AD identification. Additionally, Norton et al.  and Nortn = 296), compared to the two analyses from the cohort study that included a much larger sample size of n = 4,108  and the risk of AD in adulthood and evaluated the methodological quality of the identified studies. To our knowledge, this is the first review to systematically investigate the association between ACEs (<18 years) and AD risk. All studies found ACEs were associated with an increased risk of AD. In this view, childhood mental health may be a possible avenue for early prevention strategies targeting Alzheimer's disease. However, the number of available studies were not sufficient to determine certainty in the levels of evidence. Therefore, further research is needed to understand the relationship between ACEs and AD. Moreover, the underlying mechanisms require further exploration.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.KC, LW, and JP planned and designed the study. KC implemented the search strategy. KC and EW independently screened the titles and abstracts according to the predetermined screening checklist. Conflicts at the screening stage were resolved through discussion with LW who provided final judgement. Final inclusions were decided by full-text reading of the articles by KC and EW independently, and consensus with LW and KC analyzed and interpreted the data and reported on the present findings. AS, SQ, BK, and BM provided critical feedback throughout the study. All authors contributed to the final version of the manuscript.KC was supported by the Australian Rotary Health/Bing Taylor PhD Scholarship. LW was supported by a NHMRC Investigator grant (1174060). EW and BS were supported by a Deakin University Postgraduate Research Scholarship (DUPRS). The funding sources will have no role in the study design, data collection, data analysis, data interpretation, writing of the report or the decision to submit the paper for publication.JP was employed by Barwon Health. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


This study aims to evaluate the clinical efficacy of collagen dressing for patients with chronic wounds.Relevant randomized controlled trials were searched from the databases such as PubMed, EMBASE, and the Cochrane library as of January 2022. For dichotomous outcomes and continuous outcomes, risk ratio and mean difference were calculated, respectively. Subgroup analysis was performed according to the type of chronic ulcer and follow-up. In addition, trial sequential analysis (TSA) was performed to further verify the results. Jadad score was used to assess the quality of trials. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) was utilized to assess the level of evidence for outcomes.In 11 studies, a total of 961 patients of whom 485 were in the collagen group. Compared with standard of care (SOC) alone, the group that added an extra collagen dressing achieved a higher wound healing rate . The collagen group also showed a higher healing velocity than the SOC group . In addition, the adverse events related to dressing between the two groups were similar .Collagen dressing increases the wound healing rate and may be an effective and safe treatment for chronic wound management. However, more extensive research shall be conducted to substantiate these results.https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=245728, identifier: CRD42021245728. Skin injuries can be divided into acute and chronic wounds, according to the required time of healing. According to the definition, chronic wounds generally are wounds that cannot heal in 6 weeks . ChronicCollagen is the most abundant and widely distributed functional protein in the body and contributes to wound healing. In the hemorrhagic coagulation phase, collagen has the role of hemostat due to three-dimensional scaffolds. After interacting with fibronectin and growth factors, collagen stimulates the chemotaxis of monocytes and fibroblasts, and then granulation tissue is produced . As a poAt present, the role of collagen in wound healing is becoming more widely recognized. However, the effect of collagen dressing on chronic wounds was inconclusive . The goahttps://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=245728) and followed Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidance (The study protocol was prospectively registered at PROSPERO (registration no.: CRD42021245728) ”.The inclusion criteria were as follows: (1) studies [published randomized controlled trials (RCTs)]; (2) participants ; and (3) interventions . The exclusion criteria were as follows: (1) studies that did not include original data; (2) studies that the type of article was review articles, editorials or conference abstracts, letters to the editor, and preclinical studies; (3) studies that did not report on previously defined outcomes; and (4) non-English text.The primary outcome was wound healing rate because this was the most consistently reported outcome. The formula used to calculate wound healing rate is the number of patients who achieved wound healing during follow-up/the total number of observed patients. Wound healing was defined as complete closure as 100% re-epithelialization of the wound. Healing velocity, recurrence of ulceration, and adverse events (related to dressing) were the second outcomes. Healing velocity in follow-up duration was defined as the percentage of wound area per week that was reduced. Adverse events included amputations, skin sensitization, pain, discomfort, immunological rejection, infections, and off-odor et al.Two independent researchers  searched the database according to the search strategy designed previously and screened the retrieved studies as per the inclusion and exclusion criteria, and recorded the reasons for exclusion. If a dispute arose between the two researchers, it would be resolved by a panel discussion. Data extracted included the authors of the studies, country, year of publication, study design, population baseline, intervention, wound duration, wound area, and wound type.Based on Cochrane Collaboration's tool, the risk of bias 2.0 (RoB 2.0) was assessed by two researchers  independently , and anyI2 statistical and Chi-square tests were used to calculate heterogeneity, and it was defined as high heterogeneity when I2 was greater than 50% and if it is less than 50% it was defined as low heterogeneity. In case of high heterogeneity, a random-effect model was used for the pooled results; otherwise, a fixed-effect model was performed on the pooled data. Forest plots were conducted to visualize the effect. It was defined that P < 0.05 was considered statistically significant. For dichotomous outcomes and continuous outcomes, the risk ratio (RR) and mean difference (MD) were calculated, respectively. To evaluate the stability of the meta-analysis results, sensitivity analysis was performed by removing one study from the analysis each time. Egger's and Begg’s tests were performed to further probe publication bias . ion bias , 16. To α = 0.05, and power = 80%. If the cumulative Z-curve crosses the RIS threshold, it means that the sample size of the accumulated evidence is sufficient. However, if the cumulative Z-curve does not cross the RIS threshold, it means that the sample size is not sufficient. Moreover, the result shall be confirmed by more studies. The TSA boundary is set based on the RIS. When the cumulative Z-curve crosses the TSA boundary, the conclusions are considered statistically significant.In the present study, TSA v0.9.5.10 Beta Software was used to perform the trial sequential analysis (TSA). The required information size (RIS) is evaluated by setting relative risk reduction = 20%, the first type of error After searching according to PICOS principles, 1,960 studies were initially retrieved, of which 21 were defined as potentially eligible. Among these 21 studies, one study was excluded for case report, four studies were excluded for non-English, four studies were excluded for review, and two studies were excluded for letter. The literature search and selection processes are described in The basic characteristics of the included studies are described in I2 statistic (I2 = 28.2%). No significant publication biases were found by Egger's (P = 0.14) and Begg's tests (P = 0.64). As A total of 961 cases reported wound healing rate. In this endpoint, 53.4% (259/485) wounds in the collagen group and 34.50% (164/476) wounds in the SOC group achieved complete healing. Statistical analysis indicated that the wound healing rate in the collagen group is significantly higher than that in the control group  . No subsA total of 337 chronic wounds in two studies were included to compare the healing velocity between the collagen and SOC groups . CompareP = 0.32), and 7% for the collagen group and 10% for the SOC group during 12-week treatment (P = 1.00). As The recurrence of ulceration was reported as a safety outcome in three studies together with 172 healing wounds. Campitiello et al. indicated that the number of wounds healed in the collagen and control groups during the 6-week observation period was 20 and 12, respectively, and the rate of recurrence was 8.69% for the collagen group and 43.47% for the SOC group. Driver et al. and Edmonds et al. indicated that the rate of recurrence was 19% for the collagen group and 26% for the SOC group , as presented in Sensitivity analysis was conducted, and the results are presented in Z-curve crossed the TSA boundary, and the positive conclusions were obtained in advance, which was consistent with the above meta-analysis results. Hence, it can be asserted that collagen dressing was more effective in the treatment of chronic wounds, and the result was reliable . For the primary outcome, the result suggested that the reliable .This is the first meta-analysis that reviews the efficacy of collagen dressing on chronic wounds. In this article, available studies were combined, and a suitable methodology was used to analyze the clinical value of collagen dressing in the treatment of chronic wounds. The study design was mainly about RCTs, which enhanced the credibility of the results of this article. We specifically focused on four outcomes: wound healing rate, healing velocity, recurrence of ulceration, and adverse events. At the same time, subgroup analysis was also performed according to follow-up and wound types. In the current study, we found collagen dressing had an excellent effect on chronic wounds, which facilitated wound closure. At the same time, adverse events were similar in both groups and no immunological rejection was reported in those studies. Infections were recorded in the collagen group (8.3%) and the control group (15.0%), which suggested collagen dressing was safe and reliable.The cost of mass production of dressings from human collagen is very high. In practice, recombinant human collagen  or animaCollagen dressings are extremely advantageous in wound healing, which include the following: (1) it has low immune rejection in humans, which is based on the strongly preserved primary sequence and the helix structure , 36; (2)Although collagen dressings are costly in short term, the cost of collagen dressings can be offset by improved wound healing rate and accelerated wound healing , 51. AccChronic wound healing is a challenging problem. Tiago et al.  demonstrThe current limitations of this study should be noted. First, only 11 original studies were included and 2 of them were reported as high risk. Second, the TSA analysis indicated that the number of cases included in this article was inadequate. Third, it also should be noted that the types of collagen dressings used in the included studies were inconsistent, which may contribute to heterogeneity and bias, although we tried to harmonies the dressing criteria as much as possible during the screening phase. Apart from inconsistencies in the type of dressing, there are also inconsistencies in the factors that can influence the results, including the method of measuring wound area and duration time. Fourth, immunological rejection was an issue that requested special concern. Unfortunately, limited by available data, the current systematic not pooled this endpoint. Therefore, future studies need to take these factors into account and more multicenter, randomized controlled clinical studies are needed to further demonstrate those views.Collagen dressing combining SOC increases the rate of chronic wound healing, accelerates non-healing wound closure, and reduces ulcer recurrence compared with SOC alone. Therefore, adding extra collagen may be an effective potential wound management that holds the ability to facilitate chronic healing. However, more multicenter, randomized controlled clinical studies are needed to substantiate those points in the future.


Lupus nephritis is one of the most severe complications of systemic lupus erythematosus and it has been estimated that can occur in up to 60% of patients. Direct costs of lupus nephritis have not been studied in developing countries. This study aimed to describe lupus nephritis direct costs in Colombia.th revision codes was developed to identify patients with lupus nephritis and lupus nephritis under study. Administrative data from two Colombian health maintenance organizations for 2014 and 2015 was obtained. An algorithm based on the International Statistical Classification of Diseases and Related Health Problems 10 The average annual per-patient, all-claims, all-cause direct cost for lupus nephritis was US$ 12,624, 7.5 times higher than the average lupus patient without lupus nephritis. For lupus nephritis cases under study, estimated direct cost was US$ 3,664, 2 times higher than average lupus patient in Colombia. Difference in lupus nephritis patients is mainly accounted for the cost and frequency of procedures, exceeding by a factor of 5 the cost for durable medical equipment and the cost for drugs, respectively. Lupus patients who progress to lupus nephritis stage increased seven-fold the average annual per-patient, all-claims, and all-cause direct cost for the Colombian health system. Lupus nephritis occurs in 38.5% of patients with recent diagnosis of SLE, in the first five years of the disease in the majority of cases and it has been described that 60% of SLE patients will develop the complication through the disease evolution.,5 In a study conducted in SLE hospitalized patients, lupus nephritis was the most common organ involvement during 4 years.Systemic lupus erythematosus (SLE) is a chronic, autoimmune and systemic disease with the potential to affect any organ or system. It is well known that renal involvement, lupus nephritis, is the most severe complication due to its association with progression to end-stage renal disease (ESRD), and mortality. Specifically, in Colombia, the population is a mixture of black, white and indigenous peoples. This ethnicity confers higher risk of developing lupus nephritis as it has been demonstrated before.,8 Also, lupus nephritis affects more men than women, and contrary to what has been seen in SLE without the complication,,9,10 it is more often seen among younger patients.,11,12 In pediatric patients, it occurs in 50-75% of them and the vast majority of them have developed the complication in the first two years of SLE diagnosis, and Hispanic population is one of the ethnicities at higher risk. However, the histological form of presentation of lupus nephritis has no significant differences compared with Caucasians.Regarding ethnicity it predominance has affected by 20% of black people and 52% of Asian Pacific Islanders. However, some approaches based on urinary biomarkers are being proposed to ameliorate these issues in the future.The confirmed diagnosis remains dependent on a renal biopsy, a procedure that is not only invasive but costly as well. It may also be needed during the course of the disease when severe flares occur or discard histological transformation.The main treatment strategies consist of an induction scheme of cyclophosphamide (or mofetil mycophenolate) followed by mofetil mycophenolate or other immunosuppressants for maintenance. In spite of adequate treatment, renal flares have an incidence of 27%- 66%.,18Due to its less favorable prognosis, lupus nephritis is associated with higher rates of hospitalization, procedures such as dialysis, and surgery in cases of renal transplantation. The literature on direct cost of these patients is concentrated in the developed world. A study in Canada with a cohort of 141 patients conducted between 2004 and 2009 found direct cost of outpatient services associated with SLE with lupus nephritis totalizing Canadian US$ 12,597 Canadian dollar compared with Canadian US$ 10,585 in those without lupus nephritis. A study in the United States (US) with 2,298 patients from 1999 to 2005, estimated that lupus nephritis had a cost of US$ 27,463 in the first year including all outpatient and inpatient healthcare services, after this period cost has increased. This study also showed that patients with lupus nephritis were more than twice as costly as patients without the disease. Another paper from the US with 15,590 patients showed that between 2006 and 2008, patients with lupus nephritis spent US$ 6,029 in pharmacy, US$ 15,267 in outpatient services, and US$ 9,292 in hospitalization. In contrast, patients without lupus nephritis had a cost of US$ 3,190; US$ 6,202 and US$ 2,636, respectively.All the above mentioned healthcare resources, act as determinants of an increase in the direct costs of lupus nephritis.The Colombian health system design follows the managed competition principles. The Ministry of Health defines the national benefits package and pays a per capita premium to health plans. Enrollment in health plans is mandatory, so health plans compete to attract members. Providers of healthcare are either private or public and also compete to be part of health plan’s network. The system is divided in two subsystems. One called “contributive” because it is financed by employer-employee contributions and covers the working population and their families. The other one is called “subsidized” because it is financed by the national government and cover the poor. There is a private insurance market in which people may buy additional coverage. Lupus treatment is partially covered by the national government-defined benefits package. Treatment beyond such coverage is obtained either by judicialization or by private insurance.In a previous paper published by our group, annual direct costs of lupus care resulted in US$ 2,355, in average, per-patient, all-claims, and all-cause.We aimed to show the all-claims, all-cause cost of lupus nephritis patients for a health system for the first time in a developing country using administrative claims data.This is a descriptive data study. We used administrative claims from two private health maintenance organizations (HMOs) for years 2014 and 2015. Data was obtained under an academic agreement between Fundación Valle del Lili and Universidad Icesi, Cali, Colombia and both organizations. As this is a study based on claims data, an Ethics Committee approval was not required. In 2015, together both HMOs insured around 4 million lives accounting for 17% of the national health insurance plan for the working population, and almost half of the enrollees in Colombia´s southwest region.,25Two datasets were linked by a unique identifier. The first database corresponds to claims paid for by these HMOs using funds received from the national government to cover the government-defined public benefits package. The second, claims of services did not include in the national public benefits package, but also paid for by the government using a reimbursement mechanism. This is a characteristic of the Colombian system by which high-cost drugs or procedures are allowed in case by case basis following judicial rulings.The public benefits package data includes demographics as well as services rendered. Demographics include: gender, age, city of residence, educational level, and enrolment types (primarily-insured or beneficiaries). Services rendered include: a unique patient identification, date when the service was provided, type of service , the mechanism of reimbursement (capitation or fee-for-service), municipality, primary diagnosis, service type , and the amount paid for by the insurer to the provider. The non- public benefits package data include: patient identification, service date, amount reimbursed, and service type .th (ICD-10). Diagnosis included were: discoid lupus erythematosus (DLE), L930; subacute cutaneous lupus erythematosus, L931; drug-induced SLE, M320; SLE with organ or system involvement, M321; other forms of SLE, M328; and unspecified SLE, M329. After excluding the patients that did not have the diagnosis in both years (2014 and 2015), the final sample was 3,592 patients.Lupus patients were selected using the tenth revision of the International Statistical Classification of Diseases and Related Health Problems 10To identify lupus nephritis patients, we developed an algorithm using specific rules for diagnoses, drugs, and procedures information as present in the datasets. First, the ICD-10 was used for this purpose. The following diagnoses were included as indicators of the disease :Nephrotic syndrome with other morphologic changes, N048;Acute kidney failure with tubular necrosis, N170;Acute kidney failure with acute cortical necrosis, N171;Other acute kidney failure, N178;Acute kidney failure, unspecified, N179;Unspecified kidney failure, N19;End-stage renal disease, N180;Other chronic kidney diseases, N188;Chronic kidney disease, unspecified, N189;Kidney transplant status, Z940.th (ICD-10).International Statistical Classification of Diseases and Related Health Problems 10Second, we used the record of outpatient drugs paid for by the insurer associated with the unique ID of the patient during the period of the study. The Anatomical Therapeutic Chemical (ATC) classification system was used. Codes that were considered highly likely associated with lupus nephritis are the following:Cyclophosphamide, L01AA01;Mycophenolic acid, L04AA06.Third, the following CD-10 revision procedure classification system were included:Kidney biopsy;Kidney transplant;Hemodialysis;Peritoneal dialysis.Patients were classified as lupus nephritis if they had either a diagnosis and underwent a related procedure, or had a diagnosis and were treated with one of the listed drugs. However, not all patients coincided perfectly, filling only one criterion or the other. To avoid discarding likely cases of lupus nephritis, a category called “suspected lupus nephritis” was included in the study, composed of patients identified by one method. The classification algorithm was applied to years 2014 and 2015. Patients that were identified in 2014, but not in 2015, were revised in detail by one of the authors, a practitioner rheumatologist who studied every claim of those patients. After the rheumatologist analysis, 23 false positive cases of lupus nephritis were excluded, because they presented additional diagnoses to which renal involvement was attributable, such as toxic nephropathy, or were not taking any immunosuppressant drugs. The number of patients with lupus nephritis in 2014 and 2015 were 113 and 135, respectively. The cases of suspected lupus nephritis were 297 and 459, respectively .Direct cost for the government funded Colombian health system are defined as payments made by insurers to providers. Cost was estimated by summing all-cause public benefits package and non-public benefits package services rendered and paid for lupus nephritis patients. The official currency of Colombian is the peso (COP), however, in the results section figures are in dollars for comparability with the international literature. We used the average exchange rate from both years  to convert from COP to US$. Annual all-cause all-claims direct cost from public benefits package was calculated by type of service , point of service . No statistical inference tests were performed between years because the data is not a sample but a population of patients for both insurers. Patients with lupus nephritis were 7,46 times as costly as patients without lupus nephritis in 2015. Suspected-lupus nephritis patients were 2,16 times as costly as patients without lupus nephritis in 2015.In This paper described all-cause all-claims direct costs paid for by insurers associated with lupus nephritis patients, based on administrative data of patients enrolled for two consecutive years, 2014 and 2015, in two HMOs in Colombia. Of 3,592 patients with lupus diagnosis, we developed an algorithm to identify patients with lupus nephritis under study and lupus nephritis, that accounted for 523 and 594 patients in 2014 and 2015, respectively. In Australia, Yeo et al. evaluated 200 patients with lupus from 2013 until 2016, and found that the mean annual direct costs was of US$ 7,413, and again, renal involvement was the organ manifestation that annually incremented costs the majority in 62.5%. Tanaka et al. studied 295 Japanese patients with lupus from 2010 to 2012, with a mean cost during that period of time of US$ 27,004. They also they divided the disease severity in mild, moderate and severe, for which the costs were US$ 5,549, US$ 15,290, and US$ 43,322, respectively. In these groups, patients with renal manifestations had 78.3% greater costs than those without this disease.We found that all-cause average annual direct costs for these patients to be US$ 11,405 and US$ 12,624 in 2014 and 2015,respectively. Patients with lupus nephritis were 7.46 times as costly as patients without lupus nephritis in 2015. The Lupus erythematosus Cost of Illness in Europe (LUCIE) study evaluated healthcare costs of lupus in 427 patients of five European countries, and reported that one of the predictors of higher costs was renal involvement, adding US$ 711 to the costs.Regarding type of services, we found that for both lupus nephritis and lupus nephritis under study, procedures were the most frequent and costly expense for insurers. By the point of service, inpatient services for lupus nephritis and lupus nephritis under study were the most important in both years, except for lupus nephritis under study in 2015 that was outpatient services. More specifically for lupus nephritis, the most expensive healthcare services per procedure rendered were surgical procedures such as nephrectomy and renal transplantation, while for lupus nephritis under study, it was renal biopsy; for both high complexity hospitalization services including ICU stays. The lack of clinical data prevents us to confirm severity, but costs by type/point of services, are likely associated with patients in more advanced stages or with higher number of comorbidities, which would be proportionally associated with higher all-cause and all-claims costs per-patient. Furst et al. compared 907 lupus nephritis patients with controls in the USA, and reported that 98.90% of patients used diagnostic services annually. Renal biopsy as a mandatory procedure to confirm prognosis and sometimes to follow-up, surely contributes to the finding of this study.In a similar way, a multicentric study that included patients from the US, Mexico, Korea, Canada and Europe found that in patients with lupus nephritis and with GFR <30mL/minute or ESRD, the dialysis was the most expensive type of service whereas in patients without lupus nephritis, the most expensive issue was the drugs. Also, according to this study, the worse the renal function the higher the five and ten-year cumulative costs as in patients with ESRD that were expected to cost 23-fold that of non-lupus nephritis patients. Lupus nephritis is the main SLE complication associated with death, as well as lupus nephritis patients are at high risk of developing ESRD. In this way, management guidelines emphasize that the aims of treating lupus nephritis are to favor patients survival, to avoid flares and to preserve kidney function, among others. All of which may be accomplished when accessing multidisciplinary healthcare attention whenever possible.A recent study showed that mortality in Latin population was four times higher than expected.Our study is based on administrative data, thus accuracy may be affected by the lack of clinical data.Lupus patients that progressed to lupus nephritis stage showed seven-fold increase of the average annual per-patient, all-claims, all-cause direct cost for the Colombian health system. Lupus nephritis is associated with high morbidity and mortality, adequate access to early and periodical multidisciplinary management that could improve outcomes, and therefore, costs related with complications such as renal replacement therapy and transplant.


Most children with normal weights were at the achieving and excelling levels, while children with overweight and obesity were at the beginning and progressing levels. The correlation among PL domains in normal and overweight and obese children ranged from weak to strong (r = 0.001 to 0.737), and the knowledge domain was inversely correlated with the motivation domain (r = −0.023). PL and domain scores were inversely correlated to BMI, except for the knowledge domain. (4) Conclusions: Children with normal weight tend to have higher PL and domain scores, while those with overweight or obesity tend to have lower scores. There was a positive relationship between normal weight and higher PL and domain scores, and an inverse relationship was observed between BMI and higher PL scores.(1) Background: Physical literacy (PL) is a multidimensional concept, since it fosters lifetime engagement in physical activities and reduces obesity; however, empirical evidence is lacking to support this association. This study first aimed to establish PL levels stratified by normal weight children and children with overweight and obesity. Furthermore, this study determined a correlation between PL domains and BMI by weight status among South Punjab school children. (2) Methods: This cross-sectional study involved 1360 (Boys: 675 and Girls: 685) children aged 8 to 12, and was conducted using CAPL-2. T-tests and chi-square were used to determine the difference between categorical variables, with MANOVA used to compare weight statuses. Spearman correlation was employed to determine the correlation between variables;  In the 21st century, the high prevalence of childhood obesity and overweight has become a global epidemic and a significant public health concern ,4. This According to a consensus-based definition, physical literacy (PL) is described as “the motivation, confidence, physical competence, knowledge and understanding to value and take responsibility for engagement in physical activities for life” . PL suppIn recent years, there has been a resurgence of interest in the concept of PL as a potentially helpful approach for understanding why certain children do or do not participate in regular physical activity . AccordiThe Canadian assessment of physical literacy (CAPL) was established in 2009 by the Healthy Active Living and Obesity research group (HALO) in collaboration with national and provincial organizations in Canada . InsteadPreviously, it has been suggested that PL may be associated with healthy weight status and various physical, behavioral, psychological, and social factors ,32. HoweThis study employed stratified random sampling (SRS). South Punjab was selected as the population, and South Punjab’s three divisions , namely Multan, Bahawalpur, and Dera Ghazi Khan, were considered as three stratums. Furthermore, 3 districts out of these divisions, Multan, Bahawalpur, and Dera Ghazi Khan, were chosen as strata, based on their population representation and geographic location within the province. The sample size of the current study was determined using Cochran’s (1977) formula ,35; prevP) = 0.234Proportion (Q = 0.77 (1 − P)Z-Score = 1.96 at a 5% level of significance.e = 0.025 level of precision.D = 5 (D is the design effect)This study is a part of the Pakistan Initiative to Promote Physical Literacy (PAK-IPPL) study among children. This study employed a cross-sectional design to assess PL among 8-to-12-year-old higher secondary school children from South Punjab, Pakistan, using the CAPL-2. The research was carried out and finished during the academic year 2020–2021. In order to ensure representation of the overall population of South Punjab, 87 higher secondary schools were chosen from three strata: Multan, Bahawalpur, and Dera Ghazi Khan, with 29 schools in each stratum. However, two schools from the Bahawalpur and Dera Ghazi Khan strata refused to participate, resulting in a total of 85 schools being included in the study . A samplMoreover, the children’s enthusiasm for learning and performing new tasks, as well as their desire to compete with their peers, played a significant role in motivating them to participate in the study. Additionally, the use of pedometers to assess daily activity levels increased the children’s interest in completing the task, which led to a high response rate for the completion of the study. Prior approval to conduct the study was obtained from the district’s education department. Due to cultural constraints, the researchers were prohibited from taking photographs or videos while collecting data. Additionally, to respect cultural norms, male study assistants were not allowed in female schools and vice versa during data collection.Additionally, the consent of the parents of the children who volunteered was acquired in writing or verbally from each school’s principal. Data collection and testing were conducted during drill  classes, to avoid interference with the teaching schedule. Students were only permitted to participate in the study if they were able to carry out everyday activities normally, were psychologically healthy, had no evident physical defects, could correctly comprehend the test requirements, and were willing to comply with the completion of the tests.The ethical board of the school of Physical Education of Shanxi University, China, approved this study in letters Dated: 2 January 2019 & 7 September 2022. Furthermore, to ensure that the study was conducted ethically and in compliance with local laws and regulations in Pakistan, approval was obtained from the ethics committee and office of the School Education department of South Punjab in letter#2189/GB.This study was conducted during the academic year 2020–2021. This study used questionnaires and other evaluation tools to collect information on demographic and anthropometric variables and to assess PL and domain levels. A schedule was followed during data collection; each school took 3 days to complete the assessment, and a schedule was followed during data collection to ensure consistency and efficiency in the data collection process. Specifically, each school was allocated 3 days to complete the assessment. This schedule was standardized across all locations visited by the researcher, as different cities were visited during the data collection process. To ensure the smooth execution of the data collection process, the data collection team contacted the decision-makers of schools in advance and inquired about the availability of student and guardian approvals. This technique helped to save time and ensure that all necessary approvals were obtained prior to the start of the assessment. On the first day, students were briefed about the purpose of the study and the CAPL-2 introduction, and the data collection team answered their queries. Then, a self-designed questionnaire and CAPL-2UQ  was delivered to the children, and a member of the research team assisted the participant if they had any trouble comprehending and completing the questions.On the second day, the CAMS and a plank test were completed under the supervision of 5 appraisers. Before the assessment, an assessor demonstrated and instructed the students on how to perform the test, and each student was given one practice trial for the plank and two practice trials for the CAMS before the actual evaluation. On the third day, anthropometric data and the PACER test were completed, and the pedometer and its instructions and tracking log sheet were given to the participants. Missing pedometer day data were computed using the procedures described in the CAPL-2 manual . If a paA self-developed questionnaire containing demographic information, such as name, age, gender, grade, and city, was distributed among children to collect participants’ demographic information.In order to accurately measure the children’s weight, height, and waist circumference (WC), children were instructed to remove their shoes and any other items that could affect the accuracy of the measurements.Height: Height was measured using the metrical rod of a Digital Electronic Height-Weight Measurement Scale . The height measurement was recorded in centimeters (cm). During the test, the subjects were first asked to stand barefoot, with their back to the wall, standing on the flat machine surface, with a straight trunk and straight head.Weight: Weight was measured using a Digital Electronic Height-Weight Measurement Scale . Weight was measured in kilograms (kg). Children were instructed to stand naturally in the center of the scale and maintain a solid body position. The examiner stood on the participant’s right side; when the decimal on the weight scale increased above 0.1 kg and the displayed value stabilized for five seconds, the examiner recorded the shown value .2]” and is widely accepted as a reliable measure of health status [n = 69) were removed due to their low percentage, as this practice was also used in a previous study [BMI: The current study used the Centers for Disease Control and Prevention (CDC) standard formula and cut points (percentiles) to assess BMI and categorize the health status of participants . BMI wash status . Accordih status . To clasus study ,33.Waist circumference: To measure WC, the examiner used a standard measuring tape and asked participants to stand straight, open their upper arms properly, close their feet, breathe normally, not purposefully contract or hold their breath, and distribute their weight evenly between both feet . After eChildren’s physical literacy was assessed according to the CAPL-2 protocol , which iThe total PL scores for each child were converted to a score out of 100 by allocating 30 points to the physical competence (PC) and daily behavior (DB) domains, 30 points to the motivation and confidence (M&C) domains, and 10 points to the knowledge and understanding (K&U) domains. Composite PL and domain scores were calculated following the above distribution, and CAPL-2 proposed an additional breakdown of the PL and domain scores into four categories, corresponding to the four stages of physical literacy development: beginning, progressing, achieving, and excelling. For instance, interpretation of these categories means that a child being at the beginning and progressing phases of PL indicates that they have not yet reached the recommended level of PL. At the same time, being in the achieving and excelling stages shows that they have achieved the recommended level. The procedures used in this study were in accordance with those outlined in the CAPL-2 manual and those used in earlier studies ,45,46. TThe daily behavior domain employed two methods to assess DB patterns regarding physical activity and had 30 points, with daily step counts accounting for 25 and self-reported PA accounting for the remaining 5 points. An objective method used pedometers to count steps, and a subjective method used a self-administered question on how many days a person engages in PA (MVPA) for 60 min per week. Daily steps were measured using Yamax DigiWalker SW-200 pedometers . The participants were given pedometers to wear over their right side hip bone, fastened to the waistband of their trousers  for seven consecutive days. The first day the children received their pedometers was designated as a “practice day”. For the following seven days, except for the day used for practice, kids or parents recorded their daily step count before turning it in for the night. They recorded the entire time the pedometer was removed throughout the day on the log sheet. Moderate to vigorous physical activity (MVPA) was measured with one item from the CAPL-2 questionnaire. Participants self-reported the number of days they engaged in MVPA for at least 60 min per week ,46.Physical competence was evaluated using three separate tests. The PC domains comprised a maximum of 30 scores (10 scores per test), and all tests were evaluated and scored from 1 to 10 points, based on the children’s performance according to the criteria outlined in the test manuals.The PACER (20 m run) test measured cardiorespiratory competence (aerobic endurance) ,48. The The abdominal plank test measured muscular endurance (torso strength) ,49. The The Canadian agility and movement skill assessment (CAMSA) test was used to assess agility and mobility skills . A wide The cognitive domain was assessed using CAPL-2 knowledge and understanding questions. This domain accessed children’s K&U of how to enhance physical competence, how to execute and improve daily PA routines, and issues such as what is muscular endurance and cardiovascular fitness, which were all addressed and evaluated in this questionnaire . The K&UIn the affective domain, four motivation and confidence aspects were measured: “predilection, adequacy, perceived competence, and intrinsic motivation” . The M&Ct-test was employed to investigate differences in gender across age, height, weight, and WC. The chi-squared test was employed for categorical variables to identify differences. A multivariate analysis of variance (MANOVA) was used to determine the differences among demographic characteristics, overall PL, and domain scores between normal weight and overweight and obese children. Spearman correlation was used to investigate the association between categorical variables . Pearson’s correlation determined the relationship between BMI, overall PL scores, and domain scores. Multivariate logistic regression was used to determine the odds ratio . In this study, Partial Eta Squared (ηp2) was used to determine the effect size: a small effect ≤0.01, a medium effect ≤0.06, and a large effect ≥0.14 [p-value less than 0.05.The present study used IBM SPSS version 22  for data analysis. Descriptive and inferential statistics were used to present the data, including means, standard deviations, and percentages. Outliers were identified using the standardized variable approach, where any observations deviating more than ±5 Z-scores from the mean for all measured variables were considered outliers. However, no specific outliers were identified; thus, the entire sample of 1360 children was used for data analysis. The normality of the data was determined through the utilization of Q–Q plots and histograms, which have been widely accepted in the literature as reliable methods for assessing normality . An indect ≥0.14 . The sig2, and 59.22 cm, respectively. Furthermore, the data revealed minimal variation in the average height of both genders. However, a significant difference emerged when analyzing other anthropometric variables, such as weight and WC. Specifically, boys exhibited higher mean values for weight and WC compared to girls. Conversely, girls exhibit a higher mean value for BMI compared to boys. A t-test analysis of these data demonstrated that there was a statistically significant difference between WC for boys and girls (p < 0.001), while there were no significant differences between the other anthropometric variables.According to the data presented in r = 0.583, p < 0.01), as well as between physical competence and motivation and confidence  in healthy-weight children. Additionally, a moderate correlation was found between motivation and confidence with physical competence . However, a weak correlation was observed between knowledge and understanding, daily behavior, physical competence, and motivation and confidence .r = 0.737, p < 0.01) and a moderate positive correlation with motivation and confidence . On the other hand, knowledge and understanding were weakly positively correlated with physical competence (r = 0.089) and moderately positively correlated with motivation and confidence (r = 0.104). However, it is worth noting that knowledge and understanding were negatively correlated with motivation and confidence (r = −0.023).r values ranging from −0.171 to −0.217, with the exception of r = 0.006 for the knowledge and understanding domain).n = 1085). The distribution of boys and girls in the normal weight and overweight and obesity groups was found to be almost equivalent . Furthermore, the age and height of children with normal and children with overweight and obesity statuses differed significantly. In the normal weight category, children had a lower weight (28.86), BMI (15.39), and WC (58.33) than the children with overweight and obesity, while the weight, BMI, and WC among normal weight children and children with overweight and obesity showed a significant difference (p < 0.001).p < 0.001). Furthermore, the mean scores for total PL and the other three domains  were found to be higher among children with healthy weight, with the exception of the knowledge and understanding domain, where overweight children had higher scores. Overall, these findings suggest that children with healthy weight tend to have better PL scores and scores in the other three domains, except for the K&U domain. The differences between the scores of the healthy and overweight children were significant (p < 0.001).The first aim of this study was to determine the current status of physical literacy, and the second aim was to examine the correlation between PL and various domains in 8–12-year-old children in South Punjab, Pakistan, stratified by weight status  and using the CAPL-2. Lastly, this study also examined the relationship between BMI, PL, and domain scores. The results regarding the PL status show that normal-weight children achieved a higher level than overweight and obese children in all domains, with a significant difference found between the two groups, except in the knowledge and understanding domain.The current study established the level of PL for 8–12-year-old Pakistani children, and the results showed that 31.3% of normal and 3.5% of children with overweight and obesity were found to be at the achieving and excelling levels of PL , motivation and confidence, and daily behavior . In addition, we found similar moderate correlations  between motivation and confidence and physical competence among children with normal weight and overweight and obesity. Additionally, a weak inverse correlation (r = 0.006 and −0.023) was only found among the knowledge and understanding and the motivation and confidence domains among the normal and children with overweight and obesity. The results indicate that motivation and confidence are significant correlates of daily behavior and physical competence [This study found a moderate to strong correlation between physical competence and daily behavior  between PA and psychosocial variables in both weight groups, similarly to the findings of our study [Similarly, our study found that there was a moderate correlation between motivation and confidence and daily behavior for both normal and children with overweight and obesity. The correlation was similar for both groups, and there were no significant differences between them. These results are consistent with the findings of a Canadian study which also observed a moderate association between PA and psychological factors (similar to M&C constructs) among normal weight and unhealthy-weight children . Furtherur study . A studyur study .r = 0.42–0.39) between M&C and PC using the CAPL-1 assessment tool, with no significant differences observed between the two weight groups [r = 0.23; CAMSA, r = 0.31) [The correlation between the motivation and confidence and the physical competence domains was found to be moderate and similar among children with normal weight and those who were overweight or obese. Despite the limited research on this type of association, the findings were consistent, as demonstrated by Delisle et al., who reported a moderate correlation (t groups . A few o = 0.31) ,49,50.A weak correlation was observed between knowledge and understanding and the other domains of PL in normal weight and overweight/obese children , except Furthermore, it can be suggested that better scores in the motivation and knowledge domains could lead to a higher level of PL in children. Thus, the positive correlations between the M&C and K&U domains led to a higher level of PL in normal weight children than in children with overweight and obesity . Given tr = 0.006). While knowledge is widely acknowledged as a crucial determinant of engaging in an active lifestyle, previous research also highlighted the significance of other factors, such as motivation and confidence, in shaping physical activity behavior [The results indicated a weak to moderate inverse correlation between BMI and levels of PL and its domains, with the exception of the knowledge and understanding domain. BMI was found to be negatively associated with higher scores for PL and its domains, consistently with previous studies that reported similar negative associations and concluded that normal weight children tend to achieve higher scores in PL and its domains ,33,63. Abehavior ,56. ThusThe results of the daily behavior domain indicate that normal weight children obtained higher scores (11.06), and a significant proportion of normal weight children (30.5%) attained achieving and excelling levels compared to children with overweight and obesity. This finding is consistent with previous studies. For example, a literature review reported that most cross-sectional studies found an inverse relationship between BMI and daily behavior . Most participants 65.2%) did not attain the recommended levels of daily behavior. This finding is consistent with previous research conducted among Spanish , Canadia.2% did nPhysical competence domain results showed a similar pattern as the daily behavior domains, with normal weight children attaining higher scores (16.28) and a higher number of normal weight children (31.7%) reaching the achieving and excelling levels than overweight/obese children (3.5%). Similar results were reported in previous studies that focused on the PC domain and its components, where it was found that normal weight children performed better than their overweight and obese peers on tests of muscular endurance , aerobicThe results of the motivation and confidence domain showed that normal weight children achieved higher scores (18.37) than children with overweight and obesity, and that a significantly higher portion (30.7%) of normal weight children attained achieving and excelling levels than overweight and obese children (4.1%). In addition, the M&C domain showed that most of the normal weight and overweight/obese children were at progressing level in this domain. Lower motivation among overweight and obese children was previously reported ,63. Sevep = 0.577). A higher number of normal weight children (24.1%) attained achieving and excelling levels of PL than the overweight and obese children (4.2%). Overall the majority (55.5%) of participants reached progressing level for the K&U domain. As previously discussed, the existing literature on the topic is limited in terms of determining whether healthy or unhealthy children exhibit superior performance in the domain of K&U. The available studies also reported nonsignificant differences  scored higher than normal weight children (6.36), although the difference was not significant ( = 0.035  and p =  = 0.024 ) in the Overall, the PL and domain scores favored normal weight children. The current study’s findings revealed a correlation that fell within the range of low to moderate. This suggests that the structure and design of the CAPL-2 assessment tool is effective when measuring the relevant variables in both normal weight and overweight and obese children and for producing valid scores for the PL and domains. The results of our study revealed a concerningly low level of PL among children in South Punjab. This finding highlights the urgent need for interventions aimed at improving the level of PL among Pakistani children. One promising approach that could be utilized in this PE endeavor is using CAPL-2 to assess and improve PL levels among school children. Additionally, a longitudinal investigation should be conducted to evaluate the long-term benefits of these interventions on the children’s overall health and well-being. This is crucial to understanding the impact of improved PL on various aspects of their development and to guide future policy-making in this area.The originality and strength of the current study lie in the fact that it was the first to utilize the well-established and validated CAPL-2 instrument to examine the PL status of children in the Pakistani population and to provide empirical evidence of the association between PL and weight status in an Asian population. Furthermore, it should be noted that the instrument has only been validated in a limited number of countries ,43,44,76Furthermore, it will be valuable for comparing PL levels with children from other countries, enabling the identification of global PL trends. This study’s strengths include an adequate sample size, which addressed the limitations of previous studies ,43. AnotThe current study has several limitations that warrant further investigation. One limitation is that this study only stratified the PL and domain scores according to weight status and did not consider the potential impact of other confounding factors, such as socioeconomic status, Tanner stages, pubertal status, living area, or parental influences. These variables may play a significant role in determining the causes of low PL levels, and understanding their impact could inform the development of interventions to improve PL levels among Pakistani children. Future studies should be conducted in various regions of Pakistan to determine the overall PL level in the country, as the current study was limited to the population of South Punjab. The findings of this study suggest that future research should focus on charting the PL journey by developing growth charts and establishing normative reference values for variables such as weight, height, BMI, and waist circumference using standard deviation scores (SDS) or percentile methods. A larger population sample should be utilized to further investigate the influence of potential confounding factors in future research. An in-depth analysis would be beneficial to gain a more comprehensive understanding of the relationship between PL and weight status.Additionally, as previously suggested, longitudinal investigations are recommended, to ascertain PL levels stratified by weight status from childhood to adulthood . It is iIn South Punjab, Pakistan, the PL and domain levels of children with normal weight were significantly higher than those of children with overweight and obesity, with the exception of the K&U domain; in this domain, children with overweight and obesity achieved slightly higher scores. The correlations between domains were weak to moderate for children with normal weight but were weak, moderate, and strong for children with overweight and obesity. The inverse correlations between BMI and domains indicate that normal weight and BMI range are strongly associated with the recommended level of PL for children. Thus, better PL and domain scores are associated with better health in children. Therefore, it is imperative that policymakers, school administration, and PE teachers prioritize the incorporation of PL into existing school PE programs for Pakistani children. This proactive approach will not only inspire children to actively participate in PA, but it will also instill healthy lifestyle habits and promote the importance of maintaining a healthy weight through increased motivation and knowledge. By prioritizing PL in school programs, we can effectively encourage Pakistani children to lead more physically active and healthy lives.


Multiple studies have confirmed that breast-conserving surgery (BCS) followed by radiotherapy is a safe option for patients with We retrospectively analyzed 115 patients affected by PD treated in our institution between January 2000 and May 2021. Median age at diagnosis was 60 years and median follow-up was 82 months; 69 patients were treated with BCS and 46 were treated with modified radical mastectomy or skin-sparing mastectomy.At histological examination, 59 patients  had an underlying invasive carcinoma; in 11 patients , only PD was found. In 45 patients , only noninvasive cancer was found. Nine patients  developed a local recurrence, 7 patients  are alive with distant metastasis, and 10 patients  died.in situ cancer, and PD with invasive cancer, regardless of the surgical procedure. BCS followed by radiotherapy appears to be an effective and safe option for patients with PD.In our series, no statistically significant differences were shown between PD alone, PD associated with PD is a rare form of breast cancer and, in half of the cases, is associated with an invasive carcinoma. Separating our sample into three subgroups based on tumor histology, there were no significant differences in terms of LC, DFS, and OS rate in patients treated with different types of surgery. This study presents some limitations due to its retrospective nature and being confined to a single institution. Paget’s disease (PD) is an uncommon breast lesion associated with cancer characterized by heterogeneous clinical features, such as erythema, nipple scaling, eczematous rash, and skin ulceration. The symptoms more often reported are bleeding, pain, and itching. Described by Sir James Paget in 1874 –4 mostlyPrognosis is determined by the presence or absence of underlying invasive cancer.It is widely accepted that the intradermal Paget cells originate from an underlying ductal cancer, but the histogenesis and pathogenesis of Paget cells remains controversial. The current theory argues that luminal lactiferous ductal epithelial cells give rise to Paget cells, which migrate into the epidermis –7. Microin situ or invasive PD  followed by radiotherapy to be an acceptable or even preferable alternative to mastectomy for patients with early-stage asive PD , with loasive PD –12.Based on current standards, in all patients affected by PD undergoing mastectomy or conservative surgery for an invasive carcinoma, sentinel lymph node biopsy (SLNB) should be performed .The prognosis of these patients depends primarily on the presence of an underlying invasive component . The preThe largest series of PD in literature is the one of Yufeng Yao and colleagues  made up In this paper, we retrospectively analyzed 115 patients affected by PD and treated at our institution between January 2000 and May 2021. The aim of the present study is to describe our experience and to outline the best plan of treatment.All data were collected from our database at the Fondazione Policlinico Universitario Agostino Gemelli IRCCS of Rome, Italy. We performed a retrospective review of 115 consecutive cases of PD of the breast treated during the period 2000–2021 and presenting with or without a palpable mass. The patients consisted of 111 women and 4 men. The median age at diagnosis was 60 years . The median follow-up time was 82 months .Each patient was discussed in a multidisciplinary meeting with pathologists, surgeons, and radiologists from our Breast Unit, in order to select the most appropriate surgical treatment, on the basis of international breast cancer guidelines and careful clinical and appropriate imaging assessment of each patient. A clinical examination and radiological imaging study with ultrasound, digital mammography, and magnetic resonance imaging were performed preoperatively. After primary surgery, all cases were evaluated at a multidisciplinary meeting to select systemic therapy. Patients’ characteristics and pathologic features are detailed in in situ or invasive carcinomas and no clinically positive lymph nodes.Patients were deemed candidates for nipple-areola excision alone only when a complete removal of the disease was feasible, while a BCS and SLNB were chosen for small and unifocal Among the patients not suitable for BCS, 29 were treated with radical mastectomy and 17 patients were treated with skin-sparing/skin-reducing mastectomy.Complete axillary dissection was performed in 32 patients with positive sentinel node Table 2.Radiation therapy was performed in all patients treated with BCS , while 35 patients  were treated with adjuvant chemotherapy.Data were collected in order to evaluate oncological outcomes: local recurrence (LR), disease-free survival (DFS), and overall survival (OS).p‐value equal to or less than 0.05 was considered statistically significant. Estimates of OS, DFS, and LR were produced by cumulative incidence, using the Kaplan–Meier method. Multivariate analysis was not performed due to the limited number of events.Results are expressed as means with standard deviations and median with ranges. Statistical analysis was performed using the SPSS (version 24.0 for Windows). Fisher exact test was used for comparison of categorical variables. A At histologic examination, the majority of patients  had an underlying invasive carcinoma; in 11 patients , only PD was found. In 45 patients  only noninvasive cancer was found. Thirty-five patients  presented with a palpable breast mass, and all patients with a palpable mass were found to have an invasive cancer. Forty-nine  cases of PD have been identified in the right breast and 66  have been identified in the left breast, and the diagnosis of breast carcinoma with or without PD was confirmed histologically in all cases with preoperative biopsy or cytology.Sixty-nine patients  were treated with BCS, while 46 patients  underwent conservative (nipple/skin sparing) or radical mastectomy.With a median follow-up of 83 months , nine patients  developed a first recurrence of disease in the treated breast. All recurrences in the breast had an invasive component. Seven patients  presented with distant metastasis. Overall, 10 patients  died, all presented with recurrences Table 3.in situ, and PD associated with invasive cancer   Figure 1in situ, PD + IC). There were no significant differences in the LC, DFS, and OS rate between the subgroups  of patients treated with different types of surgery (BCS or mastectomy) was performed, separating our sample into two subgroups based on tumor histology  have received adjuvant treatments (82.6%). In addition, half of the patients in our study (61/115) were operated on between 2015 and 2021 and therefore had a short follow-up period. Magnetic resonance imaging (MRI) seems more sensitive that mammography or breast ultrasound alone in terms of its ability to identify small lesions especially in young women or to detect retroareolar tumor tissue (In our retrospective analysis, we found no significant difference in oncological outcomes between patients affected by PD alone, PD with r tissue , 19. In r tissue . Polgar r tissue , 24, buteatments 2.6%. In r tissue . By now,ries 95/1 have recries 95/1 have recr tissue . Nationar tissue . Howeverr tissue , 90.0% oPD is a rare form of breast cancer. In 30.0% of cases, it may present with a concomitant mass within the breast, and in at least half of the cases, it is associated with an invasive carcinoma; therefore, the correct treatment choices depend on the underlying staging and pathological features of the disease. The present study should be interpreted in the context of its limitations. As regards local treatment, for selected patients, BCS in association with adjuvant radiotherapy appears to be an effective and safe option; in our experience, SLNB should be considered in all PD patients with an underlying invasive carcinoma and/or suspicious axillary findings. At follow-up, the recurrences and survival rates of PD seem to be comparable to those of breast carcinoma overall. These conclusions cannot be definitive and clearly more prospective randomized trials are needed in order to establish a standard of care for these patients.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.Conceptualization: LS and EB. Methodology: LS and MS. Validation: LS and SD’A. Formal analysis: AnF and EB. Investigation: AnF, SD’A, and MS. Data curation: AnF and EB. Writing—original draft: LS, EB, and DG. Writing—review and editing: LS and SM. Visualization: GF, SM, and AL. Supervision: RM, GF, and AlF. Project administration: RM and SM. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.