An SSc pattern was significantly more prevalent in SLE (23%), SSc (82%), IIM (35%), and rheumatoid arthritis (17%) compared with both control groups. The prevalence of an elevated microangiopathy evaluation score (MES) was significantly higher in SLE, SSc, and IIM than in the HVs. Conclusion: The presence of another CTD in SSc did not influence CD or morphology. An SSc pattern may also be present in CTDs other than SSc. The MES is a useful instrument to distinguish between patients with CTDs and controls.Introduction: Nailfold video capillaroscopy (NVC) is a useful tool for measuring capillary density (CD) and capillary morphology parameters and is mainly used in systemic sclerosis (SSc). Objective: We aimed to assess the prevalence of an SSc pattern and CD in different connective tissue diseases (CTDs). Methods: NVC was performed on 268 patients with CTDs. Control groups consisted of 104 healthy volunteers (HVs) and 36 primary Raynaud’s patients (PRPs). Results: Decreased CD was more prevalent in SSc, systemic lupus erythematosus (SLE), inflammatory myopathies (IIM), and overlap CTD patients compared with both controls. Average CD, the prevalence of decreased CD, and the prevalence of an SSc pattern did not differ significantly between SSc patients with ( Capillaroscopy is a non-invasive method used to evaluate capillary density (CD) and morphology. This method has an important role in differentiating between primary and secondary Raynaud’s phenomenon (RP) ,2,3 and Capillaroscopic abnormalities are widely described in SSc ,3,6,7. CIn addition to the assessment of CD and an SSc pattern, other complex methods have been developed to describe microangiopathy in SSc . The micConcerning systemic lupus erythematosus (SLE), idiopathic inflammatory myopathies  and Sjögren’s syndrome (SS), systematic reviews on microvascular abnormalities have been published recently ,22,23,24Capillary enlargement and/or giant capillaries are often reported in patients with adult IIM ,26,27. BA systematic analysis of the few available SS-associated capillaroscopic publications revealed a lower CD compared to HVs. An SSc pattern may also be present in SS, mostly in cases with overlap syndrome or overlapping features, and a higher prevalence of an SSc pattern was reported in RP-associated cases (25%). The review suggests that NVC performed on patients with SS may identify those with a higher risk of developing overlap syndrome  and subclassify patients at a higher risk of severe disease .A few NVC studies are available on other connective tissue diseases (CTDs), including rheumatoid arthritis (RA) and antiphospholipid syndrome (APS). APS is characterized by widened afferent, apical, and efferent diameters . PreviouIn our study, we aimed to investigate the prevalence of a decreased CD and an SSc pattern in different patients with CTD in a standardized way in a single tertiary care center and compare the possible differences of microvasculature between patients with systemic sclerosis with and without overlap syndromes. In addition to the commonly used parameters (CD and SSc pattern), we also aimed to assess the possible usefulness of the more accurate but complex technique, the MES.Two hundred and sixty-eight patients with CTDs and 104 healthy volunteers, as well as 36 cases with primary Raynaud’s phenomenon (PRP), were investigated in our tertiary care center between 2015 and 2018. Regarding RP associated with SSc, SLE, RA, and SS cases, every second consecutive patient was included in the study. Each consecutive patient with SLE, RA, and SS who did not have RP was also enrolled. All consecutive patients with IIM, APS, and vasculitis attending our tertiary care center were enrolled. All patients were interviewed and examined by the same investigator (GN) using a standard protocol regarding key symptoms and complaints of CTDs independent of the already established clinical diagnosis of the particular patient ,38,39. PAs controls, 104 HVs without a previous history of CTD, RP, hypertension, diabetes mellitus, or drug abuse and 36 patients with PRP were enrolled.All enrolled patients completed a self-assessment questionnaire and were interviewed about the presence and distribution of RP based on the 2014 preliminary criteria of Raynaud’s syndrome . The intAntinuclear antibodies were tested with Quanta Lite ANA ELISA kit , and for the assessment of anti-topoisomerase I (anti-Scl70) antibodies, ORG 514 ELISA assay  was used. Anticentromer antibodies were tested with ORG 633 ELISA Assay , and anti-RNA polymerase III was evaluated with Euroimmun DL 15321601 immunoblot assay .An NVC investigation with a magnification of 200× was performed with a drop of paraffin oil and was recorded and evaluated by the same investigator (GN) . Before performing the NVC examination, all subjects remained at room temperature for 15–20 min. The NVC was performed on eight fingers on both hands except for the thumbs. Four 1 mm length areas on all investigated fingers were assessed. The investigated parameters included capillary density per millimeter. The presence of an SSc pattern was assessed, and in the case of a presence, it was subcategorized to an early, active, or late SSc pattern . The MESAs the normal capillary density was defined as 7 mm based on previous papers , patientt-test, a Kruskal–Wallis, an ANOVA, or a Mann–Whitney U test was used to compare the data. Nonparametric variables were tested with Fisher’s exact test or a chi-squared test as appropriate. As most of the data showed a non-normal distribution, the results are shown as median  values. For the statistical analysis, STATISTICA version 6.0  was used.Based on previous publications, an a priori sample size calculation with a power of 80% and α = 0.05 was performed to best differentiate CD between HVs and patients with different CTDs ,42,43,44Receiver operating characteristic (ROC) curves were used to examine the performance of the MES and CD to differentiate between patients with CTDs and the controls (HVs and PRPs). For these calculations, StatPlus AnalystSoft Inc. version 7  was used.The main clinical characteristics of the investigated patient groups and the controls are summarized in n = 1, SSc-SLE-SS n = 3, SSc-SS-RA n = 2, SSc-SLE-RA n = 1, and SSc-IIM-SS n = 1, respectively). In the case of two patients, SSc-SLE-SS-RA was classified.Out of the 39 patients with overlap SSc, 29 patients fulfilled two classification criteria. SSc-SLE overlap was present in six cases, SSc-APS overlap was detected in two cases, SSc-IIM in five cases, SSc-SS overlap in nine cases, RA overlap in six cases, and in the case of one patient, ANCA-associated vasculitis was classified in addition to SSc. In the case of eight patients, three different classification criteria were fulfilled . The prevalence of a decreased CD was significantly higher in patients with SLE, IIM, and overlap CTD compared with the HVs and patients with PRP , and prevalence of an SSc pattern and elevated MES was also significantly elevated in these particular patients .Patients with SSc positive for ANA had significantly higher CD compared with ones without ANA positivity . The presence of SSc pattern was present in SLE in 23%, in APS in 18%, in IIM in 35%, in SS in 27%, and in RA in 17%. Patients with vasculitis showed no SSc pattern. The prevalence of an SSc pattern was significantly higher in SLE, APS, IIM, SS, and RA compared with both the HVs and patients with PRP  analysis was used to estimate the optimal cut-off value of the MES. The value of 1.0625 was the best for differentiating patients with CTDs and controls (PRP + HV)  and the value of 0.738 for differentiating between patients with SSc and the HVs  .Elevated MES showed the highest prevalence in patients with SSc without overlap syndrome. The prevalence of elevated MES was significantly higher in both SSc subgroups and the overlap CTD group compared with both control groups (HVs and patients with PRP) . A signiA large comparative study on capillary density and the prevalence of SSc patterns was performed on patients with CTD in a single tertiary care center.In accordance with previous studies, a decreased CD was observed in our patients with SSc ,10,18,45Vascular complications are more prevalent in ANA-positive patients with SSc ,49, inclOur results are in accordance with previous findings; a decreased CD was present in our patients with SLE compared with the HVs ,21,24,26In the case of IIM, the median CD was significantly lower compared with the controls, but when the number of patients with a decreased CD (<7 mm) was compared with the controls, the significant difference disappeared. The prevalence of the SSc pattern in IIM is 35% in our cohort, which is within the previously observed range (26.9–88.9%) . This miPatients with RA, SS, APS, and vasculitis did not show a significant difference compared with our controls either when the median values of CD or when the prevalence of a decreased CD were investigated. Our results on CD in the group of patients with SS are not in accordance with previous findings, as Capobianco et al. discovered a significantly higher CD compared with the HVs  and anotWe demonstrated that the average CD is normal in both RA and APS, indicating a low level of microvascular damage in these diseases. Previous studies on RA and APS did not investigate CD. Our results show that a decrease in CD is not the hallmark of these diseases. In SS, APS, and RA, a significantly higher prevalence of the SSc pattern was observed compared with both the HVs and patients with PRP , and theA recent systematic review on vasculitis described the presence of SSc-specific abnormalities in GPA ; however, CD was not investigated . In our In addition to the widely used parameters, we aimed to investigate the possible usefulness of a more complex method, the MES. The complex score was developed and used in research focusing solely on SSc. As it sums different SSc-related capillaroscopic parameters, it can more accurately reflect microvascular changes. As no standard cut-off is available regarding the MES, we performed a ROC analysis to detect patients with and without an abnormal MES. Our results suggest that MES values may differentiate between patients with SSc, SLE, and IIM and HVs. The MES can differentiate between the HVs and PRPs. As the frequently used methods, including CD and the presence of an SSc pattern, cannot discriminate between these particular groups of patients, the MES clearly has additional value. Further validation steps are essential to clarify the role of the MES in CTDs other than SSc.The strength of our study is that a high number of patients was evaluated by the same investigator with the same standard protocol, including clinical laboratory findings, classification, and capillaroscopic evaluation. The presence of Raynaud’s phenomenon and overlap syndrome was carefully assessed. The weakness of the study is that this is a single tertiary center study, which may cause bias in patient selection. Future multicenter studies are required with a standardized methodology and patient selection to clarify the importance of our current findings. A limitation of our study is that we included patients with hypertension and diabetes, and these particular comorbidities might have an impact on our capillaroscopy findings ,54. AnotOur overall assumption is that a decreased CD and the prevalence of an SSc pattern are similar in pure SSc and overlap SSc. These capillaroscopic changes, including the prevalence of an SSc pattern and decreased CD, are more prevalent than previously suggested in CTDs other than SSc, including patients with SLE, IIM, and overlap syndromes. A more extensive method, the MES could also accurately distinguish between patients with CTDs and controls even between HVs and patients with PRP besides the widely used CD.In summary, a capillaroscopic examination should include both the evaluation of capillary density and an assessment of the SSc pattern. The complex MES score may be a promising candidate to be studied in future follow-up studies assessing microvascular changes.


Telehealth interventions, that is, health care provided over a distance using information and communication technology, are suggested as a solution to rising health care costs by reducing hospital service use. However, the extent to which this is possible is unclear.The aim of this study is to evaluate the effect of telehealth on the use of hospital services, that is, (duration of) hospitalizations, and to compare the effects between telehealth types and health conditions.We searched PubMed, Scopus, and the Cochrane Library from inception until April 2019. Peer-reviewed randomized controlled trials (RCTs) reporting the effect of telehealth interventions on hospital service use compared with usual care were included. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool and quality of evidence according to the Grading of Recommendations Assessment, Development and Evaluation guidelines.We included 127 RCTs in the meta-analysis. Of these RCTs, 82.7% (105/127) had a low risk of bias or some concerns overall. High-quality evidence shows that telehealth reduces the risk of all-cause or condition-related hospitalization by 18 (95% CI 0-30) and 37 (95% CI 20-60) per 1000 patients, respectively. We found high-quality evidence that telehealth leads to reductions in the mean all-cause and condition-related hospitalizations, with 50 and 110 fewer hospitalizations per 1000 patients, respectively. Overall, the all-cause hospital days decreased by 1.07 (95% CI −1.76 to −0.39) days per patient. For hospitalized patients, the mean hospital stay for condition-related hospitalizations decreased by 0.89 (95% CI −1.42 to −0.36) days. The effects were similar between telehealth types and health conditions. A trend was observed for studies with longer follow-up periods yielding larger effects.Small to moderate reductions in hospital service use can be achieved using telehealth. It should be noted that, despite the large number of included studies, uncertainties around the magnitude of effects remain, and not all effects are statistically significant. Many see the COVID-19 crisis as an opportunity to stimulate digital transformation. We can expect digital care and eHealth to receive a boost during this era. Creativity and flexibility are stimulated to formulate an answer to challenges in patients fearing infection in a hospital and to social distancing being necessary within hospital premises. Telehealth, defined as health care provided over a distance using information and communication technology (ICT) to enable interaction between patients and health professionals . GM. GM18]. We conducted subgroup analyses for health conditions that were studied in at least two articles, as well as for each type of telehealth, length of follow-up, and risk of bias. These analyses were planned a priori. The risk of bias was analyzed using the robvis package in R . To asseThe search identified 2544 records. After removing duplicates, 1410 records remained for the screening of titles and abstracts, through which 1114 (79.0%) records were excluded. We assessed 296 full-text articles for eligibility and excluded 120 articles. Of the remaining 176 articles, 127 (72.2%) provided sufficient data for inclusion in the meta-analysis . Figure An overview of telehealth types, health conditions, and outcomes is provided in We judged 50 articles to be at low overall risk of bias, 55 to have some concerns, and 22 to be at high risk of bias. Most articles were assessed at low risk of bias for all five domains , except for selection of the reported result  hospitalized patients per 1000 patients .P=.40).We found 50 RCTs reporting the risk of condition-related hospitalization, including 20,867 participants. The absolute risk was reduced by 37 per 1000 patients (95% CI 20-60), with high-quality evidence . When stratified by health condition, only the heart failure group showed a statistically significant effect (risk difference = −0.03), although the subgroup difference was not significant  hospitalizations per 1000 patients, a 5.7% reduction with regards to the number of hospitalizations in the usual care group. Only the COPD subgroup showed a statistically significant MD between telehealth and usual care of −200 (95% CI −390 to −10) hospitalizations per 1000 patients. No effects were found for heart failure and other diseases. In addition, an RCT studying malignancies reported an MD of +0.09 hospitalizations per patient compared with usual care but did not report a SD and was therefore excluded from the meta-analysis.P<.01). The difference increased gradually with a longer follow-up from an MD of −90 between 3 and 6 months up to a reduction of 1190 hospitalizations per 1000 patients for outcomes reported after more than 12 months. When stratified by health condition, only heart failure showed a statistically significant effect .The mean number of condition-related hospitalizations per patient was reported in 22 RCTs, including 3461 participants. Follow-up varied between 1 and 60 months. The analysis showed high-quality evidence for an MD of −110  hospitalizations per 1000 patients with telehealth compared with usual care. Differences between outcomes appeared to depend on the length of follow-up  hospital days per patient. In addition, 9 RCTs reported the total number of days for which patients were hospitalized, and 2 reported the rate of hospital days. Furthermore, 1 RCT reported an MD of +0.60 hospital days with telehealth compared with usual care but did not report an SD nor the necessary information to calculate one. These 12 RCTs, which included 3144 participants, could not be incorporated in the meta-analysis.P<.01), with longer follow-up resulting in larger reductions in hospital days. It is notable that when stratified by health condition, a statistically significant result was only achieved in heart failure . For COPD, an MD of −1.75 (95% CI −4.62 to 1.11) was found. In addition, 7 studies reported the total number of days patients were hospitalized, and one reported the rate of hospital days. These studies, including 2492 participants, could not be included in the meta-analysis.The mean number of days patients were hospitalized for the condition of interest was reported by 8 RCTs, including a total of 1216 participants. The analysis showed moderate quality evidence of an MD of −1.13 (95% CI −1.64 to −0.61) hospital days per patient. The quality of evidence was downgraded because of risk of publication bias. A statistically significant difference was found for the length of follow-up (P<.01) and different levels of risk of bias (P≤.01), but no clear trends were found. Three studies reported the length of hospital stay as medians and IQRs, and they could therefore not be included in the meta-analysis.A total of 12 RCTs reported length of all-cause hospital stay, including 1964 hospitalized patients. Low-quality evidence was found for an MD of −0.48 (95% CI −1.44 to +0.47 days) hospital days per stay. The quality of evidence was downgraded by one level for risk of bias and by another for imprecision. Subgroup differences were found between different lengths of follow-up .P<.01). An MD of −3.95 hospital days per stay (95% CI −6.06 to −1.84 days) was found for reporting between 7 and 12 months, whereas other MDs ranged from −1.00 to −0.42 days. An additional 3 RCTs reported the length of hospital stay as medians and IQRs and 4 did not report SDs nor any information that could be used to calculate them. These 7 RCTs, including 922 participants, were therefore excluded from the meta-analysis.Subgroup differences were found in reporting outcomes at different lengths of follow-up  and 37 (−15.6%) for condition-related hospitalizations. We found high-quality evidence that, compared with usual care, telehealth leads to reductions in mean all-cause  and condition-related hospitalizations , that is, 50 to 110 fewer mean hospitalizations, respectively, per 1000 patients. Overall, it is evident that all-cause hospital days decreased significantly with a mean of −1.07 (−17.7%) hospital days per patient and condition-related hospital days with −1.13 (−39.8%) days, although evidence for the latter was only moderate. For hospitalized patients, the mean stay for any cause could potentially be reduced , and mean stay for condition-related hospitalizations even more . The effects were similar for various health conditions and types of telehealth. A trend was observed for studies with longer follow-up periods, yielding larger effects. It should, however, be noted that, although this is a systematic review including a large number of studies, uncertainties around the magnitude of effects remain, and not all differences were statistically significant.The quality of evidence was high for most of the analyses. Downgrading was only necessary for two analyses because of the risk of bias, risk of publication bias, and imprecision because of a small cumulative sample size. Overall, there were approximately as many articles with some concerns as there were articles at low risk of bias. The main culprits were insufficient reporting of the randomization method, lack of available trial registrations or study protocols, and incomplete outcome data (mostly due to deaths). None of these aspects necessarily indicate issues with the study itself, but rather with the reporting of a study. It is desirable that more information is made available, such as by providing web-based supplementary material.In our review, the most commonly used telehealth types were device-based monitoring and STS. In general, only small differences in effects were found between telehealth types, which did not appear to be relevant. This finding is in line with a Cochrane review including RCTs investigating the effect of either STS or device-based monitoring in the management of heart failure, which also found no difference . It shouStudies including patients with heart failure or COPD accounted for the majority of the weight in the meta-analyses of this review, although the effects found for other health conditions seemed similar. No other review has combined the results for multiple health conditions. However, reviews of heart failure and COPD specifically are available for comparison. A systematic review including reviews on telehealth for chronic heart failure patients published between 1996 and 2014 found low-quality evidence for absolute risk reductions in patients with an all-cause hospitalization of 4.7% to 13.8% and of 3.7% to 8.2% for patients with a condition-related hospitalization . AnotherA systematic overview of reviews including COPD patients found 3 reviews investigating the effect of telehealth on hospitalizations, all of which found a reduction in hospitalizations . AnotherIn a systematic overview of the use of telehealth for various chronic health conditions, reviews on health conditions other than heart failure or COPD also found only a few articles, except for diabetes . This reThe length of follow-up seems to be an important factor influencing the effect of telehealth in our review. We found subgroup differences in length of hospital stay , condition-related hospitalizations, and condition-related hospital days, with larger effect sizes for studies with longer follow-up. A similar trend was observed for all-cause hospital days. One review reported a reduction in mortality at 6 months, with no differences at 1 year . No otheWhen telehealth replaces face-to-face contact, it is clear that this can aid in reducing outpatient contacts and supporting social distancing in outpatient departments. In view of the small effects on hospitalizations and moderate effects on hospital inpatient days, it is important to determine whether telehealth actually contributes to cost reduction. Telehealth comes at a cost, for example, because health professionals make phone calls, conduct video consultations, or interpret data. To reduce the costs of interventions, automation of some of these aspects, for example, by developing algorithms to recognize deterioration of patients' health status, should be studied. Although we investigated whether the mechanism by which telehealth is often claimed to reduce costs is indeed present, we did not directly investigate whether costs were reduced. Thorough budget impact and cost-effectiveness studies are needed to reach firm conclusions in this domain.This review has several strengths and limitations. First, the wide scope enabled us to find a large number of articles meeting our inclusion criteria. Furthermore, we quantitatively compared the effects achieved in different health conditions using different types of telehealth and length of follow-up. Another important strength is that we assessed all included articles for risk of bias and graded the strength of evidence for each analysis, providing a comprehensive overview of the evidence on the effect of telehealth on hospital service use.The wide scope also acts as a double-edged sword in that it makes the participants in the various studies less comparable than in a typical review. This concern is alleviated by the fact that we did not find significant differences between health conditions or types of telehealth, although for some comparisons only a few studies were available. Telehealth interventions often entail many more changes to the health care process, besides the application of technology . The effThus, the effects of telehealth are small to moderate and appear to be stronger for condition-related outcomes than for all-cause outcomes. Further research is needed to obtain more insight into the effects of telehealth on other diseases, apart from COPD and heart failure, and into which aspects of telehealth interventions result in positive effects.Finally, in the context of the COVID-19 crisis, it is important to acknowledge that a great deal of health care can be provided from a distance, eliminating the need for vulnerable individuals to come to a potentially hazardous environment to receive health care and enabling hospitals to continue providing care to all who need it.


The autism-spectrum quotient (AQ) 2. Repetitive behavior scale-revised (RBS-r). Levels of sex hormones in serum were measured in patients. The correlations between the levels of these biochemical factors and scores of the autistic traits were analysed. From July 1st, 2020 to September 1st, 2021, these patients were followed up by telephone and asked to fill out a questionnaire online. The questionnaire included date of delivery, complications, medicine used and negative events during pregnancy , delivery condition, breastfeeding, AQ scale and Autism Behavior Checklist (ABC) of their children.This is a case–control study that recruited two groups: polycystic ovarian syndrome-induced infertile subjects as the observation group and fallopian tube factor-induced infertility subjects as the control group. Both cohorts were patients undergoing infertility treatment in the Productive Medicine Center, Peking University People’s Hospital. Two types of questionnaires were completed by patients between May 1The patients in the PCOS group had significantly higher AQ scores than those in the control group. Levels of luteinizing hormone and testosterone were also higher in the PCOS group. No significant differences were found between the two groups in RBS-r levels, follicle-stimulating hormone, estradiol or progesterone. In the two combined groups, there were significantly positive correlations between the AQ scores and the luteinizing hormone concentration, as well as between scores of RBS-r and testosterone concentration. Moreover, there was a significantly negative correlation between the level of progesterone and the RBS-r score. According to the follow-up data, the AQ scores of offspring were positively correlated with the RBS-r scores of their mothers. The ABC scores of offspring were positively correlated with the RBS-r scores and the childbearing age of their mothers. No significant difference was found between the two groups in age of delivery, complications, special medication used, negative events during pregnancy, delivery situation, postpartum breastfeeding, age of children, or AQ scores or ABC scores of children. There were no significant correlations between the scale scores of children and the related sex hormone levels of mothers. This could indicate that the higher levels of luteinizing hormone and testosterone and the lower level of progesterone accompanied more pronounced autistic traits in PCOS. Furthermore, the higher delivery age and RBS-r score in mothers accompanied the higher AQ and ABC scores in children.Compared with the control group, PCOS patients had more autistic traits . The autistic traits in PCOS patients might be related to the elevation in testosterone concentration and luteinizing hormone levels and the decline in progesterone level. Moreover, the autistic traits in the offspring of PCOS patients might be related to the parental high delivery age and high tendency to autism traits. Polycystic ovary syndrome (PCOS) is one of the most common infertility causes in women and is mainly characterized by oligoanovulation, ovarian polycystic morphology and hyperandrogenism . Some reASD is a neurodevelopmental disease with core symptoms, including social communication disorder, narrow interests, and repetitive behaviors . There ast, 2015, and May 1st, 2016, from the Reproductive Medicine Center, Peking University People’s Hospital, Beijing, China, and sorted into two groups: an observation group of subjects with infertility due to PCOS [based on Rotterdam diagnostic criteria , delivery condition, breast-feeding, AQ scale and ABC  scale about their children. This study was approved by the Peking University Institutional Review Board .Approximately 5 years later, from July 12.2.1 The AQ, designed by Simon Baron-Cohen in 2001, is a self-administered quotient measure that measures autistic personality traits in adults. The score is based on five factors, namely, social ability, attention, communication ability, detail, and imagination. A higher score represents more pronounced autistic personality characteristics . RBS-r, 2.2.2 Sex steroids, including luteinizing hormone (LH); follicle-stimulating hormone (FSH); estradiol (E2), progesterone (P); and testosterone (T), were measured in the clinical laboratory of Peking University People’s Hospital.2.2.3 The acne score was determined by the clinical overall scoring method . Six par2.2.4 In this study, an improved F-G scoring method was used to evaluate hirsutism. According to the amount and distribution of the hair, 0 ~ 4 points were recorded, and a total score ≥ 8 points was used to diagnose hirsutism , 22.Data were managed and analysed using SPSS 25.0. An independent t test was used to compare continuous variables. If the sex hormones data exceeded three standard deviations, we would delete them as the extreme value when we analysed the difference between the two groups. The chi-square test or Fisher’s exact test was used to compare categorical variables. Given the large sample size of the combined two groups (n=53~195), the Pearson correlation coefficient was used to examine the correlation between sex hormone levels in plasma and behavioral scores. All statistical analyses were two-sided, and P<0.05 was considered statistically significant (unless otherwise described).This study is an observational study, with high uncertainty in estimating the sample size. According to relevant literature reports , there wThere were no significant differences in RBS scores between groups. However, the PCOS group had a higher body mass index (BMI) and AQ score than the control group Table 1.For the offspring follow-up study Figure 2In this study, we found that women with PCOS had more autistic traits than those in the control group. The total AQ scores of women in social skills, attention switching and communication were significantly higher than those of the control group. The phenotypes were similar to the clinical manifestations of ASD, for example, social and language communication disorders. There was no difference between the two groups in attention to detail, imagination, or RBS-r scores. During the follow-up, PCOS patients were more likely to refuse the follow-up (29% in the PCOS group vs 18% in the control group). From another perspective, it showed that PCOS patients are more likely to have social dysfunctions.In 2015, a population-based nationwide study in Sweden involving 23 748 ASD cases and 208 796 controls revealed that children of women with PCOS appear to have a higher risk of developing ASD . In addiWhy do PCOS patients have more autistic traits? PCOS patients are characterized by a high level of androgen, and ASD is currently considered to be associated with intrauterine hyperandrogen –32. Our Some studies have shown that testosterone easily binds to androgen receptors located in the cytoplasm through cell membranes and blood–brain barriers and then enters the nucleus, affecting the regulation of DNA transcription. It thus inhibits oxytocin (OXT), known as “social factors”, and oxytocin has been used to improve the clinical symptoms of ASD , 34. TesRegarding the relationship between LH and autistic traits, previous literature reported that the serum LH level in female patients with Asperger’s syndrome was higher than that in healthy women . LH stimIn addition, we also found that progesterone was negatively correlated with the RBS-r score. In 2014, Whitaker-Azmitia et al. found that a decrease in progesterone in maternal serum was associated with an increase in the incidence of autism in offspring . He explAQ has been widely used in both clinical and research studies as a screen for diagnosis . In thisFinally, the limitations of our study must be considered: (1) PCOS is a heterogeneous disease. According to the Rotterdam criteria in 2003, the diagnostic evidence for PCOS is rare ovulation, hyperandrogenism, and polycystic ovarian changes. In other words, not all PCOS patients have hyperandrogenism, which leads to abnormal oxytocin and social behaviors. If it can be further subtyped, it will be more convincing. (2) People’s social behaviors are extremely complex. Whether social function can be fully evaluated by simply filling out the scale needs further confirmation. (3) This study mainly focused on infertile patients in the Reproductive Medicine Center, Peking University People’s Hospital. Infertility may be one factor causing social dysfunction. (4) Follow-up is in the form of an online questionnaire rather than an on-site examination of children, so the results may be biased.In summary, our results demonstrated that PCOS patients have more autistic traits, which might be related to the elevation in testosterone concentration and luteinizing hormone levels, as well as the decline in progesterone levels. Moreover, the autistic traits in the offspring of PCOS patients might be related to the parental high delivery age and high tendency to autistic traits.The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.The studies involving human participants were reviewed and approved by Peking University Institutional Review Board . The patients/participants provided their written informed consent to participate in this study.LJ is responsible for filling out questionnaires and writing articles. LT is responsible for recruiting patients. JY, XX and FQ are responsible for statistic data. RZ is responsible for reviewing data and revising articles. JW is responsible for revising articles. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The birth of mass production started in the early 1900s. The manufacturing industries were transformed from mechanization to digitalization with the help of Information and Communication Technology (ICT). Now, the advancement of ICT and the Internet of Things has enabled smart manufacturing or Industry 4.0. Industry 4.0 refers to the various technologies that are transforming the way we work in manufacturing industries such as Internet of Things, cloud, big data, AI, robotics, blockchain, autonomous vehicles, enterprise software, etc. Additionally, the Industry 4.0 concept refers to new production patterns involving new technologies, manufacturing factors, and workforce organization. It changes the production process and creates a highly efficient production system that reduces production costs and improves product quality. The concept of Industry 4.0 is relatively new; there is high uncertainty, lack of knowledge and limited publication about the performance measurement and quality management with respect to Industry 4.0. Conversely, manufacturing companies are still struggling to understand the variety of Industry 4.0 technologies. Industrial standards are used to measure performance and manage the quality of the product and services. In order to fill this gap, our study focuses on how the manufacturing industries use different industrial standards to measure performance and manage the quality of the product and services. This paper reviews the current methods, industrial standards, key performance indicators (KPIs) used for performance measurement systems in data-driven Industry 4.0, and the case studies to understand how smart manufacturing companies are taking advantage of Industry 4.0. Furthermore, this article discusses the digitalization of quality called Quality 4.0, research challenges and opportunities in data-driven Industry 4.0 are discussed. Recent technological innovation is evolving rapidly due to emerging technologies such as artificial intelligence (AI), Internet of Things (IoT), cloud computing, machine learning (ML), big data, and the manufacturing industries ,2,3,4. TIn Industry 1.0, the first revolution began in 1784 and was marked by steam power and mechanization. The single operator was deployed in Industry 1.0 to supervise and control the entire manufacturing process from the electromechanical dials connected locally to machines in the factory. The operator had to move around the factory to track the production processes and machine statuses to gather all the knowledge about the process and equipment working in the manufacturing facility. The second industrial revolution, also called Industry 2.0, occurred at the end of the 19th century with the invention of electrification factories. The electrification of factories permitted continuous round-the-clock operation, mass production, and process parameters controlled from isolated control rooms. In Industry 3.0, the computer was introduced for the manufacturing industries to automate the manufacturing processes. Computer-based production processes and systems are implemented into manufacturing activities and include several devices . Robots are used in some operations to control the production process remotely ,10.The fourth industrial revolution is called Industry 4.0, the German government strategy group’s name. Industry 4.0 is attracting the attention of researchers and practitioners globally ,13. The Industry 4.0 uses the Internet of Things (IoT) to develop a cyber–physical production system (CPPS). The CPPS is envisioned as the core technology of Industry 4.0, which will comprise technologies such as IoT, wireless embedded network systems and network cloud computing, big data, and AI in manufacturing plants . The stuSmart manufacturing is fully integrated, and collaborative manufacturing frameworks can respond to evolving requirements and conditions in the factory, supply networks, and consumer needs in real-time ,25.Industry 4.0 opportunities can be broken down into the following key fields: performance flexibility that happens during small-batch manufacturing; the speed of serial prototypes; production capacity; minimized setup cost, fewer errors and low machines downtime; increased product quality and less rejected production; and improved consumer opinion on products .The importance of more detailed mechanisms for performance assessment schemes was widely discussed in the 1990s. The performance measurement concept began to be consolidated, and significant contributions were made, including performance images . ManaginQuality is a fundamental feature of products and processes in any manufacturing industry. For businesses and organizations in the global market, this is considered a strategic advantage. In modern history, quality models and practices have undergone many evolutionary phases, from inspection to control, monitoring, quality assurance, quality management, and design quality. These quality models are a function of industry trends and developments. After a few years of stagnation in rate, few creative quality models are being proposed, and quality professionals’ leadership roles in businesses and organizations seem to have faded. Furthermore, there is no research into modern and creative quality models. The fourth industrial revolution is an opportunity for the quality movement to become a leading power ,35.The analysis is carried out with three research questions in mind: (1) What are the various methods, tools, and standards used to measure the performance of Industry 4.0? (2) What are the different approaches and techniques used to manage the quality of the products in Industry 4.0? (3) What are the current challenges and opportunities in Industry 4.0? ,48,49,50The evolution of manufacturing is already on its path to “Industry 4.0”. According to the findings, the Industry 4.0 initiative will have high demand in the future. As the concept of Industry 4.0 is relatively new, there is high uncertainty, lack of knowledge and limited publication about the performance measurement and quality management with respect to Industry 4.0.Conversely, manufacturing companies are still struggling to understand the variety of Industry 4.0 technologies. Industrial standards are used to measure the performance and manage the quality of the product and services. In order to fill this gap, our study focuses on how the manufacturing industries are using different industrial standards to measure the performance and manage the quality of the product and services ,52,53,54The rapid change in ICT development impacts most of the manufacturing industries. Several CEOs of the manufacturing industries worldwide are thinking about implementing the Industry 4.0 concept and have many real-time questions that need to be addressed. How do we measure the performance? What are the KPIs that need to be set, and what standards need to be adopted to measure the performance of Data-Driven Industry 4.0? The most crucial part of the manufacturing industry is Performance and Quality measurement. The rapid advancement of ICTs has changed the paradigm of industries operation ,48. The Manufacturing Sectors are in a constant transition state, with the digitalization and innovation of ICTs. It is becoming a big challenge for industries to stay on the market. Big data, automation, AI, IoT, and cloud computing in the research community are widely discussed. Although there is research on performance assessment and quality management systems, it has been developed primarily in a stable environment. This study demonstrates how the latest research focuses on implementing the performance and quality measurement criteria in Data-Driven Industry 4.0, where different industrial standards are used to assess the performance and quality of Industry 4.0.The paper is organized as follows. The review methodology used for the SLR is illustrated in Ramamurthy and Jain  addresseThere were substantial productivity gains in the previous three revolutions: first, steam and water, electricity and assembly lines, and then computerization. The Internet of Things uses the network and networking infrastructure to link the fourth industrial revolution to computers, devices, machines, and people ,56. The In this article, the authors addressed the fourth industrial revolution; performance assessment of production systems in a network whose success is based on production system robustness. Efficient and reliable performance assessment can significantly impact an industrial company’s profitability . The autThe performance assessment of production processes is ultimately driven by performance indicators or Key Performance Indicators (KPIs). KPIs are modern instruments that make it easier to maintain high performance in manufacturing . In addiDifferent industrial standard and case study approaches are used as a research tool to achieve and represent the proposed concept of performance and quality assessment of smart production systems. A literature review of the associated context was also conducted to explain and understand the main techniques to establish a performance and quality measurement concept in data Driven Industry 4.0. There are many KPIs used to measure the industry’s performance. Here in the methodologies section, we discuss different KPIs used in manufacturing plants at the shop floor production level and a case study to understand the performance evaluation in Industry 4.0. Further, we will discuss the Quality measurement approach and a case study concerning Industry 4.0. TheThe evolution of manufacturing is already on its path to “Industry 4.0.” According to the findings, the Industry 4.0 initiative will have high demand in the future ,73,74 anIn this section, we discuss how to measure performance in Industry 4.0. We use two different standards and case studies to understand how performance measurement is implemented in Industry 4.0. The first is the ISA-95 standard, and the second is the ISO 22400 standard. The International Standardization creates and provides “requirements, specification, guidelines or characteristics that can be used consistently to ensure that materials, product, process, and services are fit for their Purpose” . We addrThe ISA-95 standard describes entities at the shop floor level, where Information technologies  and Operation Technologies  interact ,77,78,79The American National Standard ANSI/ISA-95 ,62,79 coManufacturing Operation Center (MOC) Using ISA 95This section will understand the concept and working principle of MOC, which is discussed in ,77. The The MOC system meets the manufacturing plant’s needs by providing exact and timely information regarding the product, production quality, manufacturing processes, and asset performance. The MOC system solves the issue of production plants from the disconnected production floor data to the connected back-office system’s enterprise situation. This integration offers real-time monitoring and analysis of production floor activities ,81.The MOC system uses Fusion Middleware’s integration framework to collect data sources, including an MES application or a quality application. The key partners such as Kepware, ILS Technologies and Matrikon provide gateways to capture real-time data from plant equipment and control systems . The OraThe MOC framework utilizes a functional contextualization engine to identify business definitions and production process guidelines for numerous tag data obtained from PLCs and different automation devices. The collected data will be processed, and the processed data will be displayed on a dashboard that interprets the data at different organization levels. The MOC has 55 predefined KPIs, ,43 and tii.Use case I: Overall Equipment Effectiveness (OEE) and production loss reviewThe initial use case of MOC is introduced to illustrate the Total Productive Maintenance (TPM). The initiative TPM describes a “synergistic relationship among all organizational functions, but particularly between production and maintenance, for the continuous improvement of product quality, operational efficiency, capacity assurance, and safety . TPM attAvailability = Actual available time/Planned available time;Performance = Effective run time/Actual available time;Quality = Good quantity produced/Total quantity produced.To determine TPM initiatives, the elimination of these losses improves OEE’s most common numerical metric ,32(1)OEDue to breakdowns, setups, and modifications, availability captures deleterious effects. The performance captures productivity loss due to lower pace, idling, lesser stoppages, and the suitable product yield that captures loss due to defects rework, and the result is quality.The OEE calculations for a multi-site production company are shown on the different KPI dashboards. The plant manager will drill down to the equipment level to investigate the cause of low OEEE when the overall OEE is near the red area (above 75 per cent). The most inferior five performing devices will be analyzed and investigated to discover the root cause. If availability is a factory’s lowest OEE part, they can browse the factory equipment over each downtime cycle and examine reasons for downtime.As seen in this use case, the advantages of ERP-level data integration with shop floor level are increased access to process performance measures and quality improvement by enabling an in-depth examination of the root cause of problems.The International Organization for Standardization ISO 22400 ,29,87 isThe development and uniformity of a structured way of producing KPIs benefit the industry . ISO 224This subsection describes the ISO 22400 standards and how to apply these standards in the industry to define the different KPIs to measure the various Smart manufacturing parameters’ performance and the most common KPIs used in the industry case study. An onion metaphor, see The second inner layers are known as performance indicators (PIs). These involve either a single KRI or a group in an equation. Both the KRIs and the PIs operate in cooperation with the KPIs. Creating a KPI means that the result and the performance of the targets can be shown and It is built to see what can be done to increase productivity and display it quantitatively. The Manufacturing Enterprise Solutions Association (MESA) investigation was conducted to see the industry’s most used KPIs ,63. The These KPIs require data from several processes and machines. Acquiring this data in a cyber–physical system is many times simpler than traditional manufacturing sites due to the interconnected nature of cyber–physical systems. Another view of the most common KPIs is the visual process, which is critical to show in different departments . These aIn , the autFurthermore, it explains how to create a pedal car step by step on the assembly line, which involves both new pedal car assemblies and the disassembly of those already made; all this teaching requirement is the main workflow to be used in actual production. In this section, we reflect on the showcase part of new systems, in which staff members can see how Smart Factory processes the data. This section has the most sophisticated technology and intelligent resources recently updated from advanced tools—a smart device that can connect with other systems . The firData acquirement/Acquisition: Atlas Copco designed the Power Focus PLC System, which provides different functionalities such as each controller’s status, communication, event monitoring, tightening, communication, Synchronization, API, Cell, etc., to automate the manufacturing process ,93. The Data identification: The KPI calculation, as possible or not possible, cannot be decided by comparing the data at hand with what is required for the new KPI calculation. However, this is closely related to the understanding and implementation of the standards. The standards create a common framework for the metrics, and measures can only be derived from this basis, creating uniform definitions according to the ISO 22400 template for each data point. The results are well-defined metrics available from the system.Data planning: Many KPI values will be calculated from the extracted data and analyzed with available matrices in the data planning. First pass yield, availability, throughput rate, downtime, OEE (time-based), scrap ratio, count, goal, and takt time are the KPIs. New KPI concepts have been made for the new KPIs following the specifications given by ISA-95 and ISO 22400.Currently, the quality of products, services, and processes are crucial for achieving sustained economic development and maintaining productivity ,37,93,95Quality 4.0 is a reference point for Industry 4.0 ,99. QualLNS defined 11 axes of quality 4.0 that organizations can use to teach, prepare, and act. Using this framework and study, leaders can define how Quality 4.0 will transform current skills and initiatives. The framework also offers a view of conventional consistency. Quality 4.0 does not replace traditional methods of quality but instead builds on and enhances them. Manufacturers should use the framework to interpret their current state and decide what improvements are required to transition to the future. Data-driven decisions have been at the center of quality management for decades. Many recently revised criteria stress the significance of evidence-based decision making ,104.The LNS report defined 11 Axes of the Quality 4.0 Framework, which allows the company to implement Quality 4.0 due to the 4th industrial revolution Quality Management System. Here are the 11 Quality 4.0 Axes discussed below ,101,104.Data: Data have always played a critical and essential role in the management and development of quality. Industry 4.0 allows the company to gain real-time visibility of quality indicators such as production efficiency, supplier performance, engineering manufacturing, and customer support with the aid of ICT developments in Industry 4.0–such as advanced analytics, AI, ML, and IoT . A core Analytics: Industry 4.0’s advanced technologies enable us to gather massive data from the production plant and apply the analytics tools to measure the quality matrices. ML and AI insights allow prescriptive analytics to forecast loss and clarify what steps to boost the results ,101,105.Connectivity: Quality 4.0 refers to the interaction among information Technology (IT) and operational technology (OT). IT refers to Enterprise Quality Management System (EQMS), Enterprise Resource Planning (ERP), and Product Life Cycle Management (PLM) in this context ,105. In Collaboration: Enterprise Quality Management System (EQMS) technologies can allow businesses to optimize and synthesize quality systems to improve compliance and efficiency. Quality 4.0 is designed to leverage modern technology and techniques, such as social listening and blocking, to analyze factors such as customer satisfaction and a more profound sense of component and product distribution across supply chains ,106.App development: Apps are valuable tools that help link users and organizations to collect essential data and feedback to enhance services’ quality. Industry 4.0 provides immense promise for designing and developing new applications using augmented reality and virtual reality.Scalability: Quality 4.0 cannot reconcile procedures, expertise, and best practices fully and efficiently. Industry 4.0’s technologies such as cloud computing, such as software as a service (SaaS), infrastructure as a service (IaaS), or application as a service or platform-as-a-service (PaaS), enables gains in scalability ,101,105.Management systems: To benefit from Quality 4.0, organizations must investigate how software automates the process and how those automated processes can be connected to other systems and operations. Improving system autonomy reduces the time that high-value workers and managers spend on implementation and encourages them to focus on improved and innovative jobs ,101,105.Compliance: The data collection tasks related to observance can be automated by integrating business information technology and operational technology. The data collection tasks regarding submission can be automated by integrating business information technology and operational technology. Quality 4.0 helps businesses to analyze existing compliance plans and recognize improvement opportunities ,101,105.Culture: Quality 4.0, by connecting data, analytics, and processes and improving visibility, connectivity, teamwork, and perspective, allows a real, corporate quality culture more feasible ,101,105.Leadership: Quality 4.0 creates the right quality culture throughout the organization more attainable by linking process, information, analytics, and thereby enhancing visibility, communication, Collaboration, and insights ,101,105.Competency: Quality 4.0 encapsulates several innovations that can be used to enhance competency. Social media platforms can be leveraged to share lessons and perspectives across organizations and even among organizations. AI and ML systems can create new skills, results from while systems of artificial reality (AR) and virtual reality (VR) can enhance the staff’s expertise ,101,105.Case Study:In this case study, one of the world’s top aircraft engine manufacturing organizations, Rolls-Royce, is a producer of aircraft engines, supplying more than 150 military aircraft engines and 500 airlines . The manThe introduction of this new technological advancement presents an opportunity to improve engine repair strategies by improving the testing process’s speed as part of the maintenance activities or eliminating the need to remove the aircraft’s engine. The Rolls-Royce Company collects data from various sources, such as design, manufacturing, and post-sales management. It analyzes the data collected to generate useful data for predictive maintenance  and qualIn this section, we discuss the challenges, opportunities, and scope of the future work of Industry 4.0. With the aid of a questionnaire, we identify the current challenges faced by companies in production systems. Companies are keen to implement innovative innovations to boost resource quality, productivity, and efficiency, reduce risk, and stay competitive ,110,111.It is generally agreed that innovations relevant to Industry 4.0 would significantly affect current industries and future sector development. Although several companies look forward to introducing new technologies to improve their services’ quality, productivity, and efficiency, they reduce risks and sustain market competitiveness ,117,118.Many challenges need to be addressed in Industry 4.0. In this section, we will discuss a few critical challenges that need to be addressed. In the manufacturing sector, the latest wave of internet technology such as cloud, IoT, big data, robotics, and cyber–physical systems has allowed the manufacturing industry to generate a vast array of business data that will bring new challenges, particularly cybersecurity ,120,121.The definition of the KPI can be further expanded by carrying out studies. The XML implementation of the ISO 22400 Standard, Automation Systems Integration-Key Performance Indicators (KPIs) for Manufacturing Operations Management, is required to implement KPI-ML from MESA. KPI-ML consists of a collection of XML schemas written using the XML Schema Language (XSD) of the World Wide Web Consortium that implements the ISO 22400 standard data models.Manufacturing is already on its way to becoming “Industry 4.0”. The findings suggest that the Industry 4.0 initiative will be in high demand in the future. Because Industry 4.0 is a new concept, there is great uncertainty, a lack of knowledge, and little information about performance measurements and quality management in Industry 4.0. Manufacturing companies; conversely, there is still a grappling with the plethora of Industry 4.0 technologies. To close this gap, our research looked at how different industrial standards are used in the manufacturing industry to measure performance and manage product and service quality.Practitioners can use the study to learn about the various industrial revolutions and how industries are utilizing Industry 4.0 to improve product/process quality and performance.We discussed the various industrial standards that industries are adopting to bridge the gap between disconnected shop floor production and connected real-time production in this paper. We have shown industrial standards and case studies to show how manufacturing companies are implementing the Industry 4.0 concept to improve overall production plant performance and quality.Practitioners should use various industrial standards to integrate MES and ERP systems, which will aid in the integration of shop floor production with enterprise systems. They should also look into MESA International’s KPI-ML, an XML version of the ISO 22400 Specifications that will be used to record, interact with, and exchange KPI knowledge.This article presents several theoretical and practical models to understand how the data-driven Industry 4.0 or smart manufacturing industries apply the different standards to measure performance and use various frameworks to manage quality. First, the paper described the multiple industrial revolutions based on a comprehensive literature review to understand the digital transformation from the 1960 to 2021. Second, the review discussed the different industrial standards applied for measuring the top-floor level performance in data-driven Industry 4.0. Various standards and case studies used to evaluate the performance of data-driven Industry 4.0 were highlighted and discussed. The ANSI ISA 95 standard focuses on the Manufacturing Operation Center (MOC). The MOC system integrates and creates common ground between the periodic and transactional ERP world suitable for manufacturing plants. Furthermore, it discusses the Overall Equipment Efficiency (OEE) and Analysis of Production loss based on MOC.The second standard is ISO 22400, which helps to create the new KPI in manufacturing and apply the standards to define the different KPIs to measure the other parameters of performance in smart manufacturing. The review also discussed the most common KPIs used in the industry. It discussed the Scania Pedal Car Line case study to understand how the ISO 22400 standards are being implemented to measure performance. The third section of this review presented quality management and digitalization of quality called Quality 4.0. We discussed the 11 Axes of Quality 4.0, designed by LNS research to understand how Quality 4.0 contributes to better quality. Furthermore, the paper discussed the case study of Rolls-Royce, one of the world’s top three aircraft engine manufacturing companies and how the organization implemented the Industry 4.0 concept to achieve better quality in the competitive market.Finally, the ISA 95, B2MML, ISO 22400, and KPIML designed by MES need to be examined more systematically, while more organizations implementing the Quality 4.0 framework and how the industries are improving the quality of the product by adopting the Quality 4.0 concept and statistics need to be developed.


Child marriage is a major public health problem globally, and the prevalence remains high in sub-Saharan African countries, including Mali. There is a dearth of evidence about factors associated with child marriage in Mali. Hence, this studyaimed at investigating the individual/household and community-level factors associated with child marriage among women in Mali.  Using data from the 2018 Mali Demographic and Health Survey, analysis was done on 8,350 women aged 18-49 years. A Chi-square test was used to select candidate variables for the multilevel multivariable logistic regression models. Fixed effects results weree xpressed as adjusted odds ratios (aOR) at 95% confidence intervals (CI). Stata version 14 software was used for the analysis. th and 15th birthday, respectively. Educational status of women , their partner's/husband's educational status , women's occupation , family size , and ethnicity  were the identified individual/household level factors associated with child marriage, whereas region  was the community level factor associated with child marriage.  The results showed that 58.2%  and 20.3%  of women aged 18-49 years were married before their 18 This study has revealed a high prevalence of child marriage in Mali. To reduce the magnitude of child marriage in Mali, enhancing policies and programs that promote education for both girls and boys, creating employment opportunities, improving the utilization of family planning services, and sensitizing girls and parents who live in regions such as Kayes on the negative effects of child marriage is essential. Moreover, working with community leaders so as to reduce child marriage in the Bambara ethnic communities would also be beneficial. Worldwichildren . Each yechildren , 7. The children , 10.Child marriage has several adverse consequences for girls' physical, mental, and social health and wellbeing –12. It eth birthday [Mali is one of the countries in the world with the highest prevalence of early marriage and the most severe child marriage crises , 19, 20.birthday . The legbirthday , 19, 20.Several studies in LMICs suggest that girls and their parents' educational status, household economic status, religion, place of residence, family size, ethnicity, and region are determinants of child marriage –26. AlthFor the analysis of this study, we extracted data from the 2018 Mali DHS, which is the sixth DHS since 1987. It is a nationally representative survey designed to provide reliable data for monitoring of demographic and health indicators, including child marriage in the country. It was implemented by l'Institut National de la Statistique (INSTAT) with the financial and technical support of United States Aid for Internal Development (USAID) and Inner-city Fund (ICF) International . The 201th birthday [th birthday and “no” if the first marriage was at 18 years and above.The outcome variable for this study was child marriage, defined as young girls married before their 18birthday . The outBased on the findings of previous studies on child marriage , 28–34, Individual/household level factors included women's educational status , partner/husband's educational status , women's occupation , partner/husband occupation , religion (Muslim and others), family size (<5 and 5+), and ethnicity . Economic status was proxied through a wealth index in the DHS computed using household assets and ownerships using principal component analysis (PCA). Detailed explanation can be found elsewhere  and was Community-level factors included place of residence , distance to health facility (big problem and not a big problem), region , community literacy level , and community socioeconomic status . Community socioeconomic status was computed from occupation, wealth, and education of women who resided in a given community. We applied principal component analysis to calculate women who were unemployed, uneducated, and poor. A standardized score was derived with a mean score (0) and standard deviation . The scoP value less than 0.05 as a cut point. Multicolliniarity test was done among all explanatory variables that had a significant association with child marriage using variance inflation factor (VIF), and the result confirmed that there was no evidence of collinearity among the explanatory variables . Evidence shows VIF less than 10 are tolerable [Descriptive analysis including frequency distribution of respondents and prevalence of child marriage was done. Then, bivariate analysis (chi-square test) was conducted to select candidate explanatory variables using olerable .Finally, multilevel multivariable logistic regression was conducted, and four models were constructed to assess the association between individual/household and community level factors and child marriage. The first model was Model 0 which is also called an empty model that ascertained whether or not the outcome variable (child marriage) varied across enumeration areas, also known as primary sampling unit (PSU). The second model (Model I) was constructed to examine the association between child marriage and individual/household level factors. The third model (Model II) was constructed to examine the relationships between community-level factors and child marriage. The final model (Model III) was the complete model that combined both individual/household and community level factors.The multilevel logistic regression analysis included both fixed and random effects –39. The http://goo.gl/ny8T6X.The analysis was based on publicly available DHS data. Since the ethical clearance was the responsibility of the institution that commissioned, funded, and managed the survey, and further ethical clearance was not required for this study. ICF international and Mali l'Institut National de la Statistique (INSTAT) ensured that the 2018 Mali DHS was conducted in compliance with the national ethical guidelines and U.S. Department of Health and Human Services regulations for the protection of the right of human subjects. More details about data and ethical standards are available at: th birthday.As illustrated in  The results in Region of residence was found to have a significant association with child marriage. Compared to women residing in the Kayes region, the odds of child marriage among women living in all other eight regions were lower. For instance, the odds of child marriage among women living in Mopti, Kidal, and Gao regions were lower by approximately by 73% , 70% , and 67% , respectively, compared to women living in Kayes region .σ2 = 0.43, 0.34-0.54). The null model showed that 11% of the total variance in early marriage was attributed to between-cluster variations (ICC = 0.11). The between-cluster variations decreased from 11% in the null model to 6% in the individual/household-level only model (Model I). In Model II , the ICC declined to 4% and then remained as 4% in the complete model , which had both the individual/household and community level factors. This indicates that the variations in the likelihood of child marriage could be attributed to the variances in the clustering at the primary sampling units.As shown in th and 15th birthday, respectively. The finding from the current study was lower as compared to a study in SSA [In this study, we investigated the individual/household and community-level factors associated with child marriage among women aged 18-49 years using the 2018 Mali demographic and health survey. The study shows that 58.2%  and 20.3%  of women aged 18-49 years were married before their 18y in SSA  that shoy in SSA  includiny in SSA , howevery in SSA  and Zamby in SSA . This miy in SSA , 42–44.Women's educational status, partner/husband educational status, women's occupation, economic status, family size, and ethnicity were the individual/household level factors, whereas region was the community level factor associated with child marriage. More specifically, we found lower odds of child marriage among women who had secondary school and higher education compared to women who had no formal education. This finding is in agreement with some studies from Mali , DemocraEducational attainment increases knowledge and awareness about reproductive health including recommended age for marriage and the negative consequences of child marriage, whereas there may be poor information and knowledge about child marriage and its related problems among girls with no formal education . SeveralChildren who drop out of school have higher chances of being married off early. However, children who are in school and acquiring knowledge have a tendency to delay marriage, childbearing and to have small numbers of healthier children . Child mIn this study, lower odds of child marriage among women whose husbands attended higher education were observed. Similar findings were reported in Ethiopia . SimilarMoreover, we found lower odds of child marriage among women with professional, technical, or managerial occupations compared to women who were not working. A study conducted in Gambia demonstrated comparable findings . SimilarAdditionally, in families where unemployed girls are living together or dependent on their families, some parents are induced to marry off their daughters early for the sake of reducing the financial burden within the family; this practice is more common among communities in rural settings . We founComparable to previous studies , 54–56, In this study, we found higher odds of child marriage among women living in large-sized families compared to women living in small-sized families. Consistent findings are reported in previous studies in Sudan  and EthiIn line with studies in Gambia , NigeriaIn this study, we found that region was significantly associated with child marriage. This is similar to previous evidence in Mali , 23 and Using the recent nationally representative data and multiple modelling approach and examining a broad array of factors, we extend the literature on child marriage by identifying predictors of child marriage at the individual/household and community-levels in Mali. However, the study has some limitations. First, the cross-sectional nature of the study design may not allow for inferring cause-effect relationships in the associations observed. Second, the study might be affected by recall bias and social desirability since the data are self-reported and surveys are interviewer-administered. Finally, even though we attempted to incorporate most factors available in the dataset, cultural factors that need qualitative study designs were not covered and we recommend future studies to fill this gap.th birthday. Women's educational status, partner's/husband's educational status, women's occupation, family size, and ethnicity were the identified individual/household level factors associated with child marriage. Region was the community-level factor associated with child marriage. Hence, in order to reduce the prevalence of child marriage in the country, enhancing girls' and boy's educational level and empowering girls or women through creating employment opportunities, especially professional or technical and managerial occupations, may be required. Improving the utilization of family planning services, working with community leaders to enhance community awareness about child marriage, giving special attention to regions like Kayes, and experience sharing from subgroups with lower child marriage rates such as from Senoufo/Minianka ethnic groups may reduce the social vulnerabilities associated with child marriage.The study highlights that more than half of the women were first married before their 18


The standard method to treat physically active patients with anterior cruciate ligament (ACL) rupture is ligament reconstruction surgery. The rehabilitation training program is very important to improve functional performance in recreational athletes following ACL reconstruction.The aims of this study were to compare the effects of three different training programs, eccentric training (ECC), plyometric training (PLYO), or combined eccentric and plyometric training (COMB), on dynamic balance (Y-BAL), the Lysholm Knee Scale (LKS), the return to sport index (RSI), and the leg symmetry index (LSI) for the single leg hop test for distance in elite female athletes after ACL surgery.n = 10), PLYO (n = 10), and COMB (n = 10), and to a control group (CON: n = 10). Testing was conducted before and after the 6-week training programs and included the Y-BAL, LKS, and RSI. LSI was assessed after the 6-week training programs only.Fourteen weeks after rehabilitation from surgery, 40 elite female athletes (20.3 ± 3.2 years), who had undergone an ACL reconstruction, participated in a short-term  training study. All participants received the same rehabilitation protocol prior to the training study. Athletes were randomly assigned to three experimental groups, ECC , LKS , and RSI . Contrast analysis demonstrated that COMB yielded significantly greater improvements in Y-BAL, LKS, and RSI , in addition to significantly better performances in LSI , than CON, PLYO, and ECC, respectively.Adherence rate was 100% across all groups and no training or test-related injuries were reported. No significant between-group baseline differences (pre-6-week training) were observed for any of the parameters. Significant group-by-time interactions were found for Y-BAL  training seems to represent the most effective training method as it exerts positive effects on both stability and functional performance in the post-ACL-surgical rehabilitation period of elite female athletes. Anterior cruciate ligament (ACL) injury incidence and patterns have been widely studied across many sports in women. Despite the fact that male athletes are less vulnerable to this type of injury, the associated risk factors are the same as they are in females with low knee flexion angles, greater knee valgus, and high ground reaction forces upon landing . As suchIn this context, recent advances in rehabilitation following ACL surgery continue to progress, with current emphasis being on patients achieving immediate weight-bearing , range on = 33) with autogenous hamstring ACL reconstructions, p = 0.012), single-leg hop (p = 0.027), and Lysholm Knee Scale (LKS) (p = 0.002) after 12 weeks of progressive eccentric and concentric training.A standard rehabilitation program typically involves concentric and eccentric exercises, with a recent critical review, indicating that eccentric training, such as Nordic hamstring curls, may be most effective in restoring hamstring strength . Indeed,Furthermore, these authors showed that neuromuscular training can be combined with strength training to maximize outcomes ; howeverN = 37). After the training period, the researchers deployed a twice-weekly program of either conventional eccentric or eccentric overload resistance training with additional load, using supervised one-legged leg-press training. The authors found that eccentric overload resistance training led to significantly greater muscle hypertrophy than conventional eccentric resistance training. However, the training program induced at the same time a slower muscle phenotype for strong and fast movements. With this in mind, further studies are required that use more advanced exercise programs such as eccentric, concentric, and combined modalities to develop a relevant training protocol of appropriate content and intensity.However, it is usually only 3–4 months after reconstruction that the focus of such rehabilitation programs shifts to the enhancement of muscular volume and strengthening . FurtherThus, the aim of this study was to assess the effects of 6 weeks of eccentric training, plyometric training, or a combination of these two modalities, on measures of dynamic stability (Y-BAL), psychological readiness to return to sport (RTS) [LKS and return to sport index (RSI)], and leg symmetry index (LSI) for the single leg hop test in the post-ACL-surgical rehabilitation period of elite female athletes. Based on a relevant literature data , we hypoForty-eight elite female athletes who had undergone an ACL reconstruction participated in this study . Only 40Participants’ inclusion criteria were as follows:1.female athletes who performed systematic sport practice at an international level and were members of the Tunisian national team in their respective sport ;2.on average, athletes exercised between six and eight times per week including competition; and3.athletes with non-contact ACL injury during sporting activity (training and/or competition).Participants’ exclusion criteria were as follows:1.recreational athlete or untrained individual;2.athletes with less than five training sessions per week;3.ACL injury caused by contact;4.athletes who were operated with techniques other than the bone patellar-tendon, bone graft (BPTB), or who were operated by different surgeons and rehabilitated by several physical therapists;5.athletes with a history of muscle or joint injuries;6.athletes with poor attendance rates (below 80%);7.athletes who had already followed a pre-operative rehabilitation program;8.athletes with complication after surgery;9.pregnant athletes and those who were taking anti-inflammatory drugs or muscle relaxers were also excluded.Participants provided informed consent after thorough explanation of the objectives and scope of this project, the procedures, risks, and benefits of the study.The study was conducted according to the Declaration of Helsinki, and the protocol was fully approved by the Ethics Committee of the National Centre of Medicine and Science of Sports of Tunis (CNMSS-LR09SEP01) before the commencement of the assessments.a priori power analysis , using GPower 3.1 software   , was comGermany) . The anaAll surgeries were performed at the Hospital Ortopédico  by the same two knee surgeons who had at least 20 years of technical experience with ACL reconstruction. Two weeks after surgery and 12 weeks before the training program, all participants received the same rehabilitation protocol  consisting of edema and inflammation control, expansion of range of motion, improvement of stability, and training of muscle strength .Participants were randomly allocated to three experimental groups and a control. Group allocation was realized by adjusting for sex, age, and BMI of the study sample. In addition, the order of each trial was changed randomly between participants, in order to avoid learning effects and fatigue. After 14 weeks of rehabilitation post ACL surgery, this latter procedure was performed by an independent researcher who was not involved in the patients’ evaluation or rehabilitation.n = 10), (2) the plyometric group , and (3) the combined eccentric and plyometric group .Two weeks after ACL surgery, female athletes who had completed 12 weeks of rehabilitation participated in the 6-week training study . The thrn = 10) was recruited from the same elite female athletes who had undergone an ACL reconstruction and was also tested and was instructed to follow their traditional program  over a period of 6 weeks   in additThe Y balance test is a dynamic balance (Y-BAL) test that requires subjects to maintain single leg stance while reaching as far as possible with the contralateral leg in three different movement directions  .For this purpose, participants stood on the dominant leg, with the most distal aspect of their great toe on the center of the grid and began in a unilateral stance with their big toe behind the line on the center of the tape. Distances were then recorded by pushing a moveable floor target with the big toe in the three different directions, with trials performed with the dominant leg. Participants were required to keep the heel of the non-reaching leg on the platform, maintaining the balance in a single leg stance, and returning the reaching foot back to the starting point before attempting the next direction. Maximal reaching distances were recorded to the nearest 0.5-cm marker on the Y-balance test kit. Balance performance was expressed as the Y-balance composite test score (YBT-CS), obtained by dividing the sum of the maximal reached distances in each of the three directions, by three times the length of the lower limb . FollowiThe LKS is an eight-item questionnaire designed to evaluate patients after knee ligament injury. It is scored on a 100-point scale from 0 to 100 , with 25 points attributed to pain, 15 to locking, 10 to swelling, 25 to instability, 10 to stair climbing, and 5 points each to limping, use of a support, and squatting .The RSI questionnaire considered three elements that have previously been correlated with returning to sport: emotions, confidence in one’s performance, and evaluation of risk. It is composed of 12 questions anchored to a visual 10-point Likert scale, in the form of boxes to be ticked, ranging from 0 to 10. The total score was obtained by adding the values of the 12 responses, then obtaining their relationship to 100 to obtain a percentage, with high scores corresponding to a positive psychological response. The tool possesses a high degree of internal consistency (Chronbach’s α = 0.96) .Data from unilateral lower limb hop tests were collected and performed as described by For the single one leg hop test for distance, the aim is to jump as far as possible on a single leg, without losing balance and landing firmly. The participant stands on the leg to be tested, jumps horizontally at maximal effort, and lands on the same limb, without touching the ground with hands and without tripping. The distance jumped was measured at the level of the big toe and recorded to the nearest centimeter from a standard tape measure that was permanently attached to the floor.With the triple jump test, the patient stood on one leg, performed three maximal and consecutive horizontal jumps, and landed on the same foot with the same procedure as performed during the single jump. The total covered distance was measured and recorded.In the triple hop test, the aim is to jump as far as possible on a single leg three consecutive times, without losing balance and landing firmly. The distance was measured from the start line to the heel of the landing leg. The goal is to have a less than 10% difference in hop distance between the injured limb and uninjured limb . For theData are presented as means and standard deviations (SD). Data normality was assessed and confirmed using the Shapiro–Wilk test. The data were then analyzed using a 4  by 2  analysis of variance (ANOVA) for repeated measures. Where the assumption of sphericity was violated, Greenhouse–Geisser correction was used to interpret the results.d. Moreover, within-group ES were computed using the following equation: ES = (mean post-mean pre)/SD.If group × time interactions turned out to be significant, a simple contrast analysis was used. Additionally, effect sizes (ES) were determined from ANOVA output by converting partial eta-squared to Cohen’s post hoc comparisons were calculated using Tukey-HSD test. Test–retest reliability of the variables was assessed using Cronbach’s model of ICCs and SEMs according to the method of In accordance with post hoc analysis, while useful, does not yield sufficient insight into multiple levels or detailing patterns in response, whereas contrast analysis allows researchers to test theory-driven expectations directly against empirically derived group or cell means  and R (Car: Anova package (The level of significance was set at 5) and R  using th package .All 40 athletes from the experimental groups completed the study according to the study design and methodology. Participants attended all training sessions and none reported any training- or test-related injury.t-test showed no significant differences between the scores recorded during the two trials for all measured variables.p < 0.001).No significant between-group pre-training differences were found for any of the analyzed parameters . Main efp < 0.001, effect size = 1.73), LKS , and RSI  (Significant group-by-time interactions were found for Y-BAL ( = 1.39) .post hoc comparisons, both the COMB and PLYO groups made similar improvements of Y-BAL  more (p < 0.001) than ECC  and CON  groups (For ) groups .p < 0.001) than the PLYO, ECC, and CON groups of LKS  and RSI  with the largest effect sizes for all groups (The COMB group showed greater improvement (l groups .p < 0.001) (p < 0.001) LSI compared to the ECC and CON groups. Finally, the ECC group is distinguished from the CON group (p < 0.001)  . In addi< 0.001) .p < 0.0001), in addition to significantly better performances in LSI   .p < 0.001, p < 0.0001, p = 0.0004, and p < 0.0001, respectively), in addition to significantly better performances in LSI  (For H2 (COMB vs. PLYO and ECC) we found that COMB yielded significantly greater improvements in Y-BAL, LKS, and RSI ( 0.0001) .p < 0.0001), in addition to significantly better performances in LSI  , we found that COMB yielded significantly greater improvements in Y-BAL, LKS, and RSI  .The present study aimed to assess the effect of 6 weeks of eccentric training, plyometric training, or a combination of these two modalities (eccentric/plyometric), on measures of stability and functional performance in the post-ACL-surgical rehabilitation period of elite female athletes.The most important findings were that the combination of eccentric and plyometric (COMB) exercises was more effective in improving Y-BAL, LKS, RSI, and LSI compared with ECC, PLYO, and CON programs.In accordance with the concept of training specificity  and prioIn this context, The combination of these results suggests that different mechanisms may play a role in contributing to a comprehensive rehabilitative with increases in muscle mass and strength being seemingly bolstered by the additive effect of plyometric training, which taxes the neuromuscular system and associated stretch shortening-cycle capabilities . SubstanThese training programs for women can improve many performance measures such as speed, strength, and power . CombineAn athlete’s balance can be improved with a strength training program that enhances the ability and speed of postural muscles to return to a more stable position following perturbation . PlyometFurthermore, the sensitivity of afferent feedback pathways may be improved with balance and motor skill training, resulting in a faster onset of stability . The dynFurthermore, the execution of strength and plyometric training may be an important determinant of functional knee assessment as an injured individual age. For instance, plyometric training has been associated with positive outcomes relating to bone mass . Indeed,This can lead to the development of an efficient stretch-shortening cycle, particularly important for deceleration movements  such as Furthermore, the present study demonstrated that the COMB group outperformed the PLYO, ECC, and CON groups on RSI scores. The probable explanation was that the protocol of the COMB group imposed a more comprehensive stress of greater magnitude and improved psychological status by way of increased confidence levels for the athlete. This assertion is supported by It is possible that the comprehensive nature of a COMB training stimulus is beneficial in this regard as it may provide athletes with the confidence they require to return to competitive play. The relatively low rate of return to competitive sport, despite high rates of successful surgical outcomes, supports the use of psychological interventions as being part of a multidimensional approach to ACL rehabilitation, alongside physical activity programs that closely reflect the demands of the athlete’s sport.This study is not without limitations. First, the sample size is small in each group and limited the statistical power and the generalizability of the findings. Furthermore, the study participants were highly homogeneous , which limits the generalizability of its findings. Second, subjects have a narrow age range. Moreover, a lack of nutritional control and of activities outside of the training program most certainly could be considered as factors to potentially impact our outcomes. Third, systematic bias due to learning effects within our participants cannot be completely ruled out. However, they were used in most of the testing protocols performed  and had also been part of a familiarization session 1 week before the start of the study. As such, although learning effects may be one possible explanation for the present results, they should be negligible. Finally, another limitation is the simplicity of the applied fitness tests , which did not extend the current mechanistic knowledge. In fact, the present variable used in the current study may be too broad and does not allow for clear speculation of the possible physiological mechanisms explaining the positive effect of combining eccentric and plyometric training for performance enhancement after an ACL-surgical rehabilitation period of elite female athletes. Therefore, future studies are advised to include research approaches to elucidate the underlying neural changes.Based on our results, it is apparent that, despite all of the training methods inducing improvement outcomes to various extents, combined (eccentric/plyometric) training was the most effective protocol to stimulate positive changes in Y-BAL, LKS, RSI, and LSI index. On this basis, combined protocol represents the most efficacious training program as it exerts positive effects on both stability and functional performance in the post-ACL-surgical rehabilitation period of elite female athletes.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.This study was conducted according to the Declaration of Helsinki and the protocol was fully approved by the Ethics Committee of the National Centre of Medicine and Science of Sports of Tunis (CNMSS-LR09SEP01) before the commencement of the assessments. The patients/participants provided their written informed consent to participate in this study.SK, RH, AH, FS, HZ, and OO conceived the manuscript ideas and design. SK, UG, ACH, AH, MC, CC, and OO drafted, revised, and edited the manuscript. SK, MC, FS, CC, SC, ACH, UG, HZ, and OO assisted in revising and editing the manuscript. All authors have read and approved the final version of the manuscript, and agreed with the order of the presentation of the authors.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.