The risk of being hospitalized for complicated varicella in subjects with at least one comorbidity was significantly higher than in subjects without comorbidities (p = 0.0016). The economic analysis showed higher costs in subjects with complicated varicella who were 0–3 years old. This age group showed higher costs also considering extra-hospital costs for both outpatient procedures and pharmaceutical costs (p < 0.0001). The results confirm the relevant burden of varicella, especially in the 0–3 age group and in children with comorbidities. Thus, vaccination with the achievement of adequate vaccination coverages is confirmed to be a necessary control strategy to reduce hospitalizations and associated complications with important economic benefits.According to WHO estimates, varicella disease is responsible of a worldwide significant burden in terms of hospitalizations, complications, and deaths, with more than 90% of cases under 12 years old. This study aims at evaluating the clinical, epidemiological, and economic burden of varicella in Ligurian children, about comorbidities, organizational variables, and vaccination coverages from 2010 to 2017, in terms of Emergency Department accesses and hospitalizations. The overall hospitalization rate was 179.76 , with a gradual but significant decline since 2015, when universal varicella vaccination was introduced in Liguria ( The varicella-zoster virus (VZV) is a DNA virus of the herpes virus family. The primary infection leads to varicella disease; viral reactivation can cause herpes zoster ,2,3.Nowadays, varicella is a vaccine-preventable infectious disease. According to the World Health Organization (WHO), the annual worldwide burden of varicella is estimated to be approximately 140 million cases with 4,200,000 severe complications that require hospitalization, and 4200 deaths ,6. It isWhile usually varicella is a mild or moderate disease ,7,8,9, aAs a result of the healthcare and economic burden of varicella, many countries have introduced immunization in infancy. In particular, the varicella vaccine was firstly produced in Japan in the 1970s but then introduced in most western countries, including Germany, Sweden, Korea, the United States, and Italy in the late 1980s and 1990s . NowadayFurthermore, vaccination against varicella reduces the number, size, and duration of varicella outbreaks ,18 and rIn Liguria, a Northern Italian Region, the varicella universal vaccination was introduced in 2015 for the 2014 birth cohort following the National Recommendation . The ItaThe European Centre for Disease Prevention and Control [ECDC] recommends implementing epidemiological surveillance in order to monitor both the spreading of the pathogen and the impact of already implemented vaccine strategies . As for This study aims to estimate the clinical, epidemiological, and economic varicella burden in children in Liguria.A retrospective cohort study was performed in order to evaluate the clinical, epidemiological, and economic burden of varicella in terms of emergency department (ED) accesses and/or hospitalization from 2010 to 2017 in Liguria. The burden was then evaluated according to vaccination coverage, organizational variables, and comorbidities.ED accesses/hospitalizations for varicella from January 2010 to December 2017 in Ligurian children  were analyzed. Patients were captured by means of the ED and hospitalizations discharge records (ICD-9-CM 052* codes in any field of diagnosis) and the regional Chronic Condition Data Warehouse (CCDWH).Different data sources were analyzed: (i) ED and hospital discharge records for the estimation of ED access/hospitalization of subjects with varicella; (ii) for Regional pediatric population: vaccine coverage using the regional vaccine registry, distribution by age group and presence of comorbidities obtained through the regional CCDWH; (iii) hospital pathways through ED and hospital discharge record; (iv) hospital and extra-hospital costs through the Regional Data Warehouse .The ED discharge record is included among the administrative healthcare data routinely collected. At the end of each ED access, ED discharge records periodically were sent to the Regional Authority. The ED discharge records include various data such as the main diagnosis field coded by the ICD-9-CM system, the procedures and treatments administered during the ED access, the way of admission and discharge, and the severity of the condition at the access time. Administrative healthcare data such as ED discharge records display weaknesses in terms of sensitivity and specificity. Incidence rates and other variables were defined by using data extracted from this registry, selecting all hospital admissions with a main diagnosis of varicella or its complications  codes. .The CCDWH records data were gathered from multiple Medicare data sources  within a specified period using a predefined algorithm based on the codes assigned to specific diagnoses and procedures. Through a record-linkage system based on a civil registry database, residents’ histories of healthcare events are constructed to depict the chronic condition of each patient. All data are archived in a relational database (RDBMS) using big-data logic. The main diseases recorded by the CCDWH are the following: organ transplantation, renal failure, HIV infection, malignancies, diabetes, cardiovascular diseases, bronchopneumopathies, gastrointestinal diseases, neuropathies, autoimmune diseases, endocrine metabolic disorders, and rare diseases. A unique code specific for each patient is used to link data from our study population and the CCDWH and to evaluate the patient’s chronic conditions on the day of ED access. To calculate crude incidence by health care setting, pediatric demographic data were extracted from the regional Chronic Condition Data Warehouse (CCDWH).In the Liguria region, the varicella vaccine was recommended only for subjects at risk, as identified by the National Vaccine Prevention Plan 2003–2005, and administered with an active offer in healthy and susceptible adolescent subjects (one dose in 11–12-year-old with negative anamnestic criterion). Subsequently, according to the 2015 Regional Vaccination Prevention Plan , the Ligurian immunization policies included a universal varicella vaccination program with an active and free-of-charge immunization strategy addresses to all children aged 15 months old (beginning from 2014 birth cohort), with a second dose administered at 5–6 years of age. A catch-up two-doses vaccination was also offered free of charge to 12-year-old adolescents with a negative history of varicella. According to the present recommendations, the coverage target was set at ≥95% coverage.In order to monitor the coverage rate, aggregated regional data collection for administrative purposes were used; provided by the local health authorities. In the present study data on vaccination coverage were retrieved from this database.Cost estimates of ED accesses, including admission to short observation, and the direct costs of hospitalizations were obtained by scrutinizing the outpatient procedures performed in the ED and the Diagnosis-related group (DRG) system, respectively. By the regional reimbursement system, the evaluation of costs related to ED accesses followed by hospitalization included only the DRG-based costs. Extra-hospital costs  were obtained through the Regional CCDWH Data Warehouse.A descriptive analysis of the pediatric varicella ED accesses and hospitalizations was performed. Results were expressed as a median and interquartile range for quantitative outcome measures and as frequency distributions for qualitative outcome measures. Rates were estimated together with the corresponding 95% confidence intervals (CIs).2 test (Pearson test) and Mann–Whitney U test, were applied respectively. Comparison of outpatient procedures and pharmaceutical costs at the 6 months before and after ED access/hospitalization was carried out using the Wilcoxon test. Data were analyzed by JMP version 13.0.0 software . A value of p < 0.05 was considered statistically significant.Different statistical association tests were used depending on the type of outcome measure: to compare qualitative and quantitative variables, the χA total of 2239 ED accesses and/or hospitalizations for varicella among Ligurian children 0 to 17 years were reported from 2010 to 2017, of which 2014 (89.95%) ED accesses and 225 (10.05%) hospitalizations were preceded or not by ED access.p = 0.145).Regarding demographic characteristics, the overall median age of varicella cases was 4 years (IQR 2–6) and 3 years (IQR 1–5) considering hospitalizations preceded or not by ED access respectively. Over the entire period, 52.88% of cases were observed in males without statistically significant difference between gender , covering the entire regional population. The highest incidence was observed in LHA2 , followed by LHA1  considering the total events and ED accesses; instead for hospitalization preceded or not by ED access the highest incidence was observed in LHA3 (23.62), followed by LHA2 (17.25).Overall, the total incidence of varicella cases in our study population was 179.76 per 100,000 inhabitants. In particular, the total incidence rate of ED accesses and hospitalizations preceded or not by ED access for varicella in children was equal to 161.70 and 18.06 per 100,000 subjects, respectively. The annual incidence rate of cases showed an increasing trend between 2010 and 2012, reached a peak in 2013, with an incidence of 218.58 per 100,000 inhabitants, and from 2015 it declined, reaching 127.46 per 100,000 population in 2017 , in partThe vaccination coverages at 36 months and 5–6 years of age showed very low values in 2015 and 2016 and higher values starting from 2017, thus we did not consider these coverages associated with the declining trend of hospitalization rates in our study period. Two further clarifications need to be made considering the annual hospitalization rates . In factThe first aspect may be explained by an underestimation of varicella cases due to a lack of accuracy of the electronic administrative regional flows in Liguria Region that was reinforced starting from 2010.While the rebound in 2016 may be related to the technical timing of implementation of the universal varicella vaccination program addressed to all children aged 15 months old. This document was published in January 2015, but implemented in the subsequent months, thus, there may have been a delay in the visibility of the most effects of vaccination.More details on downward trend hospitalization rates, in a transition period between immunization policies, were more evident in p < 0.0001, OR 1.532, 95% CI 1.225, 1.917). The average varicella incidence rate among 0–17 year-olds from January 2010 to December 2014 (before the breakpoint) was 169.83 per 100,000 person-years. Average incidence decreased to 140.84 after January 2015. The yearly peaks in varicella hospitalization rates decreased after the vaccine was introduced and then fell further as higher coverage were achieved, as previously reported in In particular, data showed a seasonal pattern of the epidemiology of varicella with a peak incidence during spring months (from February to May) and a lower incidence in late summer and early autumn. During the years January 2010–December 2014, a period in which vaccination had been already introduced, but coverage was still very low, this seasonal trend continued, however, to level up. The analysis identified the breakpoint as occurring in January 2015, in which peak incidence rates decreased significantly  and 140 cases with secondary diagnosis  were recorded. Most of the patients  was healthy, while 6.97% (156) had at least one comorbidity, of which 121 (6.01%) required ED access and 35 (22.43%) required hospitalization preceded or not by ED access.Among cases with comorbidities, the most common were bronchopneumopathies  followed by cardiovascular diseases . Asthma (98.85%) was the most frequent bronchopneumopathy, while valvular heart diseases (84.38%) were the most frequent among cardiovascular diseases .p = 0.0014, OR 1.629, 95% CI 1.204, 2.204)  .p = 0.00164, OR 2.072, 95% CI 1.282, 3.254).Overall, ED accesses and/or hospitalization with a diagnosis of complicated varicella infection were 192 (8.58%). The risk to be hospitalized for complicated varicella in subjects with at least one comorbidity  was significantly higher than subjects without comorbidities   of the hospitalizations were due to post-varicella encephalitis, 0.52% (1/192) to varicella-linked hemorrhagic pneumonia, 0.52% (1/192) to post-varicella myelitis, 67.71% (130/192) to varicella with other complications, 22.92% (44/192) with complications not specified.Regarding the hospital pathways followed by patients, the admission took place mainly in directly managed public hospitals through emergency department access. Specifically, 223 were hospitalized in ordinary regimen, while only two patients were hospitalized in day-hospital regimen.p = 0.2909). The median length of hospital stay increases with age. In particular, in the population 0–3 years the median length was four days (IQR 3–6), 4–7 years was four days (IQR 3–7), and for children ≥8 it was four and a half days . Infectious diseases represented the most frequent admission, transfer, and discharge ward, followed by emergency medicine. The main way of discharge was at the patient’s home (96.44%).Children were mainly hospitalized in Gaslini Institute, one of the major pediatric hospital in Italy, located in Genoa, that cared for 67.56% of cases. The overall median length of hospital stay was four days . It did not change over the seven-year period , €206,169 in 4–7 years old (per-capita cost €215), and €69,157 in ≥ 8 years old (per-capita cost €254).The total cost of ED access/hospitalization in patients with complicated varicella was equal to €385,889 versus €238,416 (cost of varicella without complication).The total cost of ED access/hospitalization stratified by age-groups revealed the highest costs in the 0–3 age group  than the other age groups , both for varicella with and without complications.Outpatient procedure and pharmaceutical costs in the six months before and after ED access/hospitalization stratified by age in Ligurian subjects aged 0–17 years old were analyzed. In particular, children of 0 years old showed higher cost in the six months after ED access/hospitalization vs. the six months before, both for outpatient procedures (+€1951) and pharmaceutical costs (+€525), children aged 1, 2, 9 years showed higher costs in the six months after ED access/hospitalization vs. the 6 months before for pharmaceutical costs , and, finally, children aged 3 and 5 years showed higher costs in the six months after ED access/hospitalization vs. the six months before for outpatient procedures (+€4855 and +€1380).p < 0.0001, OR 1.308, 95% CI 1.285, 1.331; p < 0.0001, OR 1.15, 95% CI 1.121, 1.18, respectively).From a comparison between the 6 months after and before ED, access/hospitalization related to extra-hospital costs, the age group 0–3 years showed costs significantly higher than the other ages in the six months after ED access/hospitalization both for outpatients procedures and pharmaceutical consumption  received at least one dose of varicella vaccine. Specifically, 44 children received the first dose at least one month before the ED access/hospitalization, 48 children after the event, and none subjects in a range from zero to 15 days before the ED access/hospitalization. In particular, eight children required ED access, and one child required hospitalization preceded by ED access developing encephalitis post varicella resolved within 16 days of hospitalization discharged at home.Among 44 children who received the first dose at least one month before the ED access/hospitalization, a second dose was administered to 15 children .Furthermore, among 48 children who received the first dose after the ED access/hospitalization, a second dose was administered to 4 children.WHO advocates routine varicella immunization in countries where high vaccination coverage can be achieved  .Furthermore, As recommended by the ECDC, the assessment of epidemiological variations linked to the implementation of vaccine strategies is mandatory to further improve national programs .In Italy, during the last decade, regional recommendations on varicella vaccination were heterogeneous and led to a marked discrepancy in vaccination coverage observed throughout the country. In particular, a 1-dose varicella vaccination program was introduced in Sicily  and ApulAdditionally, an Interregional Group on Varicella Vaccination has been established in 2013 to assess the effectiveness of the immunization programs started in these regions, providing a standardized method to collect data.In Liguria, the varicella universal vaccination was introduced in 2015 for the 2014 birth cohort following the National Recommendation . AccordiThis actual immunization scenario is in line with the results of the study that showed a gradual decline of hospitalization rate of ED access/hospitalization for varicella in patients aged 0–17 years in Liguria, starting from 2015. This could be implied with the beginning of the varicella vaccination strategy. Our findings highlight that the breakpoint occurred in January 2015, when peak incidence rates decreased. As previously described, this could be linked to prevention measures adopted. Nevertheless, observing in detail the annual incidence rate of cases  there weThe rebound in 2016 could be related to the Ligurian Vaccination Prevention Plan that included a universal varicella vaccination program with an active and free-of-charge immunization strategy addressed to all children aged 15 months old, which was published on January 2015 but implemented subsequently. Thus, it is supposed that the most important effects of the immunization program on hospitalization rates were visible starting from 2016, when higher vaccination coverages were reached. In fact, as well as confirmed in several studies hospitalization rates are strictly related to both the vaccination coverage and the number of years since the introduction of the vaccination ,26,27,28In particular, In this scenario, varicella vaccination is confirmed to be an important step in public health strategies and the introduction of universal vaccination, with high vaccination coverage, should be considered as an extremely powerful tool to reduce the risk of complications.Furthermore, it was found that the risk to be hospitalized for complicated varicella in subjects with at least one comorbidity was significantly higher than subjects without comorbidities. The comparison between comorbidities revealed that broncopneumopathy and cardiovascular disease were the comorbidities most implicated in ED access/hospitalization for varicella than the other comorbidities; however, statistical significance was reached only for broncopneumopathy. Others studies have found analogous results ,30.Estimates of the economic burden of varicella in terms of ED accesses/hospitalizations showed lower costs with respect to previous not recent Italian published data, ,32; it iWe found higher costs in children 0–3 years old both for varicella with and without complications than the other age-groups. Similarly, as regards extra hospital costs, the age group 0–3 years showed costs significantly higher than the other ages in the six months after ED access/hospitalization, both for outpatients procedures and pharmaceutical costs.An increase in vaccination coverage rate was detected starting from 2015; however, a suboptimal coverage rate was observed in 2016 and 2017, far from the threshold recommended by the Italian Minister of Health [≥95%].The vaccination coverages, suboptimal in the general population, were also unsatisfactory in hospitalized patients. Specifically, 44 children received the first dose at least one month before the ED access/hospitalization, showing a vaccination failure of 1.95%. Other authors found higher percentages in similar populations: Kuter et al. and Prymula et al. reported 4% and 5%, respectively ,34.These observations, derived from our results, imply that varicella disease has a relevant impact on public health in terms of hospitalizations, complications, and costs, especially in early childhood. Furthermore, the costs related to hospitalizations for complicated varicella and extra-hospital costs  were also a considerable issue. Nevertheless, it is also worth considering indirect costs, not assessed in this study, relating, for example, to the number of lost working days by parents or family members for the care of children affected by varicella and also the indirect effects of the disease on the health of adults and elderly, often more at risk of severe effects of the disease. Thus, reaching higher vaccination coverages is necessary not only to prevent severe cases of varicella in children but also to avoid the risk of increased incidence of severe varicella in older age groups, where VZV infection can have more severe adverse consequences .Thus, our experience supports the intention to reinforce the national universal routine vaccination against varicella in children and the routine assessment of the epidemiology and disease burden of varicella to better address the planning and evaluating varicella control strategies.This study could have some limitations that have to be considered. Firstly, our data, based on a large administrative database, may pose concerns relating to miscoding and data reporting inaccuracies. We cannot exclude the presence of underreporting of ICD-9 CM codes suggestive for varicella complications, in particular in the pediatric population. It should be also considered that, in Italy, in a large majority of cases, reporting varicella complications have a trivial impact on economic reimbursement and thus could be omitted by clinicians. Nevertheless, we are confident that, if errors occurred, they were similar throughout the whole study period. Furthermore, this study reports only severe cases requiring hospitalization, not considering mild cases, so, unfortunately, our data cannot be considered conclusive as the number of cases might be too low in general to provide robust results.Despite these potential limitations, a strength of the present study is that we investigated varicella-related hospitalizations through data collected from all over the Liguria Region (population 1.56 million). The CCDWH platform consists of a sophisticated system that integrates several administrative regional flows and it is used to identify comorbidities with accuracy and precision. Furthermore, to the best of our knowledge, few studies in the world evaluated varicella-related hospitalization rates over a long temporal period, comparing these rates with varicella vaccine coverage. In this scenario, this study adds updated and suggestive findings to the international literature and shows that varicella hospitalizations in Italy, from 2010 to 2017, are an important healthcare burden, especially during years before varicella vaccination.Our study demonstrates that varicella causes a substantial burden especially on early children and in children with comorbidities, better defining the picture of the real burden of this vaccine-preventable disease. These data support the strengthening of varicella vaccination programs in the infancy and high-risk children. The continuous updating of epidemiological data in terms of disease impact  is crucial for the overall assessment of the impact of vaccination against varicella.


The prevalence of diabetes mellitus (DM) is increasing rapidly worldwide. Simultaneously, technological advances are offering new opportunities for better management of type 1 diabetes mellitus (T1DM). Telemetry, the remote acquisition of patient data via a telecommunication system, is a promising field of application in eHealth and is rapidly gaining importance.The aim of this study was to summarize the current evidences available on the effectiveness of telemetric approaches in T1DM management. This systematic meta-review examined different types of interventions of the technologies used in communication between health care professionals and patients as well as the key outcomes.1c (HbA1c) values and different quality assessments were performed.We performed a systematic search in Web of Science Core Collection, EMBASE, Cochrane Library, MEDLINE via PubMed, and CINAHL databases in April 2020 with regard to the effectiveness of telemetric interventions for T1DM. We classified the interventions into 4 categories according to the technology used: (1) real-time video communication, (2) real-time audio communication, (3) asynchronous communication, and (4) combined forms of communication . We considered various study designs such as systematic reviews, clinical trials, meta-analyses, and randomized controlled trials and focused on the key outcomes. Additionally, a funnel plot based on hemoglobin A1c levels; 65% (11/17) of the studies reported overall (mildly) positive effects of telemetric interventions by addressing all the measured outcomes. Asynchronous interventions were the most successful for patients diagnosed with T1DM, but no technology was clearly superior. However, there were many nonsignificant results and not sustained effects, and in some studies, the control group benefited from telemetric support or increased frequency of contacts.We identified 17  eligible publications: randomized controlled trials (n=9), systematic reviews and meta-analyses (n=5), cohort studies (n=2), and qualitative publications (n=1). Of 12 studies, 8 (67%) indicated a (significant or nonsignificant) reduction in HbA1c levels and result in overall positive effects in T1DM management. However, more specified effects of telemetric approaches in T1DM management should be analyzed in detail in larger cohorts.Based on the currently available literature, this systematic meta-review shows that telemetric interventions cause significant reduction in HbA The historical origins of digital health date back to the 1970s, when telematics, the science of telecommunications and informatics, emerged . NowadayTelemedicine is a digital field of application and part of eHealth and digitalization in the health care sector . The excthe therapy goal to reduce and prevent such diabetic complications and comorbidities. Intensive therapeutic measures address the delay of onset of diabetic complications as well as comorbidities in T1DM [This systematic meta-review focuses on telemetry by using the example of patients diagnosed with type 1 diabetes mellitus (T1DM). DM is one of the most prevalent chronic diseases worldwide . Globall in T1DM . Therefo in T1DM . Several in T1DM -14. The  in T1DM ,14. HoweWe performed a systematic search in Web of Science Core Collection, EMBASE, Cochrane Library, MEDLINE via PubMed, and CINAHL databases in April 2020. The systematic meta-review was carried out based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines . Peer-reWe included publications written in English and German with the target group patients diagnosed with T1DM. These publications addressed interventions in the field of telemetry, telemedicine, and telemonitoring for their diabetes therapy. The intervention involved direct interaction between the patients and health care professionals, that is, feedback from health care professionals based on the transmitted patient data. We included the following study designs: systematic reviews, meta-analyses, clinical trials, and RCTs.Since this systematic meta-review focused on T1DM, we excluded participants diagnosed with other forms of DM  as well as mixed collectives, meaning that studies included not only patients with T1DM but also people diagnosed with other types of DM. Moreover, we excluded individual studies that were already included in the identified systematic reviews and meta-analyses; therefore, no data from systematic reviews/meta-analyses and individual studies are pooled, leading to a possible bias. Abstracts, posters, comments, letters, study protocols, notes, and proceedings papers were excluded. In addition, publications that focused on the description of the technology were rejected. Telemetry is a wide term and may cover different technologies. Since the way of communication between patients and health care professionals is different compared to that in telemetric interventions, we analyzed interventions with mobile apps in other studies separately. We also eliminated studies providing only pooled data . Furthermore, duplicates and studies that addressed prevention or diagnosis of DM were rejected. The literature search is documented in the PRISMA flowchart . As Figuoverall effects were extracted . The quality of life (QoL) was divided into diabetes-related quality of life (DRQoL) as well as health-related quality of life (HRQoL).We extracted the year of publication, study designs, durations, intervention and control groups, outcome measures, sample sizes, country, statistical significances, and conclusions. Intervention and control group data included the technologies used, feedback methods, the frequency of contact, and data transmission. The significance involved the comparison of the intervention group with the control group (intergroup) and the comparison within the intervention group, that is, from the baseline to the end of the study (intragroup), depending on what was reported. In relation to the systematic reviews and meta-analyses, the A qualitative analysis was conducted. The selected studies differed regarding sample, design, and measures. A proper meta-analysis was therefore not possible. For analysis, the studies were classified into different categories based on a scheme that we developed. First, the publications were systematized into 4 categories according to the technologies used to communicate between the health care professionals and the patients .Different intervention typesReal-time communication video: Synchronous face-to-face communication by videoconferencing and videoconsulting.Real-time communication audio: Synchronous communication by telephone calls (telephone coaching and counselling).Asynchronous communication: Asynchronous communication by email, SMS text messaging, internet/web-based platforms, server, home gateway, or post.Combined forms of communication: The intervention involves real-time and asynchronous communication.1c (HbA1c), body weight, blood pressure, QoL, cost-effectiveness, and time saved  and excluding a study that compared 2 telemetric applications, we generated a funnel plot based on 6 RCTs. Intervention effect was expressed as the mean difference using HbA1c values at the end of the study.A quality assessment of the studies was conducted to determine the risk of bias. Since we included different study designs, we applied 3 different quality appraisal tools. First, we applied A MeaSurement Tool to Assess systematic Reviews (AMSTAR 2), a validated and widely used tool for the evaluation of systematic reviews and meta-analyses. AMSTAR 2 rates the study quality as high, moderate, low, or critically low. Second, we used Effective Public Health Practice Project (EPHPP), a validated instrument that addresses studies on health-related topics. Since this tool is suitable for quantitative intervention studies, we used it for RCTs and cohort studies. EPHPP consists of the following components: selection bias, study design, confounders, blinding, data collection methods, and withdrawals and drop-outs. The instrument rates the study quality as strong, moderate, or weak. Third, we applied the validated National Institute for Health and Care Excellence (NICE) quality appraisal checklist for qualitative studies. The NICE checklist includes the following components: theoretical approach, study design, data collection, trustworthiness, analysis, and ethics. This tool rates the study quality as ++ (high), + (moderate), or – (low). In addition, the publication bias was assessed visually as a funnel plot by using HbAThe database search resulted in 1647 records. After removing duplicates, 1116 publications were screened for eligibility. We excluded 875 of these records based on titles/abstracts for the reasons given in HRQoL and DRQoL were evaluated using very different methods. Validated instruments were used to measure these outcomes, for example, 36-item Short Form Health Survey, Diabetes Quality of Life questionnaire, PedsQLTM 3.0 Diabetes Module questionnaire, 12-item Short Form Health Survey, and European Quality of Life survey. There were also specially designed questionnaires.1c levels in the intervention group. Descriptive examination of the funnel plot by using HbA1c values based on 6 RCTs indicated a mild form of asymmetry  reported overall (mildly) positive effects of the telemetric interventions in relation to all measured outcomes . Table 2symmetry .1c levels as the targeted outcome. Three studies (60%) reported overall positive effects in terms of reducing HbA1c levels significantly. Lee et al [P=.01). Peterson [1c levels in their intervention groups. However, Viana et al [1c levels following telemedical interventions  found no effects ,24 and aOne high-quality study described that the limited data available on the costs of telemedicine suggested no differences between the groups . One of 1c levels at the end of the assessment phase (P=.01) [1c values between groups  reported significantly reduced mean HbA (P=.01) . Howevers (P=.84  and P=.44 [P=.49 ). One of4 [P=.49  examinedOne moderate-quality RCT observed that changes in HRQoL between the first visit and the final visit did not differ between the groups .1c. Only 1 study  showed significant improvements in the HbA1c levels in the patients undergoing interventions (8.7% to 7.7%) compared to the controls  [1c levels between the telemedicine and usual care groups. In addition, 1 moderate-quality publication mentioned no improvement in HbA1c levels, with no statistically significant difference  [All 4 RCTs considered the outcome HbA, P<.05) . Gandrud, P<.05)  and Yaro, P<.05)  (high-qu groups) .P<.05) [P=.06), respectively [According to an RCT , a number of QoL indicators increased significantly due to telemetry compared to that in the control group (P<.05) . Howeverectively .Yaron et al   and Bert1c values was found. HbA1c was by far the most investigated outcome in these studies. Overall, most systematic reviews and meta-analyses  showed a significant reduction in HbA1c values. The other systematic reviews and meta-analyses also indicated positive effects, but they were not statistically significant. The study of Lee et al [P=.01). Moreover, HbA1c levels were improved significantly in most asynchronous interventions. HbA1c values clearly decreased when combined interventions  were applied, but 1 moderate-quality study showed significant improvements and 3 more  reported positive but not significant effects. Our findings indicated a trend toward better glycemic control for patients with T1DM by means of telemedicine. This result has potential practical implications. The fact that HbA1c levels could be significantly improved in many studies is a promising result in view of the fact that an optimized glycemic control reduces the risk of comorbidities and complications as well as progression of microvascular and macrovascular consequences among patients with T1DM [This systematic meta-review highlighted the variety of telemetric interventions and technologies used in diabetes care by focusing on T1DM management. Considering all the study designs, asynchronous interventions were found to be the most successful for people with T1DM in improving the key diabetic outcomes, but no technology was clearly superior. However, the results might be inconsistent in terms of the different key outcomes, but fortunately, an improvement in terms of HbAee et al , a high-ith T1DM . Howeverith T1DM . Aside fIn our view, telemetry enables close diabetes management and offers the advantage of overcoming the physical presence. Telemetric technologies allow a higher frequency of contacts between patients and health care professionals. Telemetric interventions also increase, in our view, patient compliance, reliance, and empowerment. The patients implement recommendations for action more successfully in everyday life. They are supervised and managed effectively and more closely and may feel more secure in terms of diabetes therapy. Another systematic review and meta-analysis  that recThe systematic reviews and meta-analyses were heterogeneous since telemetry can cover various interventions and technologies and the authors used different definitions of telemedical approaches. Additionally, the variability of the methods used in the studies made it difficult to reach firm conclusions. Studies often suffered from small sample sizes, poor study designs, lack of controls, or no long-term intervention effects. Some studies had samples of patients with poorly controlled diabetes that led to greater intervention effects. Overall, there were not many significant results both for intergroup and intragroup comparisons.P values. Furthermore, based on the findings, the long-term effects can be questioned. Some studies found significant positive postintervention effects, but they did not last for a long term. Long follow-up periods are therefore important.Interestingly, the control group was often not a real or pure control group with usual care. The control group often had an increased frequency of contacts with health care professionals (more than 4 times a year), which led to improved outcomes. In some studies, the control group benefited from telemetric support. Moreover, several studies did not adequately define usual care. The intervention effects might be greater if the telemetric group was compared to a pure control group. Besides, the high number of nonsignificant results is particularly noticeable. This could be related to an often low statistical power. It is also concerning that some studies did not publish Our review is, as far as we know, the first systematic meta-review on telemedicine in T1DM management. Compared to other papers, this systematic meta-review included different study designs, looked at a variety of outcomes, and carried out a differentiated analysis based on a developed scheme. We also analyzed the findings in detail and differentiated them based on the intergroup or intragroup comparison, significant or not significant effects, and effect sizes. In this way, we were able to contribute to a multifaceted view of the topic.Some limitations have to be considered when interpreting and using the results. To the best of our knowledge and the elected inclusion and exclusion criteria, we included all suitable studies. Some of the systematic reviews and meta-analyses reported that the poor quality of the included studies was a weakness. Furthermore, numerous definitions of telemetry and telemedicine include different technologies. For the reasons mentioned above, we decided to exclude smartphone app–based interventions, which may be a limitation. Besides, the definition of usual care was insufficient and heterogeneous across the publications. Some studies did not use a control group in the sense of usual care. It is notable that in some studies, the control group had a similar frequency of contacts as the intervention group. In some studies, the control group received telemetric support. These circumstances influence the results achieved and must be considered. Overall, the studies displayed different characteristics and methods, which lead to heterogeneity and can influence the reliability of the results.1c values and found no decrease in HbA1c levels after telecare (P=.09). Another systematic review [1c levels in 24 studies and found inconsistent evidence for T1DM.In a nutshell, other reviews showed similar inconsistent findings. Lee et al  observedc review  mentionec review  investig1c but also address other outcomes, in particular, fasting blood glucose, blood pressure, QoL, cost-effectiveness, and time saved. Additionally, future studies should provide sufficient statistical power. Further research regarding T1DM is required to examine the special needs of this subgroup in more detail and to develop and adapt suitable interventions. The alarming number of findings with nonsignificant P values reveals a need for better study planning as well as RCTs with large sample sizes. In conclusion, telemetry might be a promising approach for people diagnosed with T1DM, especially asynchronous interventions, but its potential should be explored further.This systematic meta-review offered a comprehensive summary of the effectiveness of telemetric interventions in T1DM management and provided insights into the application of telemetric interventions. The evidence for the effectiveness of telemetric approaches in the management of T1DM might be inconsistent. Further studies with a clear and homogeneous methodology are necessary for research and for patients. In addition, we need further research to understand how, why, and when technology can improve the outcomes. Studies should not only focus on HbA


Gossypol, a terpenoid compound mainly synthesized in the cotton roots, acts as a phytoalexin in protecting the plants from biotic stress. Roots are critical for both the secondary metabolism and the growth of the plant. Light plays an important role in plant growth and material metabolism, however, the effect of root illumination (RI) on the cotton seedling growth and gossypol metabolism remains unclear. In the present study, the cotton genetic standard line TM-1 and four pairs of near-isogenic lines (NILs) were used as materials to study the impact of RI on cotton seedlings. Results showed that, compared with the cotton seedlings cultivated without RI, the photosynthetic rate, leaf area, and dry weight of roots and leaves were significantly increased, while the gossypol content in leaves and roots was significantly reduced in seedlings cultivated with RI. GO and KEGG enrichment analysis of the differentially expressed genes (DEGs) with and without RI both indicated that photosynthesis and terpenoid biosynthesis-related GO terms and pathways were significantly enriched, the expression profile confirmed that RI positively regulated the photosynthesis system and negatively affected the gossypol biosynthesis pathway in roots. This study revealed the effects of RI on seedlings’ growth and gossypol biosynthesis in upland cotton, and provided important insights for the engineering of cotton with low gossypol accumulation. Cotton is not only an important fiber raw material, but also a source of vegetable oil and vegetable protein. Cottonseed contains protein and oil of a high nutritional value , and theGossypium and its relative species. There are two optical isomers of gossypol, (+)-gossypol and (−)-gossypol [Rhizoctonia solani, Xanthomonas spp., and Verticillium dahliae. [Heliothis virescens [Gossypol is a yellow dimeric sesquiterpene compound, which is synthesized in gossypol , with thgossypol ,10,11. Fdahliae. ,7,8 but irescens ,5. Besidirescens ,13, and irescens ,15. ThusGossypol is mainly synthesized in roots, then transported to the above-ground parts of the plant and stored in the brown punctate pigment glands, which are located on the epidermal tissues of cotton roots, stems, leaves, and seeds ,17. The Light is an essential environmental factor that contributes and regulates plant growth and development . Aside fGossypium hirsutum L. accessions, including TM-1 and four pairs of near-isogenic lines (NILs), were used in the present study. The genetic standard line, TM-1, was kindly provided by the USDA-ARS, College Station, Texas, USA. Four pairs of NILs included CCRI12, CCRI12W, CCRI16, CCRI16W, CCRI17, CCRI17W, Coker 312, and Coker 312W, among which CCRI12, CCRI16, CCRI17, and Coker 312 were kindly provided by the Cotton Research Institute, Chinese Academy of Agricultural Sciences. CCRI12W, CCRI16W, and CCRI17W were the glandless NILs of CCRI12, CCRI16, and CCRI17, respectively, and their glandless traits were controlled by the dominant glandless gene gl2 and gl3. All the above materials were maintained in our laboratory by self-crossing.The −2 s−1, photoperiod of 14 h light period/28 °C, 10 h dark period/24 °C.The seeds of the tested material were sown in pots containing the nutrient soil. After the cotyledons were flattened (soil culture for 10 days), the seedlings were transferred to the transparent bucket with complete light transmission and to the black bucket with no light transmission, which were hydroponically cultured in Hoagland’s nutrient solution for 20 days, and the nutrient solution was changed every three days. The pots and buckets were all put in a climatic chamber with the light intensity of 1500 μmol m−2 s−1, relative humidity of 60%, and a temperature of 28 °C. The measurement time was settled as 10:00 am, and the Li-6800 Photosynthetic Measurement Instrument  was applied for the measurement. Then, samples were harvested, separated for roots and leaves, taken for measurement of the biomass and leaf area. The leaf area was measured by Leaf Area Survey Instrument YMJ-D . Subsequently, the separated roots and leaves were washed by distilled water, dried in the oven at 70 °C for 96 h, and measured for the dry weight.After twenty days of culture with and without root illumination, nine seedlings of each treatment group were taken for the measurement of net photosynthetic rate. The third leaf was measured in all seedlings in the climatic chamber with the light intensity of 1500 μmol m−1). Organic microporous filter membrane (0.45 μm) was applied to filter the supernatant into a 10 mL brown volumetric flask, then 2 mL acetonitrile was added for washing the sediment three times and then filtered into the 10 mL brown volumetric flask, and the total supernatant after centrifugation was fixed to 10 mL with acetonitrile. The samples were stored in a refrigerator at −20 °C away from light.Fresh samples of leaves and roots from seedlings with and without root illumination were vacuum dried at −40 °C, ground with a high flux tissue grinder, and sieved with a pore diameter of 0.178 mm. Each sample (0.1000 g) was weighed and put into a 10 mL centrifuge tube, then 2 mL derivatization reagent  was added into each sample. The samples were placed in an ultrasonic cleaning machine  for ultrasonication for 30 min, then heated in a water bath for derivatization , and centrifuged for 10 min  was set up. The mobile phase was acetonitrile: 10 mM KH2PO4 (pH = 3) = 80:20 (v/v). A reverse C18 chromatographic column was used, the column temperature was set at 25 °C, and the UV detection wavelength was set at 238 nm. The samples were measured in triplicates.The content of gossypol was determined by high performance liquid chromatography (HPLC). Gossypol standard solution . Six libraries in total were sequenced by Illumina Hiseq 4000 platform . Clean reads were obtained by removing reads containing adapter, reads containing ploy-N (N means that the base information cannot be determined) and low-quality reads (bases with Qphred <= 20 accounted for more than 50% of the entire read length) from raw data. All the downstream analyses were based on the clean reads of high quality. The TM-1 reference genome was used for alignment by HISAT2 software [Roots from TM-1 seedlings with and without root illumination were sampled by liquid nitrogen, and stored at −80 °C. Three biological replicates were set in each treatment. The mRNA was purified from total RNA using poly-T oligo-attached magnetic beads. First strand cDNA was synthesized using random hexamer primer and M-MuLV Reverse Transcriptase, and second strand cDNA synthesis was subsequently performed using DNA Polymerase I and RNase H. Then the cDNA library was constructed by NEBNext Ultrasoftware ,27. The software , the scrsoftware .One-way analysis of variance with the least significant difference (LSD) was applied to determine the significant differences between treatments by using SPSS 22.0. Figures were drawn by GraphPad Prism 8 and TBtools according to the obtained results .p < 0.01), and CCRI17 had the largest increase in dry weight of leaves . The second leaf area of CCRI12 increased the most  in RI. The four pairs of NILs increased differently in biomass under RI conditions, the average increase of dry weight of roots, dry weight of leaves, and area of the second leaf in the glanded cotton seedlings were 39.84%, 31.98% and 20.31%, respectively, while in the glandless NILs cotton seedlings were 35.66%, 15.96% and 18.76%, respectively. Besides, after the cotton seedlings were cultivated with root illumination, the net photosynthetic rate of the leaves was higher than CK, with an increase of 8.93–23.50% (p < 0.05), while the net photosynthetic rate of the leaves in TM-1 and CCRI17 were significantly (p < 0.01) higher than those of CK. The average increase of net photosynthetic rate in the glanded cotton seedlings was 12.80%, while in the glandless NILs cotton seedlings the increase was 14.74%. Therefore, it was indicated that RI significantly promoted the growth of cotton seedlings, and the promoting effect on glanded cotton was greater than that on glandless cotton.The cotton seedlings cultivated with and without root illumination are shown in 3–23.50% f. Among p < 0.01). The four pairs of NILs decreased differently in (±)-gossypol content under RI conditions, the average decrease of (±)-gossypol content in the glanded cotton seedlings was 44.78%, while in the glandless NILs cotton seedlings the average decrease was 37.44%. It indicated a greater decrease of gossypol content in the glanded cotton seedlings under RI.The (+)-gossypol content in the roots of nine cotton accessions under RI were 20.29–70.79% lower than those in CK a, the dep < 0.01), while that of CCRI16 decreased the least . Thus, it was suggested that RI negatively affected the accumulation of (±)-gossypol content in the leaves and roots of cotton seedlings.The gossypol content in leaves of glandless cotton accessions was extremely low, thus, the gossypol content was only determined for the five glanded cotton accessions. The results showed that the (+)-gossypol content in leaves of RI was 17.23–54.86% lower than CK d, the deThe quality inspection results of the transcriptome sequencing data showed that the GC content range of samples was 42.44~44.13%, and the ratio of Q30 was more than 93%. After filtering out the unqualified sequences from the original data, the ratio of alignment to the reference genome was 92.11~97.08%, of which more than 88.08% was aligned to a unique position , which cA total of 4361 differentially expressed genes were identified. Compared with CK, 2135 genes were upregulated and 2226 genes were downregulated in RI a.GO enrichment analysis was carried out for DEGs, and a total of 72 GO terms were significantly enriched (padj < 0.05), and the top 30 terms with the most significant enrichment are shown in a scatter plot b. It is KEGG enrichment analysis was carried out for DEGs, and a total of 29 KEGG pathways were significantly enriched (padj < 0.05), and the most significantly enriched 20 metabolic pathways are shown on a scatter plot c. The upPsaE, PsaF, PsaG, PsaH, and PsaL were significantly upregulated in photosystem I, PsbO, PsbP, PsbQ, PsbR, PsbS, PsbT, PsbW, and Psb28 were significantly upregulated in photosystem II, PetM was significantly upregulated in the cytochrome b6/f complex, Lhca1 and Lhcb4 were significantly upregulated in the light-harvesting chlorophyll protein complex, PetF and PetH were significantly upregulated in the photosynthetic electron transport -gossypol and (−)-gossypol were all inhibited. However, the mechanism of light regulation of the gossypol biosynthesis in cotton needs further study. It may be that the molecular mechanism of RI-mediated gossypol biosynthesis inhibition depends on the sensitivity to light of one or more biosynthetic enzymes. Generally, the present study revealed that light could inhibit the gossypol biosynthesis in cotton and provides a theoretical basis for understand the light impact on the metabolism of compound synthesizes in the root system.Gossypol is a specific compound which mainly synthesized in the root system of cotton and its relative species, and was then transported to each part of the pigment glands in plants ,17,37. AIn summary, root illumination could significantly promote the growth of seedlings and inhibit gossypol biosynthesis, both in glanded and glandless cotton. (1) Root exposure to light could upregulate the genes’ expression of the photosynthetic pathway in roots. The photosynthesis efficiency in leaves was positively regulated by root illumination, which promoted the growth of cotton seedlings. Roots may function as a supplement to the above ground parts in promoting seedling growth. Then, subsequently, the biomass of the roots and leaves were increased, and the leaf area was enlarged. (2) Root exposure to light significantly downregulated the expression level of genes participating in the gossypol biosynthesis pathway, and the accumulation of (+)-gossypol and (−)-gossypol in roots and leaves were all decreased. Further research should focus on the mechanism of the root illumination effects on the seedling growth and gossypol biosynthesis by integrating methods such as transcription, signal transduction, and function verification. Overall, this study provided evidence for understanding the effect of root illumination on seedling growth and gossypol biosynthesis in cotton, and provided a theoretical basis for revealing the light impact on root system.


Macrophages are important immune cells in innate immunity, and have remarkable heterogeneity and polarization. Under pathological conditions, in addition to the resident macrophages, other macrophages are also recruited to the diseased tissues, and polarize to various phenotypes (mainly M1 and M2) under the stimulation of various factors in the microenvironment, thus playing different roles and functions. Liver diseases are hepatic pathological changes caused by a variety of pathogenic factors , including acute liver injury, viral hepatitis, alcoholic liver disease, metabolic-associated fatty liver disease, liver fibrosis, and hepatocellular carcinoma. Recent studies have shown that macrophage polarization plays an important role in the initiation and development of liver diseases. However, because both macrophage polarization and the pathogenesis of liver diseases are complex, the role and mechanism of macrophage polarization in liver diseases need to be further clarified. Therefore, the origin of hepatic macrophages, and the phenotypes and mechanisms of macrophage polarization are reviewed first in this paper. It is found that macrophage polarization involves several molecular mechanisms, mainly including TLR4/NF-κB, JAK/STATs, TGF-β/Smads, PPARγ, Notch, and miRNA signaling pathways. In addition, this paper also expounds the role and mechanism of macrophage polarization in various liver diseases, which aims to provide references for further research of macrophage polarization in liver diseases, contributing to the therapeutic strategy of ameliorating liver diseases by modulating macrophage polarization. The liver is an essential organ for maintaining normal life activities of the human body, because it not only regulates the metabolism of many nutrients and chemical drugs, but also has many functions such as synthesizing and decomposing proteins, regulating systemic blood volume, excluding body toxins, and regulating immunity . Liver dMacrophages are essential components of the innate immune system, and the activation of macrophages has been shown to be indispensable in several aspects, such as immune defense, inflammatory response, tissue remodeling, and homeostasis . Macrophvia regulating macrophage polarization.In recent years, a large body of literature has shown that macrophage polarization plays a crucial role in many pathophysiological processes, such as inflammation, tumor, tissue repair, and metabolism –13. InteHepatic macrophages account for 90% of the total macrophages in the human body and are remarkably heterogeneous, including liver-resident macrophages and a variety of infiltrating macrophages , 17. LivMacrophage polarization means that macrophages are activated under the stimulation of pathogenic microorganisms, inflammatory responses, cytokines, or some physicochemical factors, and differentiate into different phenotypes depending on the state and changes of the microenvironment . In the In general, the phenotypes of macrophage polarization can be divided into classically activated M1 and alternatively activated M2 . NowadayAlthough M1 and M2 are the main macrophage phenotypes which are commonly studied and applied currently, the phenotypes of macrophage polarization are not restricted to them. The study by Erbel et al.  has showToll like receptor (TLR) 4 is an innate immune receptor expressed on the surface of macrophages that can efficiently recognize pathogen-associated molecular patterns, and is the main receptor of LPS . LPS binThe Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway mainly mediates the signaling of cytokine receptors . IFN-γ bIn addition, STAT3 is important for M2 macrophage polarization. Studies have shown that the inhibition of IL-6/STAT3 and JAK3/STAT3 signaling pathways results in the polarization of macrophages from M2 to M1 phenotype , 49. Supvia peroxisome proliferators-activated receptors (PPARs).TGF-β acts on type II receptors first, and then binds to type I receptors to form a receptor complex, which leads to the phosphorylation of type I receptor domain, thus regulating the expression of the related genes by activating their downstream signaling molecules (Smad2 and Smad3) . The stuPPARγ is an important transcription factor for cell differentiation and has many functions, such as regulating glucose and lipid metabolism, anti-inflammation, reducing oxidative stress, and so on . PPARγ uvia miRNAs. M2 macrophage-derived exosomes led to the exacerbation of pancreatic ductal adenocarcinoma through the inhibitory effect of miR-501-3p on TGFBR3, and down-regulated TXNIP expression as well as inhibited the TLR4/NF-κB/NOD-like receptor protein 3 (NLRP3) inflammasome signaling pathway via miR-148a, thus attenuating myocardial ischemia/reperfusion injury  on macrophage polarization has been gradually highlighted, mainly relying on their regulation of other signaling pathways. For example, miR-221-3p promotes M2 macrophage polarization toward M1 phenotype by inhibiting JAK3/STAT3 signaling pathway . MiR-124n injury , 67. Morn injury –72.Notch signaling pathway includes a series of highly conserved surface receptors, and is involved in cell proliferation and apoptosis, affecting the development of various biological organs and tissues . A studyInterestingly, the current studies have shown that Notch signaling regulating macrophage polarization is closely associated with miRNAs. Li et al.  found thIn addition to the pathways described above, multiple other signals and targets have been included in the underlying mechanisms of macrophage polarization. Mammalian target of rapamycin signaling pathway was shown to be involved in regulating M1/M2 polarization, mainly relying on the feedback effect between mechanistic target of rapamycin (mTOR) complex 1 and protein kinase B (Akt) signaling . InsulinIn fact, the mechanism associated with macrophage polarization is very extensive, and the induction of macrophage polarization by most factors involves the co-regulation of multiple signaling pathways, which is perhaps an important factor for macrophage polarization to have multiple roles in liver diseases. The detailed mechanisms of macrophage polarization are shown in ALI is the acute hepatic inflammation and hepatocyte necrosis caused by endotoxin, certain drugs and their metabolites, or other physicochemical factors, which may cause liver dysfunction or even acute liver failure . Empiricin vivo and in vitro experiments, Xie et al.  infection, is one of the leading causes of chronic hepatitis worldwide . It is gi et al.  found thi et al.  found thi et al.  have proi et al. .Hepatitis C is a viral hepatitis caused by hepatitis C virus (HCV) infection with a worldwide prevalence of approximately 3% and an increasing trend . G. DultVaccine is an important means to prevent and control viral hepatitis, and the development of an effective vaccine against HCV infection is of great importance. Ohtsuki et al.  showed tvia IL-6 and resist alcohol-induced hepatocyte apoptosis and hepatic steatosis /protein kinase A (PKA)/STAT3 signaling pathway, and attenuate HFD-induced inflammation, which improves MAFLD  . LF is e4)-induced LF, whereas M2 macrophage polarization seems to predominate in schistosome infection-induced LF , primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and their overlap syndrome . Interesvia the portal circulation, also involving the changes of gut microbiota and the secretion of auxins, hormones, and bile acids , the effects of M1 and M2 macrophages in liver diseases may be opposite to the above. It is worth mentioning that current research is almost exclusively focusing on the M1 and M2 phenotypes of macrophages, so more macrophage phenotypes closely associated with disease progression are expected to be uncovered and studied. Therefore, due to the dual complexity of macrophage polarization and liver disease pathogenesis, more in-depth research on the role and mechanism of macrophage polarization in different liver diseases are worthwhile and necessary.Taken together, macrophage polarization plays an important role in a variety of liver diseases. In general, M1 macrophages have antigen presentation, pathogen clearance, and anti-tumor functions, having a protective effect in viral hepatitis, parasitic infection-induced LF, and HCC. In contrast, M2 macrophages have an anti-inflammatory effect and promote wound healing, which can effectively ameliorate the liver diseases mainly characterized by inflammatory injury, such as ALI, ALD, MAFLD, and CClCW, CM, and YL designed the paper and recommended a structure for the review. CW, CM, YG, YZ, and HZ wrote the initial draft and prepared figures. LG, KF, and YL helped to revise the manuscript. All authors contributed to the article and approved the submitted version.The work was supported by National Natural Science Foundation of China , Sichuan Province Science and Technology Program (No: 2021JDRC0041), and Xinglin Scholar Research Premotion Project of Chengdu University of Traditional Chinese Medicine (No: CXTD2018019).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.


Respiratory viruses spread fast, and some manners have been recommended for reducing the spread of these viruses, including the use of a facemask or respirator, maintaining hand hygiene, and perfoming social distancing. This systematic review aimed to assess the impact of facemasks and respirators on reducing the spread of respiratory viruses.We conducted a systematic review using MeSH terms, and reported findings according to PRISMA. PubMed, Embase, Cochrane Library, Scopus, ProQuest, Web of Science(WoS), and Google Scholar were searched for articles published between 2009 and 2020. Two independent reviewers determined whether the studies met inclusion criteria. The risk of bias of studies was assessed using Newcastle-Ottawa (NOS) and Consolidated Standards of Reporting Trials (CONSORT).A total of 1505 articles were initially retrieved and 10 were finally included in our analysis (sample size: 3065). 96.8% of non-infected participants used facemask or respirator in contact with people infected with a respiratory virus, facemask and respirator have a significant effect on reducing the spread of respiratory viruses. Evidence support that using a facemask or respirator can reduce the spread of all types of respiratory viruses; therefore, this result can be generalized to the present pandemic of a respiratory virus (SARS-COV-2) and it is recommended to use a facemask or respirator for reducing the spread of this respiratory virus.  In recent decades, humans have been threatened by a variety of viruses that lead to acute respiratory infections affecting human life and human societies, sometimes leading to death. There are several routes of respiratory virus transmission: contact, droplet, and aerosol. Respiratory viral infections cause a wide range of overlapping symptoms, known as acute respiratory illness (ARI) or, usually (more commonly) “the common cold” as a whole, which is chiefly mild but may cause severe illness and death . To protCommon types of PPE include surgical masks and respirators. It should be noted that surgical masks are loose and disposable and create a physical barrier between the wearers' mouth and nose and environmental contaminants (large respiratory droplets or sprays of blood and body fluids). They are not designed to filter out small airborne particles and have very different level of protection , 4. In tThe world is currently suffering from a pandemic , caused This systematic review is reported based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines .2.1. Search strategy In this systematic review, Google Scholar, PubMed, Embase, Cochrane Library, Scopus, ProQuest, and Web of Science (WoS) were searched for articles published between 2009 and 2020. Boolean operators such as "AND" and "OR" were used to make different combinations for search . In addi1--"facemask" [Mesh] OR "facemasks" [Mesh] OR "mask" [Mesh] OR “N95 Respirator” [Mesh] OR “Respirator, N95” [Mesh] OR “N95 Face Masks” [Mesh] OR “Face Mask, N95” [Mesh] OR “Mask, N95 Face” [Mesh] OR “N95 Face Mask” [Mesh] OR “N95 Masks” [Mesh] OR “Mask, N95” [Mesh] OR “N95 Mask” [Mesh] OR “N95 Filtering Facepiece Respirators” [Mesh] OR “N95 FFRs” [Mesh] OR “N95 FFR” [Mesh] 2-"respirators"[Mesh] OR"Device, Respiratory Protective" [Mesh] OR "Protective Device, Respiratory" [Mesh] OR "Respirators, Industrial"[Mesh] OR "Respirators, Air-Purifying"[Mesh] 3-"respiratory virus"[Mesh] OR " Severe Acute Respiratory Syndrome Virus" [Mesh] OR "SARS-Related Coronavirus" [Mesh] OR "SARS-CoV"[Mesh] "SARS Coronavirus"[Mesh] OR "SARS-Associated Coronavirus"[Mesh] OR "Coronavirus, SARS-Associated"[Mesh] OR "SARS Associated Coronavirus"[Mesh] 4-#1 AND #2 AND #32.2. Type of studiesAll studies published between 2009 and 2020, which were conducted to assess the effect of facemask on preventing the of spread respiratory viruses and reported the number or percentage of participants using a facemask and getting or not getting infected with a respiratory virus, were included in the study. Publications such as reviews, letters, comments, and case reports and studies that were conducted just for comparing different types of facemasks, or evaluated people with a tissue graft, or their sample size was not clear were excluded from the study. There were no language restrictions for using and entering articles in this study. If the language used in an article was not Persian or English, we asked a translator to translate the article.2.3. Types of participantsThe studies were selected if their participants were:-people in contact with those infected with respiratory viruses-people who were members of specific groups such as healthcare personnel, emergency department and general ward staff, public health workers, Hajj pilgrims2.4. Types of interventionsThe studies were reviewed if:- participants used PPE-measured the effect of facemask or PPE on preventing transmission of respiratory viruses 2.5. Type of outcome measureAll studies measured the number and percentage of participants who used facemask, PPE, vaccine, and distance or did not use them and were infected after being in contact with a person infected with respiratory viruses. 2.6. Study selectionThe title and abstract of all studies retrieved during the electronic and manual follow-up search process were assessed based on the inclusion criteria. The full texts of relevant papers were examined based on the mentioned criteria.2.7. Quality assessmentIn this study, the quality of Cohort and Cross-Sectional studies was assessed according to the Newcastle-Ottawa scale (NOS) ; and the2.8. Data extractionTwo investigators independently searched for relevant scientific publications, carried out validity assessments, and resolved any disagreements by consulting a third investigator . Data we1. Research information )2. Characteristics of the participants 3. Intervention and comparison of the details 4. Outcome measures 2.9. Statistical analysisWe calculated the number and percentage of infected and non-infected people in all included studies and reported them in tables.The systematic search in the databases identified 1505 articles. After reviewing their titles and abstracts, 753 duplicate articles, 654 records with undesirable study types, and 88 irrelevant articles were removed. Finally, 10 articles (Sample Size=3065) were included in the systematic review. The flowchart of studies included in this review is shown in 3.1. Factors examined in the studiesThe factors presented in table one include the author’s name, study design, type of population, sample size, age, result, and quality score. Table two includes type of virus, type of contact with an infected person, PPE type, facemask type, and infected participants who used masks after contact with the patient. 3.2. Type of virus, contact, PPE, facemask, and the number of infected people who used a facemaskType of VirusThe types of virus assessed in this systematic review included SARS-CoV-2 , MERS 1, MERS-Co3.3. Type of ContactThe type of contact with an infected person was assessed in nine articles and varied in different studies. Generally, the contact was between health care workers and infected persons , 22, 24,3.4. PPE TypeThe PPE type was mentioned in all assessed studies. PPE types in the studies included gloves 16-20, 22), kind/various types of facemask -20, 22, , N95 res3.5. Type of FacemaskThe type of facemask was mentioned in nine studies and the number of participants who wore each type of facemask was mentioned in seven studies. Surgical masks , 23, 25 3.6. The number of infected people who used a facemask or N95 respiratorGenerally, 3.2% of participants who wore a facemask became infected with the respiratory virus through contact with an infected person. In studies that all participants wore surgical masks , 23, 25,3.7. Distance and time of contactDistance between people and the duration of contact with an infected person was mentioned in five studies , 19-22. 3.8. Duration of using a facemask and vaccinatedThe duration of facemask use and the number of vaccinated people were evaluated in five studies , 23-25. The results of the present study showed that using facemask or respirators has a preventive effect on the spread of respiratory viruses including SARS-CoV-2, MERS-CoV, Rhinovirus, Influenza A virus (H1N1), Influenza B viruses, Parainfluenza 1,2 and 3 viruses, Enteroviruses, Adenoviruses, Human metapneumoviruses, Respiratory syncytial viruses A/B, Coronaviruses, Picornaviruses, and Enteroviruses. Moreover, the percentage of transmission of respiratory viruses in people who wore any type of facemask or N95, respectively, was 0.3% in the surgical mask group, 1.4% in the N95 respirators group, 0.2% in N95 respirators and surgical mask group, 1.7% in N95 respirators and medical mask group, 0.3% in N95 respirators and another facemask group, and 0.5% in P2 masks and surgical mask group.In COVID-19 disease pandemic, due to the lack of access to appropriate antiviral medications and the lack of a suitable vaccine, infection control was the most important way to control it . Therefo In this regard, the rate of Influenza virus transmission between HCWs in the H1N1 pandemic were 14%, yet 67% of them did not have any signs . BesidesIt should be noted that in studies, the proportion of infected HCWs among the confirmed cases of Coronavirus disease-2019 is 10% in Italy, 20% in Spain, and 40% in the United States . InfecteTherefore, in addition to providing PPE for HCWs, health organizations should emphasize continuous training on donning and doffing for effective protection , 35. StuStudies state that in a household setting, due to the increased cumulative exposure time of index patients with family members, the possibility of transmitting viral respiratory infections is higher , 38. In In a random retrospective cluster clinical trial study, MacIntyre et al. revealed that less than 50% of participants had the necessary compliance for wearing a facemask and in this group had a significantly lower risk of Influenza-like illness due to infection . ResultsOne of the important religious rituals is Hajj, in which large numbers of people from different countries congregate in a particular region. Thus, it naturally increases the risk of transmitting respiratory viral infections. Results of studies show that use of facemasks by people with the influenza-like illness and those around them (those who were in a tent together) provided more protection against the Influenza-like illness compared to those in the control group, who did not wear protective equipment, and the percentage of infection in each group was 31% vs. 53%, respectively. A significant point in this report was the presence of a positive correlation between duration of facemask use and protection against influenza-like illness, so the incidence of disease in pilgrims who wore facemask more than eight hours a day compared to those who wore a mask for less than eight hours a day was 3% vs 43% . Currently, due to the intensity of the COVID-19 pandemic, wearing a facemask is common everywhere, including hospitals and communities . In thisTherefore, PPE should be selected for special settings and they should be used logically . It was The limitations of this study included lack of access to full-text of some studies, lack of data on the effect of facemasks on prevention of each type of respiratory viruses in articles that had studied different viruses, the lack of data on the effect of each type of facemask on reducing the transmission of respiratory viruses and count or percentage of participants who used a facemask. Moreover, some studies conducted on recent viruses (SARS-Cov-2) were not published in English, which is another limitation of the study.This systematic review showed that using facemasks or respirators aided in preventing the spread of respiratory viruses. The result of the present systematic review showed that using facemasks could prevent the spread of virus. We recommend conducting more studies on the effect of each type of facemask and respirator, individually, and on the prevention of the spread of different viruses. Moreover, we suggest assessing the effect of simultaneous use of masks, duration of using a facemask, and distance between healthy people and the person infected with respiratory viruses. The authors acknowledge Alborz University of Medical Sciences.FA and NSH fulfilled an advisory role. ZA carried out the literature survey. NSH edited this manuscript in English. MD commented on the manuscript. All authors passed the criteria for authorship contribution based on recommendations of the International Committee of Medical Journal Editors.This study did not receive any funding support.The authors state no conflicts of interest.


To evaluate the real aerobic capacity is difficult due to impaired limbs function in stroke patients. Oxygen uptake efficiency slope (OUES) could represent the aerobic capacity in submaximal exercise test. Hence, we designed this observational study to investigate the application of the OUES for evaluating aerobic capacity in these patients.Thirty-seven stroke patients were classified into 2 groups according to their Brunnstrom stage of affected lower limbs. Patients underwent cardiopulmonary exercise testing to assess cardiorespiratory fitness. Minute ventilation and oxygen consumption were measured, and OUES was calculated, compared with healthy reference values, and correlated with the peak oxygen consumption. The predictive validity of submaximal OUES was derived.r = 0.835) (P < .01). The predictive validity of oxygen uptake efficiency slope at 50% of maximal exercise duration (OUES50) and oxygen uptake efficiency slope at 75% of maximal exercise duration (OUES75) for oxygen uptake efficiency slope at 100% of maximal exercise duration (OUES100) was 0.877 and 0.973, respectively (P < .01). The OUES50, OUES75, and OUES100 groups were not significantly different; agreement of submaximal and maximal OUES values was strong.Study participants’ OUES  was 60% of healthy reference values and correlated positively with the peak oxygen consumption (50 and OUES75 for OUES100 suggest maximal exercise testing in stroke patients who cannot reach maximal exercise is unnecessary.OUES is a valuable submaximal index for evaluating cardiorespiratory fitness in stroke patients. Moderate-to-high concurrent validity of this parameter with peak oxygen consumption and the high predictive validity of OUES Therefore, developing a valid measure to assess accurate cardiorespiratory fitness (CRF) in patients with stroke is important for designing an appropriate exercise prescription to reduce risk.There are several risk factors for stroke, including age, sex, obesity, smoking, hypertension, diabetes, hyperlipidemia, and atrial fibrillation.2peak). For some, the longer-term consequences of stroke may include impaired motor function, reduced muscle strength and metabolic functioning, and reduced CRF.,4 These patients have exercise intolerance and often have cognitive, motor, and sensory dysfunction, as well as gait disorders. Hence, patients with stroke may have difficulty meeting the criteria for maximal exercise and require submaximal exercise testing to assess their CRF.Currently, the most popular tool used to assess CRF is the cardiopulmonary exercise test (CPET), which measures peak oxygen consumption (VO2) and the log transformation of the minute ventilation (minute ventilation [VE]), first introduced by Baba et al As an advantage of OUES, its calculation is independent of the CPET protocol and patient effort. Hence, OUES is a good surrogate, replacing the role of VO2peak, which represents the CRF in patients who cannot attain maximal effort during CPET.However, for some reason, submaximal exercise testing may deviate from the criteria specified for maximal testing, including premature termination of the test, preset intensity, or discomfort reported by patients, rendering the adequate assessment of CRF in stroke patients difficult. This indicates the necessity for applying a specific objective and independent measure for submaximal testing. The oxygen uptake efficiency slope (OUES) is derived from the curve-linear relation between oxygen consumption  and was registered on clinical trial (NCT03960918). After the experimental procedure was explained, all enrolled patients provided written informed consent. Between June 2019 and December 2019, 37 stroke patients capable of independent ambulation who could pass a previously familiar test  and walking independently for 30 minute) with stable clinical presentations under optimized treatment for 6 months were enrolled. The inclusion criterion was the first primary stroke diagnosis, as confirmed by a neurologist, with admission to the rehabilitation ward of Keelung Chang Gung Memorial Hospital, Taiwan. Any participant meeting 1 or more items listed on the American College of Sports Medicine (ACSM) contraindications to exercise was excluded from the study. were recorded. Medication use and comorbidity were also recorded. Health-related quality of life of these participants was evaluated by the Medical Outcomes Study Short Form-36, and physical and mental component was measured separately by the user manual. The mini-mental state examination was used to assess cognitive function.The age, sex, height, and bodyweight of eligible candidates were recorded before the CPET. Disease specifics, including stroke type , involved side , and neurological disability, according to the Brunnstrom recovery classification,2.2 the details of the CPET were as follows: The exercise test protocol starts with a 2-minute resting phase without any body motion, then a 2-minute warm-up phase with free pedaling without any loading, followed by a ramping workload increase of 10 W/min until exhaustion. The test ends with a 5-minute cool-down phase under free pedaling. During the CPET, participants were asked to keep a cadence of 55 to 65 revolutions per minute. If the patient could not easily keep the hemiplegic leg on the pedal, appropriate taping was done to keep the leg anchored. The workload, VO2, carbon dioxide production (VCO2), VE, and the end-tidal partial pressures of oxygen and carbon dioxide were measured for each exhalation during CPET using an integrated auto-system . Concomitantly, variables to ensure safety during the CPET such as heart rate (HR), blood pressure, electrocardiogram, subjective rating (Borg rating of perceived exertion), and clinical signs and symptoms were recorded. The work loading during the CPET was stopped by volitional exhaustion, a pedaling cadence <40 revolutions per minute, or when the termination criteria listed in the ACSM guidelines for clinical exercise testing were met. The termination criteria included: ST elevation (>1.0 mm) in leads without preexisting Q waves because of prior MI ; a drop in systolic blood pressure of >10 mm Hg, despite an increase in workload, when accompanied by other evidence of ischemia; moderate-to-severe angina; central nervous system symptoms ; signs of poor perfusion ; and sustained ventricular tachycardia or another arrhythmia, including second- or third-degree atrioventricular block. If a participant experienced any single item listed on the ACSM termination criteria for CPET and the symptom or sign persisted for 1 minute, the test was halted, and the presence of an adverse event was recorded. Emergency intervention from the cardiologic ward would have been introduced in the case of adverse events. After test completion, the maximal values for VO2, VCO2, VE, HR, blood pressure, and workload were recorded. Maximal value was defined as the average value over the last 30 second. The following secondary parameters were calculated: respiratory exchange ratio (RER): defined as the ratio between VCO2 and VO2; VE-VCO2 slope: defined as the slope of the linear regression line between VE and carbon dioxide output; anaerobic threshold (AT): determined with the V-slope method, defined as the point at which a linear relationship between VCO2 and VO2 is lost,19; oxygen uptake efficiency slope (OUES): derived from the slope of the natural logarithm plot of VE (l/min) vs VO2 (ml/min), which indicates the constant representing the rate at which oxygen consumption increases in response to VE, showing an estimation of ventilation efficiency with respect to VO2. Greater OUES values indicate higher ventilatory efficiency. To assess the accuracy of OUES in submaximal exercise intensity and to determine the predictive validity of the submaximal OUES, we calculated the OUES at 50%, 75%, and 100% of maximal exercise duration .Enrolled participants performed a symptom-limited incremental CPET on a stationary bicycle  supervised by certificated physiatrists. According to the recommendation of previous literature,2.3 Because of the small number of participants in the study, Mann-Whitney U test  and Chi-square test  were used to compare the participants’ characteristics as well as CPET outcomes between the 2 functional groups. Pearson correlation was used to check the relationship between AT, OUES50, OUES75, OUES100, and peak oxygen consumption to validate the predictive validity of the submaximal OUES and concurrent validity of maximal OUES. The agreement between peak OUES and submaximal OUES was assessed using the Bland and Altman plot. Statistical analyses were performed using SPSS version 25.0. . A P value of less than.05, 2-tailed, was considered significant.For a small number of participants in the study, baseline characteristics are described using the medians with interquartile ranges (IQRs) for continuous variables and counts and percentages (%) for categorical variables. We divided the participants according to the Brunnstrom (Br.) stage of the affected lower limbs , into low function (Br. stage ≤ IV) and high function (Br. stage > IV) groups as reported in Watanabe et al's study.33.1P = .001) and lower Br. stage  than that in the high function group. There were no significant between-group differences in any other demographic variables, including stroke type, lesion site, medication, and comorbidity.Thirty-seven patients with definite stroke participated in this study. Participant characteristics are summarized in Table 3.2P > .05). The mean maximal RER was 1.10  in the low function group and 1.11  in the high function group. The mean peak oxygen consumption in all the participants was 15.6  ml/min/kg  with no significant difference between the low and high function groups . The average time taken for all participants to reach the maximal exercise level was 7.7 minute with no significant difference between the low and high function groups . The AT was attained by 35 participants (35/37 = 94%), who reached a mean of 619  ml/min, with 57.0%  of peak oxygen consumption. The 2 participants who did not reach the AT level belonged to the low function group; hence, the average value of AT in the low function group was divided by 15. The mean AT in the low function group was 677  ml/min, with 60.0%  of peak oxygen consumption and that in the high function group was 581  ml/min, with 56.0%  of peak oxygen consumption; these differences were not significant. The mean OUES in all participants was 566.2  with no significant difference between the low and high function groups . According to the criteria for maximal exercise in the ACSM guidelines for exercise testing, the maximal HR achieved by 13 participants (13/37 = 35.1%) was >85% of the age-predicted maximal HR, and 21 (21/37 = 56.8%) achieved an RER > 1.10. This ratio is also not significantly different between the low function group and the high function group . All participants reported a Borg rating of perceived exertion >17. Hence, all participants terminated their CPET due to subjective feelings of exhaustion. The only statistically significant differences between the low and high function groups were seen in the ratio of peak HR reached in the CPET to aged-predicted maximal HR .During the CPET conducted in this study, no adverse events occurred. CPET variables are presented in Table 3.350, OUES75, and OUES100  ; OUES75 and OUES100 ; OUES50 and OUES75  . The Bland-Altman plots in Figure 50 and OUES100 . The mean difference between OUES75 and OUES100 was 41.06 , as shown in Figure OUES42 and indicating the effectiveness of the OUES measure in submaximal CFR assessment.Stroke patients frequently experience varying degrees of physical disability and are thus unable to perform maximal CRF assessments, necessitating the use of submaximal assessments. Here, we investigated the effectiveness of OUES values in submaximal CRF assessments for stroke patients. We found that stroke patients in both the low and high function groups had diminished aerobic capacities. In addition, we demonstrated the validity of OUES as a measure of CRF in stroke patients showing strong correlations between OUES and peak VO a phenomenon that can be explained by primary distortion or secondary deconditioning from motor function impairment. In total, 56.8% of participants reached an RER >1.10, and all participants reported a Borg rating of perceived exertion scale >17, demonstrating that these stroke patients applied maximum effort in the CPET. However, only 35.1% of participants reached a peak heart rate ≥85% of the age-predicted maximal heart rate, without considering the influence of beta-blockers. If we account for the effect of beta-blockers , the proportion of qualifying CPETs increases to 59%. Furthermore, there is no statistical difference in these 3 variables between the low and high function groups. According to these points, we could postulate that the lower aerobic capacity of stroke patients is attributed to the secondary deconditioning rather than to the primary distortion. However, this may be because we recruited more chronic stroke patients in this study .The aerobic capacity of the stroke patients demonstrated a mean peak oxygen consumption of 15.6  ml/min/kg, which is only 61.58% of healthy individuals, This was even demonstrated in the group with a higher function, which was significantly lower than that of the healthy population previously reported . These results demonstrate that the OUES could be used as a measure of CRF in stroke patients. Some studies have found similar correlations between OUES and VO2peak in different disease populations, mainly in heart disease,,9 pulmonary hypertension, and pediatric fields.,25 Meanwhile, some diseases, such as cystic fibrosis, do not show this correlation.In addition, we assessed the validity of the OUES, a parameter that could be derived from the submaximal CPET, using the commonly used parameters derived from the maximal CPET, such as maximal oxygen consumption, in patients with stroke. Similar to the peak oxygen consumption, the average OUES value of stroke patients was 566.2 , only 59.66% of that of healthy individuals.50 and OUES75) with those derived from the total CPET duration (OUES100) to validate the predictive validity of a submaximal OUES and to demonstrate the application of OUES in the “submaximal” status. The results showed that the accuracy of OUES50, OUES75, and OUES100 (the correlation between log VE and VO2) was high. These findings indicate that the OUES from submaximal exercise duration was stable. In addition, both OUES50 and OUES75 were highly correlated with the OUES100  and full consistency between OUES75 and OUES100 (ICC = 0.935)  Table . These f Owing to the heterogeneous pattern of stroke sequelae, all these components were shown to be involved in patients with stroke. For example, regarding cardiovascular function, Yperzeele et al reported that the autonomic dysfunction in the cardiovascular system, expressed by a decrease in HR variability, may be a precursor to adverse outcomes after a stroke episode. Regarding muscle function, the muscle strength of the hemiplegic side is obviously affected, as is the metabolic function of the muscles. Severinsen et al reported that the muscle type in stroke patients shifts toward a more fatigable type, and the oxidative enzymatic capacity is reduced. Regarding breathing function, Teixeira-Salmela et al demonstrated that the strength of the respiratory muscles is also decreased in stroke patients. These are partial mechanisms that could reduce OUES in stroke patients.Variables affecting OUES might include the effects of various systems involved in cardiovascular, respiratory, muscular, and metabolic functions. In this study, the AT was reached in 94% of the studied subjects , which had a strong correlation with peak oxygen consumption. Its high accessibility hints that AT could be another indicator for exercise capacity, comparable with the finding of Pierre Boyne et al However, the AT is 57% of the measured peak VO2, which is in the “normal” range of the healthy population. If motor impairment is the main limitation for these stroke patients to achieve maximal effort in an ideal CPET, the AT level should be higher. In addition, the correlation between AT and VO2peak is more fluctuating than OUES, with the correlation coefficient decreasing from 0.745 without adjustment to 0.529 after adjusting for age, sex, body mass index, and co-morbidity. Hence, using AT as an indicator for stroke patients needs further validation.There are still other submaximal physiological outcomes that can be considered as indicators of aerobic capacity. AT, which is 1 of these submaximal variables, could be a direct indicator of aerobic capacity.2peak shows a tendency to be dependent on the severity of hemiparesis in the leg of stroke patients. In our study, there was no difference in peak oxygen consumption between the low and high function groups regardless of whether we used VO2 peak or VO2peak/kg. The low function group in our study actually had a lower peak workload but had similar VO2 compared with the high function group. Although it was not statistically significant, the low function group had a lower peak workload but had a similar VO2 compared with the high function group. The phenomenon could be explained by the impaired motor skill or the incoordination of the motor process, which will lead to more energy expenditure. In fact, it could be demonstrated by the energy efficiency, expressed by oxygen consumption divided by absolute workload, which was shown to be significantly different between the 2 groups   was difficult in beta-blocker users (only 12.5% of beta-blocker users met these criteria).This study had some limitations. First, many of the recruited patients were receiving neuro-rehabilitation treatment for their chronic sequelae of stroke. Hence, these selected participants may have more motivation to engage in exercise, particularly the low function group with more motor impairment. Therefore, this group is less representative of the general stroke patient population. Second, following the tradition of our laboratory,2 peak, nor can we have a critical cut-off value to express stroke severity. Hence, the definitive formula for converting the value of OUES into the prescription of exercise is still ambiguous. Further study is needed to fill the gap of the clinical use of OUES from evaluating to prescription.In summary, our data show that the OUES is a good variable for expressing the CRF of patients with stroke because of its objectivity, validation, and reliability. It could be calculated under a submaximal exercise test regardless of the severity of motor impairment, thereby increasing its suitability for patients with stroke. However, we still cannot interchange OUES to VOThe authors thank the Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital, Keelung, Taiwan, for providing the patient cohort. We also thank Professor Juei-Chao Chen for statistics consultation.Investigation: Sheng-Chieh Han, Chih-Chin Hsu, Shu-Chun Huang, Hsin-Yu Lin, Jong-Shyan Wang, Tieh-Cheng Fu.Resources: Tieh-Cheng Fu.Validation: Tieh-Cheng Fu.Writing – original draft: Sheng-Chieh Han, Tieh-Cheng Fu.Writing – review & editing: Sheng-Chieh Han, Chih-Chin Hsu, Shu-Chun Huang, Hsin-Yu Lin, Tieh-Cheng Fu.