Objective: To identify risk and protective factors for mental health symptoms associated with lifestyle changes caused by home confinement in pediatric subjects and in children and adolescents with a neuropsychiatric disorder.Study design: This was a prospective, cross-sectional study conducted from May 10 to May 31, 2020. Two online anonymous surveys were developed: population-based and clinical-based (children with neuropsychiatric disorders). Outcomes included emotional and behavioral symptoms, as assessed by psychometric scales , and lifestyle changes during home confinement .Results: The sample included 9,688 pediatric subjects, and 289 children and adolescents with a neuropsychiatric disorder. The presence of siblings was a protective factor in all ages. In pre- and school children: male sex, a diagnosis of autism, residency in highly affected areas, high parental educational level or job loss, and screen time (>2 h/day) were risk factors. Physical activity, home-schooling, reading, talking with other people were protective factors. Residency in highly affected areas, a diagnosis of mood disorder, parental job loss, and screen time, were associated with a worsening of the depressive symptoms, whereas physical activity, talking with other people, playing with parents were protective activities. Screen time was also a risk factor for anxiety symptoms, while physical activity, reading and talking with other people were protective factors.Conclusions: This study identified risk and protective factors for mental health symptoms associated with lifestyle changes caused by COVID-19 home confinement to promote mental well-being in pediatrics during pandemic times. During the coronavirus disease 2019 (COVID-19) pandemic, most national governments have temporarily imposed severe disease containment measures to prevent the spread of the infection. In Italy, one of the earlier and most affected European countries, a rigid home confinement was enforced from March 9, 2020 to May 4, 2020 , 4. DuriThe interaction between changes in daily habits and psychosocial stress in children and adolescents needs to be more investigated. Thus, we proposed that a better understanding of the psychological impact and lifestyle changes caused by home confinement on the Italian pediatric population, and on children and adolescents with a neuropsychiatric disorder, might contribute to identify protective and risk factors for mental health symptoms during the COVID-19 pandemic.This study collected a convenience sample of Italian children, immediately after the end of home confinement and national lockdown due to the Covid-19 outbreak. Data for this study were collected from May 10 to May 31, 2020, by using a survey distributed through a specific online platform. All families with at least one child <18 years and having access to internet and/or social media were eligible to participate. This project was advertised by a media sensitization campaign with the hashtag #understandingkids on social media to shortly collect a large sample.Parents were asked to fill out an age-specific questionnaire for each household child. Specific questions for both parents and children were considered for participants ≥6 years, while only the parent's section was required for younger kids. The statement “I permit my child to participate in the survey” was presented to the guardian before the survey. Data were completely anonymized since no personally identifiable information was required. A second sample of children and adolescents with a neuropsychiatric disorder, followed by the Child Neurology and Psychiatry Unit at the Department of Human Neuroscience at Sapienza University of Rome, were collected during the study period. All families with a child affected by a neuropsychiatric disorder who have contacted the Unit during the Home Confinement were asked to participate. A separate online platform was created to collect data from this participants group. Parents filled out the same survey of the general population, except for a specific question on the neuropsychiatric diagnosis.The questionnaire includes 22 items measuring participants' demographics (both in children and parents), and children and adolescent's daily habits before and during the lockdown.Demographic data for parents included: age range , sex, educational level, employment status (including job loss due to the outbreak), residency, nationality, number of children, and civil status. Information on the other parent was also required regardless of the civil status. While in children the following demographics features were considered: age range , sex, number of siblings, and schooling activity (hours/weekly). The known diagnosis was recorded for subjects affected by a neuropsychiatric disorder.Daily habits were collected by asking parents about the frequency at which their children spent time before and during the lockdown in the following activities: (1) reading a book or playing with parents; (2) physical activity; (3) home-schooling; (4) reading or playing alone; (5) using social media; (6) interacting with other people by video chat, or phone; (7) gaming with a notebook, smartphone or other devices; (8) gaming with other people; (9) watching television; (10) watching video, movies or tv-series on any device; (11) talking with other people in person. The first three items  were measured using a 5-point weekly scale, while in the remaining a 5-point daily scale was preferred.Three common age-standardized pediatric primary care instruments were considered for the emotional and behavior assessments: the Baby Pediatric Symptom Checklist (BPSC), for infants (0–12 months); the Preschool Pediatric Symptom Checklist (PPSC), for pre-school children (1–6 years); and the Pediatric Symptom Checklist (PSC), for school children and adolescents (≥6 years) –7. TheseDemographic characteristics of the study population were described using absolute and percent frequencies. A multiple linear regression model was used to evaluate the effect of demographics on the BPSC score. A model for each BPSC sub-score  was defined considering the change from baseline (before lockdown) as the outcome, the baseline BPSC score value as adjustment covariate and all demographics characteristics as covariates.A mixed-effect model was applied to estimate the effect of demographics and lifestyle changes on the PPSC score. This model included all demographic variables, time (before and during lockdown), the possible two-by-two interactions time and demographic variables, the autism diagnosis, and most age-significant lifestyle covariates. A subject-specific random intercept was used to account for dependence between repeated measurements on the same subject. Lifestyle variables were included in the model as baseline and as changes from the baseline in order to distinguish the cross-sectional and the longitudinal impact they have on PPSC score.A multiple regression model was used to estimate the effect of demographic and lifestyles changes on PSC, CES-DC and SCARED in children ≥ 6 years. A model for each score was defined including all demographic characteristics, the presence of a neuropsychiatric disorder and the lifestyle changes categorized with respect to time.Model selection was performed by stepwise procedure based on the Akaike Information Criterion (AIC). All analyses were performed using R version 4.0.0 software. The study protocol was defined in accordance with the Declaration of Helsinki and approved by the local Ethical Committee.The survey on the general population was completed by 6,870 parents for a total of 9,688 children and adolescents , while the survey for families of subjects with neuropsychiatric disorders collected 255 answers, for a total of 289 participants . Remarkable lifestyle changes during the home confinement were observed in all participants of the two groups. In children <1 year, 75.5% of subjects (649/860) from the general population had a positive BPSC test during the home confinement. An increase of 35% was observed from the period before the lockdown.In pre-school children, the PPSC was above the threshold of positivity in 73.3% of normal subjects  and 80.3% (53/66) of children with a neuropsychiatric disorder, respectively, with an increase of 68 and 3.9% in both groups.In school children and adolescents, 40.5% , 60%  and 42.4%  of the general population and 31.8% (71/223), 66.4% (148/223), and 38% (85/223) of participants with a neuropsychiatric disorder reported scores above cut-offs for clinically relevant symptoms on PSC, CES-DC and SCARED scales, respectively.p < 0.001). When examining PPSC in pre-school age, several demographic variables were predictors of a positive score: male, diagnosis of autism, residency in a highly affected area , high parental educational level (both graduated), parental job loss because of the pandemic (p < 0.01); while the presence of siblings was a protective factor (p < 0.005). After adjusting variables for the changes during the lockdown, the diagnosis of autism spectrum disorder and parental job loss were associated with higher worsening of test scores (p < 0.05). With regards to lifestyle changes, the use of smartphone >2 h/day, watching television >2 h/day, or their increase during the lockdown were independently predictors of a clinical score above the normal cut-off on the PPSC.The presence of siblings was a protective factor for each BPSC sub-score (p < 0.001). Time (>2 h) spent on social media or chat, watching television or tv series/movies on digital devices, and using smartphone were risk factors, while physical activity, home-schooling, reading a book, talking with other people were considered protective (p < 0.05).In school children and adolescents, male and residency in Northern Italy were predictive of a PSC clinical score during the lockdown, while a diagnosis of anxiety disorders or learning disabilities were inversely associated (p < 0.005). Lifestyle changes more associated with depressive symptoms were time spent on social media/chat, watching tv series/movies on digital devices (p < 0.001), whereas physical activity, talking with other people, playing with parents were protective activities (p < 0.05).When examining depressive symptoms through CES-DC, children and adolescents with residency in Northern Italy, with a diagnosis of mood disorders, and with the loss of parental job were more likely presenting clinical scores (p < 0.001). Time spent on social media/chat and watching tv series/movies on digital devices were risk factors (p < 0.001), whereas physical activity, reading and talking with other people were protective factors (p < 0.05).Lastly, in evaluating anxiety as per SCARED results, no demographic characteristic was associated with clinical scores, but the presence of siblings and the diagnosis of learning disabilities were inversely associated  and 57.8% (129/223) were worried about the pandemic in the general population and in the group with a neuropsychiatric disorder, respectively. In subjects with positive psychometric scores among the two groups, lack of optimism or worry about getting infection were more frequently reported .This study aimed to address the lifestyle changes and psychological effects caused by home confinement in the Italian pediatric population, and in children and adolescents with a neuropsychiatric disorder. The main findings highlight emotional and behavioral symptoms considerably increased in pediatric population during the national lockdown. Several demographic and clinical characteristics  seemed associated with a higher risk of psychological consequences. Moreover, since the enforced social isolation has generated remarkable lifestyle changes in all, several protective and risk factors were identified for mental health symptoms. The presence of siblings, the time spent for physical activity, talking with other people or reading, resulted protective factors, whereas using a smartphone, watching television/tv-series/movies on digital devices, or time spent on social media or chat, were risk factors in an age-specific manner.These findings are important for several reasons. First, this study comprehensively addresses the psychological impact caused by a long home confinement (2 months) on children and adolescents, including those with a neuropsychiatric disorder. Higher frequencies of psychometric tests above the clinical cut-off were obtained in pre-school children (>70%) compared with school children and adolescents (40.5%). Overall, the available evidence addresses an increased rate of psychological problems during the containment measures (ranging from 20 to 40%), considering that the international prevalence of all pediatric mental disorders was 13.4% before the pandemic –13. A moSecond, the use of an extremely detailed survey without missing data allowed the identification of both protective and risk factors among demographic characteristics and lifestyle changes owing by home confinement.The presence of siblings was the only protective factor for infants. This confirms the idea that positive sibling relationships may be protective to the development of psychological difficulties and maladjustment . DifferePhysical activity was the most important protective factor for all tests in school children and adolescents. A recent study has found that children and adolescents' physical activity was at very low level during the pandemic, but it considerably reduced child mental distress related to COVID-19 , 18. In This study also confirms previous evidence about the correlation between screen exposure and neuropsychiatric symptoms . ProlongHome-schooling might also participate in increasing screen time exposure. However, in our analysis, home-schooling was a protective factor. School closure is one of the most disruptive forces in the COVID-19 era, but home-schooling helps to keep learning activities going on, while reducing stressors related to home confinement. Surely, home-learning should be a temporary solution because schools support social, emotional, and physical well-being. Since the real effect of school closure in curve mitigation has yet to be defined , a carefThis study also provides the first evidence that pre-school children with a diagnosis of autism spectrum disorder were at higher risk of symptom intensification during the lockdown. Conversely, subjects with an anxiety disorder or learning disability were less affected. Likely, they positively perceived home confinement, thus experiencing less psychological distress and more life satisfaction. A longer time spent with parents and siblings has possibly contributed. Moreover, home-schooling likely determined new forms of accommodation and personalization in learning.Reading, playing with parents, and talking with other people were all confirmed as protective factors for mental health symptoms.Lastly, the rate of psychometric tests above the clinical cut-off significantly differed when children and adolescents reported negative feelings toward the epidemic. This confirms the necessity of increasing positive communication to address children and adolescents' fears and concerns during home confinement .Certain limitations must be acknowledged. Our data are cross-sectional and collected by an online survey, which limits the quality of answers and assessments of daily habits. However, this was the only way to efficiently collect data while respecting containment measures.Although our sample was recruited from across all Italian regions, participants self-selected into this study via social media or internet, which may be prone to selection bias. This may limit the generalizability of our findings by potentially influencing comparisons. The statistical methods we applied in the different ages aimed to minimize these limitations. Finally, we cannot exclude that a proportion of children with neuropsychiatric disorders might also be included in the sample from general population, as our populations were recruited from two different scenarios . This may have led to overestimate the results obtained from general populations. However, despite having two groups with unequal sizes, the number of participants well-represents the actual ratio between general population and children with a neuropsychiatric condition.Overall, our findings highlight that lifestyle changes caused by home confinement during the COVID-19 pandemic had a significant psychological impact on pediatric population. In particular, subjects with autism spectrum disorders seem the most affected. Encouraging physical activity or other positive behaviors , can reduce the psychological impact that children and adolescents may feel. Relieving children's distress by media entertainment negatively impacted the pediatric mental health. Effective measures to promote a positive psychological attitude toward the pandemic needs to be supported in childhood. At the beginning of the second wave in Europe, more attention should be paid to the children and adolescents' mental health status before adopting important containment measures, including school closure.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Policlinico Umberto I Ethics committee. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.SO, GR, SV, AD, and FM: conception and design of the study. LR, RG, AD, FM, MR, and AC: data collection. LR, AS, and DA: analysis and interpretation of data. SO, GR, SV, and FM: drafting the article. SO, MR, and AC: literature review. All authors critically revising the article, final approval of the manuscript, and have verified the collected data.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.


N = 52) with analytic and holistic thinking styles were equally successful at solving the cognitive tasks but response times were longer in the analytic group, compared to the holistic group. Heart rate complexity, as measured by sample entropy, was higher in the analytic group during the cognitive tasks but did not differ from the holistic group at rest or during the simple motor task. Analytic participants had longer response times and higher heart rate complexity when evaluating objects in relation to the field than when evaluating objects irrespective to the field. No difference in response times or heart rate complexity between tasks was observed in the holistic group. Our findings demonstrate that differences in individual behavior, including those related to holistic and analytic thinking styles, can be reflected not only in brain activity, as shown previously using fMRI and EEG methods, but also at the level of neuro-visceral coordination, as manifested in heart rate complexity.Analytic and holistic thinking styles are known to be associated with individual differences in various aspects of behavior and brain activity. In this study, we tested a hypothesis that differences in thinking styles may also be manifested at the level of neuro-visceral coordination. Heart rate variability (HRV) was compared between analytic and holistic thinkers at rest, during a simple motor choice reaction time task and when solving cognitive choice reaction time tasks in conditions with varying instructions contrasting the role of the field when evaluating objects. Participants ( A theoretical model of analytic vs. holistic thinking was proposed by Differences in cognitive performance between holistic and analytic individuals have been demonstrated across various tasks involving attention , categorHeart rate variability (HRV) reflects the dynamics in the time intervals between adjacent heartbeats that are in coherence with the functioning of the entire body. It is widely accepted that the source of HRV originates in the regulation of transport of resources through the body in order to adapt an organism’s functioning to external challenges by achieving optimal performance ratio. From the physiological perspective, the primary origin of HRV is related to the activity of the autonomic nervous system through its sympathetic and parasympathetic parts . VariousThe system-evolutionary theory , buildinIn this work, we compared heart rate complexity between groups of participants with holistic and analytic thinking styles during performance of holistic (field-dependent) and analytic (field-independent) tasks. Based on the assumption that functional systems are comprised by different components of the brain and the rest of the body, our hypothesis was that cognitive and behavioral specificity of analytic and holistic thinking styles is not only manifested in brain activity but reflects the system organization of individual experience at the level of the whole organism. More specifically, we hypothesized that there are differences in heart rate complexity between analytic and holistic thinkers when solving cognitive tasks and these differences are related to their task performance. We expected analytic individuals to be faster and more successful at solving tasks in a field-independent condition and holistic individuals to be faster and more successful in a field-dependent condition. We hypothesized that the cognitive effort and the system complexity of current behavior would be manifested in neuro-visceral activity so that higher HRV complexity would correspond to performance in the tasks that are harder for individuals: field-dependent tasks for analytic thinkers and field-independent tasks for holistic thinkers.All of the participants gave written informed consent to take part in the study after receiving an explanation of the procedures.The study was conducted in accordance with the Declaration of Helsinki. The Ethics Committee of Institute of Psychology of Russian Academy of Sciences (Moscow) approved the experimental protocols and the specific consent procedure used in this study and assessed it as safe for the participants’ psychic and physical health. All of the participants were paid for their participation (500 rubles).M = 21.2, SD = 4.34). All participants were Russian citizens speaking Russian as their native language. None of them reported any history of neurological or psychiatric disorders. All participants had either normal or corrected-to-normal vision. One participant was excluded from the analyses due to corrupted ECG recordings. The holistic and analytic groups were formed on the basis of participants’ answers to the items of AHS questionnaire (see below). It was not possible to calculate AHS scores for 5 of the participants because they used the option “difficult to answer” too often. Finally, the electrophysiological data of 46 participants were included into the analyses.We studied 52 healthy participants , during a simple motor task involving familiarizing with keys to be used in the following experimental sessions (2 min), and in the process of four experimental sessions .Four experimental sessions included solving tasks in two analytic and two holistic conditions. Analytic tasks were constructed to allow successive stages in the process of searching for a solution; holistic tasks could only be solved in one stage, simultaneously . It is aIn all tasks, participants were presented with two frames of different sizes which contained vertical lines. A screenshot example of one of the experimental tasks is presented in After reading the instructions, an experimenter started a training trial and asked the participants whether presented figures were similar or different according to the principle indicated in the instructions . The experiment began only after the participant understood the instructions and correctly performed the training task.Response times (RT) were analyzed for three conditions: simple motor trial, blocks of holistic and analytic tasks. Medians and between-subject variances were also calculated for all of the parameters.Rest, or baseline, condition was viewed as a situation when an individual was not acquiring a new skill. A simple motor task was used, firstly, to control the response rate with the right and left hands, and, secondly, it was used as a “neutral” condition which did not involve thinking styles. Analytic and holistic tasks are considered as situations of operating and developing thinking styles based on prior individual experience.All the participants filled the Analysis-Holism Scale (AHS) questionnaire prior to the experiment.Choi and colleagues  developeN = 5).The AHS questionnaire consists of 24 statements. Participants were asked to rank whether they agree or disagree with each of the statements on a 7-step Likert scale . The test provides a total score of analytic-holistic thinking, and four subscores of the individual components of the analytic-holistic thinking type. The detailed description of the subscales can be found in The internal consistency reliability  of the AHS in our study was 0.696.On the basis of AHS scores , the participants were divided into two groups with a cut-off at the median value for all participants so that we had a holistic group and an analytic group, containing 23 participants each.1ECG was recorded using monopolar surface silver chloride electrode in the medial part of the thorax. The electrode had conductive adhesive hydrogel for better signal conductivity. The sampling frequency ECG was 250 Hz with 0.1--70 Hz band-pass range and 50 Hz notch filter. Encefalan EEGR--19/26 for ECG recording was used.For HRV analyses, we used SampEn as an index of complexity, SDNN as an index of variation, and averaged RR-intervals as an index of mean frequency of the heart rate. It is accepted that heart rate complexity measured with non-linear algorithms can correlate with statistical measures of HRV, such as SDNN, but these correlations are not linear . Such moECG processing, RR-intervals detection and HRV calculations were made using open-sourced python library neurokit 2 0.1 .Raw ECG signal data obtained for experimental periods  underwent signal preprocessing. It was detrended to remove the linear trend and mean value from the signal. After detrending, it was filtered using a Butterworth band-pass filter with a gain of 1 and frequency range between 5 and 40 Hz to remove the baseline drift, white noise, and any motion artifacts. In the resulting ECG, R-peak detection was based on the Pan and Tomkins algorithm .Acquired sequences of RR-intervals were pre-processed before proceeding to the analyses with the aim to select sequences that were free from artifacts. Sequences with abnormal beats and any artifacts  were excluded from the analyses. Sequences containing RR-intervals that did not satisfy the condition (1) were excluded from the analyses.Heart rate complexity was described using sample entropy (SampEn) as a set of measures of system irregularity reporting on similarity in time series. SampEn can be applied to relatively short and noisy data; it is largely independent of the length of time series, displays relative consistency under circumstances and has been widely used in physiological studies with different signals analyses . SampEn m = 2, r = 0.2 × SDNN .The parameter N is the length of the time series, m is the length of vectors to be compared, and r is the tolerance for accepting matches. A is the number of pairs of vectors (x) for m points that satisfy the condition d ≤ r, and B is the number of pairs of vectors (x) for (m+1) points that satisfy the condition d ≤ r. Thus, a low value of SampEn reflects a high degree of regularity. SampEn values are largely independent of the time series length and display immunity to signal noise. The length of the analyzed time series was within the range 200–400 RR-intervals. The parameters m and r were fixed: Additionally, the time domain indexes of HRV  and standard deviation  of RR-intervals) were calculated to characterize the average level and general variance of heart rate dynamics.2 Distributions were tested for normality using Kolmogorov-Smirnov tests. Where distributions were not different from the normal distribution, parametric statistics was applied: t-tests for independent samples for between groups comparisons and paired samples t-tests for comparisons within subjects. Where distributions differed from the normal distribution, non-parametric tests were used: Mann-Whitney U test, to compare between groups, and Wilcoxon signed-rank and Friedman tests, to compare conditions within subjects. Cohen’s d was calculated as an estimate of effect size for parametric tests. Spearman’s rank correlation coefficient was computed for analyses of relationships between AHS scores, behavioral metrics and HRV indexes. We used an alpha level of 0.05 for all statistical tests.Statistical analyses were performed using IBM SPSS 17.0 software and open-sourced python SciPy library.Response times (RTs) were averaged after excluding RT values exceeding two standard deviation units in either direction. RTs for each subject were distributed normally (Kolmogorov-Smirnov test). No difference from the normal distribution was observed for RTs in the entire sample or in separate groups of analytic and holistic participants.M = 778, SD = 201) were shown to require longer solution time than holistic tasks  during the first presentation ; however, solution time did not differ between the two types of tasks  during the second presentation .RTs were compared between the analytic and holistic groups when they were solving tasks in analytic and holistic conditions. The results are presented in M = 781, SD = 182 for analytic participants, M = 651, SD = 132 for holistic participants, t(45) = 2.78, p = 0.01, d = 0.83; second block of holistic tasks: M = 688, SD = 146 for analytic participants, M = 570; SD = 120 for holistic participants, t(45) = 3.00, p = 0.01, d = 0.44; first block of analytic tasks: M = 844, SD = 200 for analytic participants, M = 719, SD = 202 for holistic participants, t(45) = 2.11, p = 0.05, d = 0.37; second block of analytic tasks: M = 716, SD = 191 for analytic participants, M = 601, SD = 144 for holistic participants, t(45) = 2.31, p = 0.05; d = 0.34). As can be seen from the effect sizes, this was more pronounced for the holistic tasks.Holistic participants solved all tasks faster than analytic participants  = 5.29, p < 0.001; holistic tasks: M = 718, SD = 182 for the first presentation, M = 640, SD = 165 for the second presentation, t(51) = 5.27, p < 0.001] as well as separately in analytic  and holistic  groups.In addition, tasks were always solved faster during the second presentation, as compared to the first presentation in the whole sample .The results are presented in M = 67.2, SD = 22.4 for analytic tasks, M = 87.8, SD = 9.9 for holistic tasks, t(50) = –6.30, p < 0.001] and second  presentations. These results were also observed separately in analytic  and holistic  groups.Analysis of task performance within groups showed the following results. Participants were less successful at solving analytic tasks than holistic tasks at the first  and holistic  conditions, probably reflecting the learning effect. However, in the analytic group, this temporal dynamics was significant only for holistic («nonspecific») tasks  while no significant shift was observed for analytic tasks . Similarly, in the holistic group, significant dynamics in success rate was observed in analytic («nonspecific») tasks , with only a tendency observed for holistic tasks .Success rate of the entire sample significantly increased in the second block of tasks compared with the first block of tasks in both analytic [No correlation was observed between AHS score and success rate see .We compared HRV indexes  between holistic and analytic groups in four conditions: baseline, simple motor task, analytic and holistic blocks of experimental tasks. The results are presented in U = 186, p = 0.04) and holistic  tasks. No difference in SampEn was observed between analytic and holistic groups in the baseline condition  or during the simple motor task . No significant difference between the groups was found in SDNN values for any of the four conditions: baseline , simple motor task , analytic tasks  or holistic tasks . No difference between the groups was observed in the length of RR-intervals (av-RR) for baseline , simple motor task , analytic tasks  or holistic tasks .Higher values of SampEn were observed in analytic participants, as compared with holistic participants, in both analytic  and highest holistic scores . Despite the smaller sample sizes, this contrast replicated the findings shown for the entire sample. Higher values of SampEn were observed in participants with high analytic scores, as compared with participants with high holistic scores, in both types of tasks: analytic  and holistic . SampEn did not differ between the subgroups in the baseline condition  or during the simple motor task . No difference between the subgroups was observed in SDNN values for the baseline , simple motor task , analytic tasks , or holistic tasks . No difference was found in av-RR values: baseline , simple motor task , analytic tasks , and holistic tasks .In addition, we further compared the HRV indexes between the subgroups of participants with the highest analytic scores . In general, SampEn was increasing from the rest condition to experimental tasks , with the highest values observed during the holistic tasks.Significant difference in SampEn values was shown between analytic and holistic tasks , which may be accounted for by light fatigue participants developed during the experiment. However, no difference was observed between the analytic and holistic tasks .SDNN dynamics was also significant: the index values decreased from the rest condition to experimental tasks  and no difference in av-RR was shown between the analytic and holistic tasks .No trend was found for av-RR . No difference was found between the analytic and holistic tasks .SampEn was increasing from the rest condition to the experimental tasks in the holistic group ; and no difference was observed between the analytic and holistic tasks .SDNN dynamics was not significant between the experimental conditions  or between the analytic and holistic tasks .No difference was shown for av-RR dynamics between the experimental conditions  approach to achieving a deeper understanding of analytic and holistic thinking requires further investigation into the nature of psychophysiological organization of behavior in analytic and holistic thinkers.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by the Ethics Committee of Institute of Psychology of Russian Academy of Sciences (Moscow). The patients/participants provided their written informed consent to participate in this study.AB performed the experiments, analyzed, interpreted the data, contributed reagents, materials, analysis tools or data, and wrote the manuscript. VA performed the experiments, analyzed, and interpreted the data. KA conceived, designed the experiments, performed the experiments, analyzed, interpreted the data, and wrote the manuscript. YA conceived, designed the experiments, analyzed, and interpreted the data. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


We briefly review the current knowledge on how bacteria produce and use H2S and CO. We address their potential antimicrobial properties when used at higher concentrations, and describe how microbial systems detect and survive toxic levels of H2S and CO. Finally, we highlight their antimicrobial properties against human pathogens when endogenously produced by the host and when released by external chemical donors.Hydrogen sulfide and carbon monoxide share the ability to be beneficial or harmful molecules depending on the concentrations to which organisms are exposed. Interestingly, humans and some bacteria produce small amounts of these compounds. Since several publications have summarized the recent knowledge of its effects in humans, here we have chosen to focus on the role of H However, the two compounds have long been recognized as also being produced by mammalian and bacterial cells in low amounts that mediate important physiological processes  oxygen sensor cluster and represses over 100 genes, raising the possibility that it could be inactivated through CO binding to the iron–sulfur cluster. Additionally, the elevated expression of genes involved in arginine, taurine, and methionine biosynthesis, iron acquisition, and sulfur utilization/uptake, suggests that, in response to CO, cells undergo a shortage of amino acids, sulfur, and iron [Several works on the bacterial response to the stress imposed by CO and CORMs have been published. A transcriptomic study of e genome . In aeroand iron .E. coli exposed to CO donors, such as CORM-2 and CORM-3 also caused major alteration of the mRNA abundance of a large number of genes [cyoABCDE and sdhABCD operon). However, small induction of the cydAB genes encoding cytochrome bd-I was observed, which is consistent with cytochrome bd-I being the more CO resistant oxidase [E. coli under oxidative stress . Interestingly, in uropathogenic E. coli isolates, CORM-2 induced up-regulation of some virulence genes [of genes ,116. In  oxidase . Up-regu oxidase ,116. In ce genes ,82.S. mitis and B. cereus, cause hemolysis during infection [Corynebacterium diphtheriae. Over the years, several other heme oxygenases, regulated by intracellular iron concentration, have been found in pathogens, such as Cj1613c in C. jejuni, HugZ in H. pylori, and HemO in Neisseria meningitides [Several pathogens, like nfection , and usengitides ,123,124.S. aureus monooxygenases IsdG and IsdI, and M. tuberculosis MhuD [S. aureus, IsdG was proposed to link biosynthesis and uptake heme pathways, thus protecting the bacteria from intracellular heme toxic accumulation [Of note, some bacterial heme oxygenases release formaldehyde instead of CO, as for example the sis MhuD . In S. amulation ,127. E. coli growth in the presence of the antibiotics such as doxycycline, trimethoprim or cefotaxime [As mentioned above, endogenously produced sulfide appears to protect bacteria from a broad range of antibiotics. However, no similar effect was, so far, observed with CO, since CO gas only marginally improved fotaxime . Plasmodium berghei infected mice from development of cerebral malaria, although it did not decrease parasitemia. Authors proposed that binding of CO to heme prevents the disruption of the blood–brain barrier and the consequent development of cerebral malaria associated to high toxic levels of free heme in erythrocytes derived from hemolysis [The finding that HO-1 is highly induced in macrophages in response to bacterial infections, and that animals with blocked HO-1 were highly sensitive to bacteria and presented signs of systemic inflammatory response led to the proposal that CO enhances bacterial clearance . In addiemolysis ,132.M. tuberculosis that induced HO-1 in infected macrophages with release of CO that triggers the dormant stage of M. tuberculosis [However, some bacteria seem to be able profit from induction of host-derived CO production as a self-protection mechanism, as was shown for rculosis .2S and CO are interconnected due to the shared capacity of these molecules to interact with metal centers and cysteine residues in proteins. Both molecules are involved in related signaling pathways, in which they promote activation/inactivation of the target proteins and may interfere in the level and activity of each other. For example, the H2S-generating CBS enzyme is reversibly inhibited by the CO derived from heme oxygenase, which is proposed to have pathophysiological implications including on the metabolism of cancer cells. Theregulatory heme-binding domain of the human CBS is absent from the homolog enzymes from prokaryotes or unicellular eukaryotes [The chemistry and biology of Hkaryotes .2S was reported to increase the expression of heme oxygenase, through the action of the Keap1/Nrf2 system on the HO-1 enzyme and because the intracellular sulfide levels seem to modulate the HO-2 activity through the several Cys-Pro signatures present in HO-2 that regulate heme binding [2S is proposed to react with ferric verdoheme, an intermediate of the HO-2 activity, thus modifying its oxygen-sensing activation mode [2S was shown to upregulate the heme oxygenase in the pulmonary arteries of hypoxic rats and stimulate heme oxygenase levels in mouse retinal ganglion cells [H binding . Moreoveion mode . Accordion cells .2S deplete bacterial intracellular zinc levels and that in M. tuberculosis the two molecules induce the dormancy phase. Although several prokaryotes encode simultaneously in their genome enzymes that produce CO and H2S, the relationship between the function of the two molecules in bacterial physiology remains to be addressed. As mentioned above, both CO and H2S and CO are double-edged molecules—if on the one hand are essential signaling molecules to human cells, on the other hand they can cause death. This duplicity of function, which took decades to be recognized, is reminiscent of what also happens with metals. As with these, everything depends on the concentration, which when high is toxic but in small amounts is beneficial and even essential for the normal maintenance of organisms.Along with nitric oxide, H2S can function as antimicrobials. There are already several examples of the effectiveness of CORMs as antimicrobials (2S. In fact, sulfide and CO-based compounds may represent a novel kind of antimicrobials, with modes of action and targets that are different from those of the currently available antibiotics. And new antimicrobial drugs are urgently needed due to the growing number of infections caused by antibiotic-resistant pathogenic strains.More recently, it has been shown that CO and Hcrobials , but sim


This study aims to examine the mediation role of satisfaction with children on the association between contact with children (CCT) and healthy aging among middle-aged and older parents in China.Data from 9,575 parents over 45 years old were obtained from the 2018 China Health and Retirement Longitudinal Survey. A multinomial logistic regression model was applied to measure the association between contact, satisfaction, and healthy aging with potential confounders controlled. We used the Sobel–Goodman Mediation test to analyze the mediation role of satisfaction on the association between types of CCT and healthy aging.RRR) = 2.44, CI = 1.92–3.10] and higher healthy aging . Satisfaction was strongly related to healthy aging , and mediated 19.05% of healthy aging for weekly contact . Subgroup analysis further revealed that satisfaction with contact played a partial mediating role between monthly contact and healthy aging in female and rural groups.Parents with contact with adult children had higher satisfaction with children [for contact weekly (satisfied/unsatisfied): relative risk ratio (Monthly CCT is more appropriate for older parents. Satisfaction with children in older parents seems to act as a significant and partial mediator of the relationship between contact and healthy aging. The contribution of satisfaction to healthy aging could be important to be considered and promoted in women and rural older parents, independent of CCT. China's population is rapidly aging; by 2050, there will be nearly 400 million Chinese citizens aged 65 years old or older, 150 million of whom will be 80 years old or older . DemograAs the conventional central family model is increasingly uncommon , one- anHealthy aging is defined by the WHO as the process of developing and maintaining the functional ability that enables wellbeing in older age. Healthy aging is a holistic view that encompasses both biological and medical aspects of aging, as well as subjective experiences and meanings, and emphasizes functional definitions of autonomy, participation, and wellbeing . As healThe role of adult children has become an important aspect of assessing the health status of the parents. Consistently low levels of positive support and an increase in negativity from children have been associated with increased mortality . AnticipFilial piety is a key virtue in Chinese culture and was considered the bedrock of the social care and health system that protected and supported older people in China . The relThe role of CCT in the relationship between children satisfaction and healthy aging has not been explored in any previous studies, despite the potential role of relationship satisfaction as an efficient intervening measure that could promote healthy aging . This stHypothesis 1. CCT improves CSF and HAI among the middle-aged and older population.Hypothesis 2. CSF is also positively correlated with HAI. That is, CSF plays a mediation role in the association of CCT with HAI.http://charls.pku.edu.cn/) and in many other studies. The CHARLS research team and field teams collect the data and make the data publicly available. The total sample size of the CHARLS survey in 2018 was 19,816 individual respondents. We limited our sample to parents who had at least one alive child. Parents who had missing dependent values, independent variables, and mediation variables were excluded. The final sample contained 9,575 parents.China Health and Retirement Longitudinal Study (CHARLS) national survey of wave four was conducted from August, 2018 to March, 2019. The CHARLS is a biennial/triennial survey conducted by the National School of Development of Peking University, collecting high-quality micro-data from middle-aged and older individuals aged 45 years and above in China. The individual questionnaire includes basic demographics and information on family interaction, health status and functioning, healthcare and insurance, employment, retirement, and pension, income and consumption, household assets, and so on. Details on the sampling method and questionnaire are available at the official website  developed by the Aging Trajectories of Health: Longitudinal Opportunities and Synergies (ATHLOS) project . Item reSatisfaction is a new variable added in the fourth round of the survey. Parents were asked, “how satisfied are you with your relationship with your children.” The item was rated from 1 (completely satisfied) to 5 (completely dissatisfied). Based on this, CSF was categorized into 3 groups: 1 = satisfied ; 2 = somewhat satisfied; 3 = not satisfied .The parents were asked how often do they have contact, in person or by phone, with each of their adult children. Based on this, we categorized the CCT into 4 independent variables: daily CCT, weekly CCT, monthly CCT, and two times-yearly CCT see .Covariates were selected on the basis of their association with the independent variable and their impact on the change of the association between the independent and dependent variables. Age and gender were included as fixed covariates to be adjusted. The other covariates were included as potential confounders in the final models if they changed the estimates of CCT/CSF on HAI score by more than 10% or were significantly associated with HAI score. The following covariates were selected based on established associations and/or plausible biological relations and tested: hukou status , residence, education levels, public health insurance coverage, current work status, smoking, alcohol intake, self-report of health, chronic condition, household per capita consumption, whether they live near children, number of living children, gave money to children, and received money from children. The associations of each confounder with HAI score are detailed in SD and the frequency (%) for continuous and categorical variables, respectively. HAI groups (Q1–Q5) across the categories of CCT (yes and no) and CSF  are presented as the frequency (%). Characteristic differences were examined using Student's t-test for continuous variables and the chi-squared test for categorical variables. Multinomial logistic regression models (MLRM) were employed to estimate the association between CCT, CSF, and HAI. Relative risk ratio (RRR) with 95% CIs was calculated after adjusting for age, gender, hukou status, residence, education levels, public health insurance cover, current work status, smoking, alcohol intake, self-report of health, chronic condition, household per capita consumption, live near children, number of living children, transfer to children, and transfer from children. We analyzed the mediation role of CSF on the association of CCT  with HAI through Sobel–Goodman Mediation Test, with all the selected covariates controlled.Characteristics of parents across the categories of weekly CCT  are presented as the mean ± p-values were 2-sided, and an alpha level of 0.05 was used to define statistical significance. Data were analyzed using Stata (version 16) and R version 3.6.3 .The The mean age was (65.17 ± 8.39) years old. Approximately, 52.32% of the parents had three or more alive children. Most (84.31%) of subjects contacted their children weekly, but only 49.22% live together with their children. Approximately, 45.94% of them were male and 83.72% of them were married. The vast majority (89.35%) of them was graduated from junior high school and below. Approximately, 66.38% of them were from rural areas and 61.34% had a job. Approximately, 96.60% of them were insured and 68.52% of them seldom drank. The prevalence of smoking was 25.93%. Four-fifth of the subjects had one or more chronic diseases. The rate of subjects satisfied with their relationship with their children was 57.46%.2 = 94.991, p < 0.001) : RRR = 1.41, p = 0.003, CI = 1.13–1.77] as shown in RRR = 3.44, p < 0.001, CI = 2.14–5.51].A multinomial logistic regression model was conducted to investigate whether CCT affected the CSF and HAI adjusting for potential confounders. The null hypothesis was βi = 0. Parents who had CCT had higher satisfaction with their relationships [for weekly CCT (satisfied/unsatisfied): Two subgroup analyses of gender and residence were performed through MLRM see . Weekly,via CSF. CSF played a partial mediating role between CCT and HAI in this study, and the role of this mediation accounted for from 7.42% (monthly CCT) to 19.05% (weekly CCT) with potential confounders adjusted  and related to HAI . CSF was also related to HAI . CSF mediates 19.05% of HAI for weekly CCT . The final mediation models of the independent variable (HAI), the mediator variable (CSF), and the dependent variable (CCT) were shown in Weekly CCT was related to CSF , and rural . CSF also played a partial mediating role between twice a year CCT and HAI in rural .Subgroup analysis of gender and residence was shown in Since the 1980s, the household system in almost all Chinese regions has evolved from a large unitary model to a small diversified one . In thisCCT improves CSF and HAI among the middle-aged and older population, was supported. Interdependency and relation-oriented responsibilities are culturally emphasized in China . Older pCSF is associated with HAI, and plays a mediation role in the association of CCT with HAI, which was also supported. HAI was higher in the parents who had higher CSF. And CSF in the parents seems to act as a significant and partial mediator of the relationship between CCT and HAI. More specifically, better HAI was achieved through CSF that was improved by weekly, monthly, and twice a year CCT. CSF may be associated with both physical and mental health for the older parents –30. Reguvia CSF in the rural group. Workforce participation helps healthy family members  cope with chronic illness in older parents aged 60 years and older, and maintain normal family functioning  nor low frequency (contact two times a year) was significant. This suggests that monthly CCT may be a more appropriate rhythm. This frequency of CCT may maintain a balance between intimacy and alienation and lead to better results, which is also consistent with the psychological effects of interpersonal interactions.The results and implications of this study should be considered in light of several limitations. First, given the exploratory cross-sectional design of this study, no causality inferences could be made. Second, we used secondhand data and were unable to capture certain information; the lack of data on the personality traits and preferences of children does not support further in-depth analysis of the role of these aspects in terms of how CCT affected parents' HAI. Third, the results obtained in this study may be related to its particular cultural and environmental context. Considering that filial piety is a key virtue in Chinese culture and is considered the bedrock of the social care and health system to protect and support older people in China . It is lIn conclusion, this study highlights the importance of evaluating HAI through an approach that considers both CCT and CSF. CCT and CSF had significant predictive effects on HAI. CSF both mediated and moderated the influence of CCT on HAI. These findings indicate that improving CCT and CSF may meaningfully improve HAI. The public health implications of this study are that it provides the basis for intervention strategies for a family centered program to promote healthy aging for older Chinese parents, especially for those who live in rural China.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by the Biomedical Ethics Review Committee of Peking University approved CHARLS. The ethical approval number was IRB00001052-11015. The patients/participants provided their written informed consent to participate in this study.JC contributed to conceptualization and writing the original draft preparation. YZ contributed to data curation and writing the original draft preparation. WH contributed to software and validation. JY contribute to data curation. DX contributed to resources, supervision, and funding acquisition. HL contributed to writing, reviewing, and editing. All authors contributed to the article and approved the submitted version.The project has received support from the Guangdong Basic and Applied Basic Research Foundation (2021A1515110743), the Swiss Agency for Development and Cooperation (Grant#81067392), and the Medical Scientific Research Foundation of Guangdong Province (Grant#A2020420). The funders had no role in the study design, data collection, data analysis, data interpretation, or writing of the report.The corresponding author had full access to all the data in the study and had the final responsibility for the decision to submit for publication.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.


Present work was aimed to gather accessible evidence on the eradication rates and related postoperative complications of antibiotic-loaded calcium sulfate (CS) as an implant in the treatment of chronic osteomyelitis (COM).Databases including PubMed, EMBASE, Medline, Ovid and Cochrane library were searched from their dates of initiation until November 2021. Two independent authors scrutinized the relevant studies based on the effectiveness of radical debridement combined with antibiotic-loaded CS for COM; data extraction and quality assessment of the Methodological Index for Non-Randomized Studies (MINORS) criteria were also performed by the authors. In addition, clinical efficacy mainly depended on the evaluation of eradication rates and complications, and all the extracted data are pooled and analyzed by STATA 16.0.A total of 16 studies with 917 patients (920 locations) were recruited, with an overall eradication rate of 92%. Moreover, the overall reoperation rate, overall refracture rate, overall delayed wound healing rate, and the rate of aseptic wound leakage were 9.0%, 2.0%, 20.0%, and 12.0%, respectively. Moreover, the choice of tobramycin-loaded CS or vancomycin combined with gentamicin-loaded CS did not affect the eradication rate, and the incidence of postoperative complications in COM patients (all Our meta-analysis indicated that the overall eradication rate of COM treated with antibiotic-loaded CS was 92%. Delayed healing is the most common postoperative complication. The choice of tobramycin-loaded CS or vancomycin combined with gentamicin-loaded CS did not affect the eradication rate and the incidence of postoperative complications in COM patients. Chronic osteomyelitis (COM) is defined as a significant and long-standing infection of bone tissue, which lasting more than several months or even years and involved in any bone including periosteum, bone marrow and surrounding tissue. Most infections occur after trauma, surgery or secondary to vascular and neurologic insufficiency (e.g. diabetic foot ulcers), characterized by persistent bacteria, low-grade inflammation, and the prevalence of fistula and dead bone , 2. WithThe mainstays of COM treatment are radical debridement, then supplemented with targeted antimicrobial therapy  for long time. A recent study suggested that the combination of antibiotics and surgery seems to be more effective than any single method ; despiteCalcium sulfate (CS) is a kind of biodegradable material with low immunoreactivity, easy reabsorption and good tolerance, which has been proved to be effective and safe as an antibiotic carrier in the past two decades –18. CS iThe major purpose of this meta-analysis was to investigate the eradication rates and local complications of antibiotic-loaded CS in treating COM patients. Second, we explored difference of curative effect and related postoperative complications between two antibiotic regimens. To provide reference for orthopedic surgeons using antibiotic-loaded CS in the treatment of COM.This study was presented in accordance with the PRISMA  . The PRIOnline databases were used to identify eligible studies, we searched all articles in PubMed, EMBASE, Medline, Ovid and Cochrane Library up to November 2021. We also performed a supplementary search in the Ovid database to avoid missing articles. In addition, a manual search of references and similar documents of identified articles was also performed to determine potential relevance. Medical subject heading (MeSH) and Embase Tree tool (EMTREE) were used to guide the choice of appropriate search terms in all databases. We performed a search using the strategy (“osteomyelitis” OR “osteitis” OR “bone infection” OR “osteoarticular infection”) AND . The last search was performed on November 15, 2021.The study selection criteria were established in accordance with the PICOS strategy : population—Patients with COM who underwent radical debridement and antibiotic-loaded CS; intervention—Operation with antibiotic-loaded calcium sulfate; comparison—none; outcomes—Eradication rate and complications of failure, including reoperation, refracture, and delayed healing; study design—consecutive case–control studies or case series. Several eligibility criteria were applied in the present study. Only case series and consecutive case–control studies regarding the clinical application of antibiotic-loaded CS in the treatment of COM were eligible for inclusion, case reports, review articles, meta-analysis, animal researches, or unpublished studies were excluded. Articles written in a language other than English or German were excluded. Publication, studies involving patients with COM due to any causative mechanism except diabetic ulcer were eligible for inclusion. In order to be included, each eligible report had to contain at least one of the outcomes of interest. The main outcome of interest was eradication rates of infection, but studies that described postoperative local complications  were also eligible for inclusion. Patient selection was not restricted by age, gender, or other personal characteristics.All the identified studies were selected according to the title and abstract by two independent authors (XW.S. and YP.W.). Extracted data were performed by 2 other authors independently (NH.N. and MJ.L.) and they screened articles with potential relevance through overall assessment based on the inclusion and exclusion criteria. The extracted data was summarized into a table, divided into three parts: (1) specific information of eligibility studies, including the authors’ names, year of publication, region of research, and study design; (2) basic information of each case, including age, total number of cases and gender, follow-ups, treatment, bacterial culture and application of antibiotics; (3) postoperative condition of each patient including failure, refracture, reoperation, delayed wound healing, local complications and other adverse events. For studies with incomplete or unclear data, we attempted to contact the authors for details. If any disagreement existed, a third reviewer participated and reached consensus.The Methodological Index for Non-Randomized Studies (MINORS) criteria was used to evaluate the quality of the included studies independently by two authors, which was established to assess the quality of comparative and noncomparative studies . The higI2 statistic. When P > 0.1 and/or I2 < 50%, the heterogeneity was evaluated to be low, and a fixed-effects model was used for the meta-analysis. Otherwise, a random-effects model was used. We calculated the postoperative eradication rates and incidences of complications in COM patients, as well as its 95% confidence interval (CI) for each study. Further, the pooled rates were calculated and publication bias was evaluated with a funnel plot. All results are presented in the form of forest plots and tables, and P < 0.05 was considered statistically significant.Stata 16.0 was used to pool the all results of the included studies were for the meta-analysis. A chi-squared-based Q statistical test was used to estimate the statistical heterogeneity. The degree of heterogeneity for each included study was quantified using the Initially, 816 articles were identified by searching, and two authors selected 162 studies by reading the title and abstract. Finally, through scrutinizing the full text and performing a manual search, a total of 16 articles conforming to requirements were included in our study. The implants used in one study  were selAll the included 16 studies were published between 2002 and 2021 , 29–41. The data were extracted and evaluated independently by two authors from the included studies. For 8 noncomparative studies, the results showed that average MINORS score was 8.5 (range from 6 to 13), suggesting fair quality. The remaining two comparative studies had scores of 14 and 15, both suggesting fair quality. Overall, the methodological quality of the included studies was moderate Table .Table 2P = 0.07), a random-effects model was used due to the low level of heterogeneity (I2 = 36.57%) , and the refracture rate was 2% in 9 studies  , and the reoperation rate was 9% reported by 15 studies that enrolled 827 cases4  , and the delayed healing rate was 20% reported by 14 studies that enrolled 815 cases  , and the incidence of aseptic mouth leakage was 12% reported by 14 studies that enrolled 794 cases   receiving antibiotic-loaded calcium sulfate implantation was 92% reported by 16 studies  and 90% , respectively, and there was no significant difference (P = 0.96). In terms of the incidence of complications, the reoperation rates of tobramycin-loaded CS and vancomycin combined with gentamicin-loaded CS were 7%  and 11% , the aseptic wound leakage rates were 24%  and 26% , the bone fracture rates were 5%  and 5% , the incidence of delayed healing rates were 34%  and 17% , respectively. The results showed no significant difference  (Table In order to further explore the difference between the two kinds of antibiotics in the treatment of COM, the eradication rate and complications were summarized. However, the results showed that the eradication rates of tobramycin-loaded CS group and vancomycin combined with gentamicin-loaded CS group were 92% (95% CI 0.88–0.95; P = 0.882 > 0.05, which meant that the funnel graph was symmetrical. Therefore, it can be judged that there was no publication bias in current study.A funnel chart would reflect whether there was publication bias in this study, and the symmetry of the funnel chart meant that there was no publication bias Fig. . FurtherWe eliminated each included study one by one, and summarized and analyzed the remaining studies to assess whether the individual study had an impact on the results of the meta-analysis. None of the studies had an excessive impact on the results of the meta-analysis, indicating that the results of the remaining studies were stable and reliable Fig. .Fig. 8ThCS was discovered in 1970 until it was used clinically in the past two decades, and achieved good results in Europe . HoweverThe successful eradication of COM remains a challenge for clinicians. Except for a study on chronic jaw osteomyelitis that did not specify the use of antibiotics , the treWhile infection elimination had shown encouraging results, associated local complications were also of concern. Delayed wound healing was the most frequent complication in our study, with a relatively high incidence of 20%. Bibbo et al.  reportedAntibiotic-loaded CS delivery system had been put into clinical application in the past 20 years, loaded with several of the most common antibiotics which made into a variety of products, such as vancomycin, gentamicin and tobramycin. However, the efficacy of calcium sulfate-loaded antibiotics in the treatment of COM is not clear. In an in vitro experiment, vancomycin and tobramycin impregnated materials had similar germicidal properties and elution efficiency . A systeOur study has some limitations. First, the sample size is not big enough and the summary of patient population characteristics is incomplete, which may hinder the interpretation of research results. Therefore, the results should be interpreted cautiously, and more patients should be enrolled in future studies to draw more precise conclusions. Second, we did not analyze the risk factors of infection relapse and complications because of most included studies’ retrospective design. To better identify potential risk factors, a good comparison of these antibiotics-loaded materials requires large-scale prospective clinical trials, especially multi-center joint studies; crucially, the potential risk of aseptic wound leakage after local CS implantation should be fully considered when patients receive this treatment. Future studies may focus on the risk factors of local complication and infection relapse following local CS implantation, as well as the efficacy of other substitute materials. Third, we all know that the release time and concentration of such antibiotic sustained-release systems are critical to the treatment of COM, but the studies we included lack a detailed description of the pharmacokinetics, which is not conducive to further compare the efficacy of several types of antibiotics. We should pay more attention to the clinical research on the species and drug resistance of COM bacteria in the future . Fourth,In conclusion, this meta-analysis revealed that the eradication rate of implantation of antibiotic-loaded CS in the treatment of COM was as high as 92%, and the incidence of complications including delayed healing rate, aseptic wound leakage rate, refracture rate and reoperation rate were relatively low. Although there is no significant difference in efficacy and complications between the two antibiotic-loaded CS regimens in the treatment of COM. The clinical efficacy of antibiotic-loaded CS in the treatment of COM needs to be confirmed by further study.


To evaluate the effect of transcutaneous electrical nerve stimulation (C-TENS) in the rehabilitation of rotator cuff injury. st treatment and after the 5th treatment. The differences of those indicators between the two groups were analyzed statistically.  A total of 60 patients diagnosed with mild to moderate rotator cuff injury were randomly divided into the control group and test group. Both groups received conventional rehabilitation treatment including physical therapy, joint mobilization, interventional therapy, and family recovery training. The test group additionally received TENS treatment on the upper area 4 or 5 of the wrist, based on the wrist-ankle acupuncture (WAA) theory. The results of the visual analogue scale (VAS), shoulder range of motion (ROM), and Constant-Murley score (CMs) were collected before and after the 1st and the 5th treatment (p < 0.05), and the improvements in the test group were better than those in the control group. The ROM of flexion, extension, abduction, adduction, internal rotation, and external rotation after the 1st treatment and 5th treatment in both groups were all improved compared with those at baseline. There was no significant difference between two groups. The CMs of the two groups after the 5th treatment were all improved compared with those at baseline. There was no significant difference between two groups. No adverse events occurred during the treatment.  The VAS scores of measurement points after treatment were all improved compared with those at baseline. There was a significant difference between the two groups after the 1 Electrical stimulation on the wrist combined with conventional rehabilitation is more effective in relieving pain than the conventional rehabilitation alone. Electrical stimulation on the wrist combined with conventional rehabilitation has no obvious effect in improving shoulder joint mobility and shoulder function. Shoulder pain is a common clinical symptom that leads to limited shoulder joint movement and affects the quality of life. It is estimated that the incidence of shoulder pain among adults aged 45–64 is 2.4% . Common A total of 60 patients with rotator cuff injury treated at the Department of Rehabilitation Medicine of Changhai Hospital between June 2017 and December 2017 were selected. Diagnostic criteria were as follows: clinical symptoms such as shoulder pain and decreased range of motion; physical examination such as tenderness in the space between the anterior shoulder and the greater tuberosity and positive result in the painful arc test, impact test, Jobe test, Lag test, or lift-off test; and MRI: according to the Zlatkin classification, imaging findings were of grades 1–3, and conservative treatment or postoperative rehabilitation can be performed after medical evaluation. Inclusion criteria were as follows: meet the diagnostic criteria for rotator cuff injury, aged 20–80 years old; no analgesic drugs, local closure, or any other treatments were used in the last 24 hours; no other chronic pain diseases; good mental state can cooperate with experimental research; and voluntarily receive treatment. Exclusion criteria were as follows: the history of tumor or tuberculosis; diseases of the heart, liver, spleen, lung, or kidney or other major viscera diseases; epilepsy, pregnancy, or infectious diseases; with pacemaker; and vascular expansion or scars or wounds on the wrist. Termination criteria were as follows: adverse reactions, including subcutaneous bleeding, electric burns, and allergies; symptoms worsen; and demanding further treatment or painkillers.ChiECRCT-2017051) and was listed on the China Clinical Trial Register (No. ChiCTR-IIR-17012275).This study was a monocentric, prospective, randomized, single-blind, controlled trial. The subjects who met the inclusion criteria were assigned to the test group  or the control group  by using a simple computerized random number generator. All the subjects were blind to the group assigning. This study was approved by the China Clinical Trial Ethics Review Board . ③ Operation methods: participants should wear the device during rehabilitation training. Two electrical stimulation electrodes were placed on the upper area 4 or 5 with the skin of the treatment area exposed, and the upper and lower juxtaposition method was also adopted. Therapists should select appropriate pulse parameters for the subjects, with symmetrical two-way wave, voltage of 40 V, frequency of 70 Hz, pulse duration of 200 -3 weeks .Therapists only performed conventional rehabilitation training on the patients.st treatment and after the 5th treatment.The time points for outcome collection are before and after the 1Visual analogue scale (VAS) was used to evaluate the degree of rest pain. Generally, 0–10 represents various degrees of pain, “0” represents no pain and “10” represents the most severe pain.Therapist measured the active movement of shoulder joint within painless range in six directions, i.e., flexion, extension, abduction, adduction, external rotation, and internal rotation, with a protractor. In the standing position, the long axis of the humerus is used as the moving arm, and the longitudinal axis of the trunk is the fixed arm; then, the flexion, extension, abduction, and adduction were measured with the acromion as the center. In the supine position, the long axis of the ulna was used as the moving arm, and the fixed arm was perpendicular to the torso plane; then, the internal rotation and external rotation were measured with the olecranon as the center.The Constant-Murley score consists of pain (15 points), activities of daily living (20 points), movement (40 points), and strength (25 points). The total score was 100 points. Pain and activities of daily living scores were given by patients themselves; movement and strength required physical assessment.All interventions were performed under the supervision of therapists to prevent the complications of the rehabilitation training or TENS stimulation. The subjects were asked to inform the therapists if they felt any discomfort after TENS.Q1), and the third quartile (Q3) and were evaluated by the Wilcoxon ranks test, while the enumeration data were processed by the chi-square test. The p value less than 0.05 considered as the difference was statistically significant.SAS 9.4 was used for statistical analysis. Descriptive statistics, e.g., mean and standard deviation (SD), were adopted to analyze participants' demographic data. GEE was used to evaluate VAS, ROM, CMs, and other trends over time. Measurement data in the results were expressed by median, the first quartile . The VAS scores after the 1st treatment and the 5th treatment in both groups were all improved compared with those at baseline. There was a significant difference between the two groups after the 1st and the 5th treatment (p < 0.05), and the scores of the test group were better than those of the control group . The ROM of flexion, extension, abduction, adduction, internal rotation, and external rotation after the 1st and the 5th treatment in both groups were all improved compared with those at baseline. There was no significant difference between two groups (p > 0.05)  .χ2 = 56.59, p < 0.000; ADL: Waldχ2 = 90.00, p < 0.000; ROM: Waldχ2 = 126.76, p < 0.000; strength: Waldχ2 = 21.82, p < 0.000; and the total score: Waldχ2 = 221.11, p < 0.000). The CMs subscale scores of the two groups after the 5th treatment were all improved compared with those at baseline, and there was no significant difference between two groups (p > 0.05)  .There are no skin allergies, scalds, burns, tingling, pain, muscle numbness, other physical damage, leakage, output disfunction, unstable output, electrode piece/lead wire damage, or other equipment malfunction during the treatment.Rotator cuff injury is the degeneration and tear of the rotator cuff muscle at the stop point of the humerus. It is a common sports injury and a common degenerative injury for manual workers and middle-aged and elderly people. Its incidence increases with age . Its cliThe reason of rotator cuff injury limiting the movement of the shoulder joint was that it can lead to the shoulder kinematic change due to avoiding pain , in addiµ-opioid receptors in the spinal cord, while the high-frequency TENS (>50 Hz) can produce analgesic effects by activating acetylcholine and δ-opioid receptors in the spinal cord [One of the main hypotheses for the analgesic mechanism of TENS is based on the gate-control theory of pain. Electrical stimulation of large-diameter peripheral fibers inhibits the transmission of pain pulses in the spinal dorsal horn and, therefore, prevents pain signals from being transmitted into the brain. Other theories point out that electrical stimulation activates the descending inhibitory pathway from rostral ventromedial medulla (RVM) to spinal cord and mediates various neurotransmitters . Among tnal cord . Howevernal cord , for exanal cord . In addinal cord , which, As the analgesic effect of acupuncture is widely recognized , the wayst and 5th treatment in the test group was significantly improved, indicating TENS on the wrist is effective in reducing pain due to rotator cuff injury.Compared with the control group, the VAS scores after the 1Regarding the improvement of the shoulder joint mobility, there was no significant difference in the ROM and CMs between the two groups. This may be explained by the limited treatment period of our study; according to the literature, the abduction mobility of the rotator cuff that is difficult to repair has increased by 34.4° after 5 months of exercise training , the ROMIn this study, we did not set up a sham TENS group because setting TENS at other frequencies or place electrodes at other locations may interfere with the results to a certain extent, and simply wearing the band without stimulation may not achieve the blind effect to the patients. We, therefore, used a randomized single-blind trial. In this study, the subjects did not know which group they were assigned to, and they were all told to treat with physical factors. The subjects of the two groups were assigned to different rooms and treated at different times. They had no contact with each other, which eliminate the placebo effect. This trial confirmed the analgesic effect of TENS on rotator cuff injury, but the difference and mechanism of pain relief between noxious pain and neuropathic pain remain unclear. Larger sample size and further basic and clinical research will be carried out in the future to explore the effect of electrical stimulation on muscles and nerves injury.This experiment innovatively used the WAA theory of TCM combined with TENS to develop an analgesic band, which is effective and safe, and provides the reference value for the application of this device in other sports injury diseases. This combined treatment also provides ideas for the research and development of integrating Chinese and Western medicine rehabilitation equipment. It also provides support for portable and wearable physical therapy equipment in postrehabilitation treatment, especially individualized training at home.


Polemonium caeruleum L. During a 5-year study in several populations of P. caeruleum , we assessed the degree of pollen limitation based on differences in seed set between open-pollinated (control) and hand-pollinated flowers. We analysed the effects of flower visitors, population size, and meteorological data on plant reproductive success and pollen limitation. Our study showed that pollen limitation rarely affected P. caeruleum populations, and was present mainly in small populations. Pollen limitation index was negatively affected by the size of population, visitation frequency of all insects, and when considering the visitation frequency of individual groups, also by honeybee visits. Seed production in control treatment was positively influenced by the population size, average monthly precipitation in June and visits of hoverflies, while visits of honeybees, average monthly temperature in September, and average monthly precipitation in August influenced seed production negatively. As generalist plant P. caeruleum can be pollinated by diverse insect groups, however, in small populations their main visitors, the honeybees and bumblebees, may be less attracted, eventually leading to the disappearance of these populations. In pollination of P. caeruleum managed honeybees may play a dual role: while they are the most frequent and efficient flower visitors, their presence decreases seed set in open-pollinated flowers, which is most probably related to efficient pollen collection by these insects.A vast majority of angiosperms are pollinated by animals, and a decline in the number and diversity of insects often affects plant reproduction through pollen limitation. This phenomenon may be particularly severe in rare plant species, whose populations are shrinking. Here, we examined the variability in factors shaping reproductive success and pollen limitation in red-listed  Mutualistic interactions between plants and their pollinators play pivotal roles in the functioning of terrestrial ecosystems and global food production. Almost 90% of angiosperms are pollinated by animals , mainly Insect-pollinated plants that reproduce exclusively by means of seeds may suffer from a decline in insect populations. As a consequence of a decline in insect diversity and abundance, plants may be subjected to pollen limitation, during which pollen grains of the lowest quantity and quality (i.e self or otherwise incompatible pollen) are delivered on the stigmas by insects, resulting in the production of fewer fruits or seeds than normally produced with adequate pollen receipt .Pollen limitation is among the main causes of decrease in seed and fruit production, which further affects the stability of plant populations . This phPolemonium caeruleum – a rare, red-listed species, whose some of populations are shrinking in its Polish range. In Poland, fragmentation of P. caeruleum populations, loss of pollinators, and presence of mixed mating systems (both self-compatible and self-incompatible populations) indicate that this species is adapting to the changing environment. According to a previous study on a single population of P. caeruleum, pollen limitation may affect even larger populations of this species  is one of the most immediate factors affecting pollen limitation  is a perennial plant distributed in the temperate zone of the Northern Hemisphere. Poland represents the southernmost point of its distribution range, with most populations distributed in the northeast of the country  from roads accessible by a 4WD car. The population size was defined as the number of flowering shoots estimated every year at the peak of the flowering season , two occurred in forests or in their immediate vicinity (KOP and SIE), one occurred in a fen (ROS), and one occurred on a peninsula surrounded by sedgelands and a lake SPN; . Of thesP. caeruleum and spatiotemporal variations in this phenomenon, if any, we performed supplementary pollination experiments in all populations. During 2014–2018, at the peak of flowering (June to July in Poland), we randomly selected and marked approximately 40–50 flowers with receptive (open) stigmas from different individuals in each population. There were fewer experimental flowers in smaller populations (<100 flowering shoots). Half of the marked flowers were left for open pollination, and the rest were hand-pollinated with pollen obtained from another individual growing at a minimum distance of 3 m. Hand pollination was performed by brushing the dehisced anthers against the stigma using tweezers. The procedure was continued until the stigma was covered with pollen.To assess the extent to which pollen limits seed production in At 4–5 weeks after pollination, mature fruits were collected, and seeds were counted under a stereomicroscope. Empty seeds (aborted seeds) were excluded from the analysis. Depending on the year and population, we noted the different degree of fruit damage caused by herbivores. In some populations, we could collect almost all experimental fruits, while in others, only 30% of the fruits were undamaged. Damaged fruits and seeds were excluded from the analysis.The pollen limitation (PL) index – a measure of the magnitude of pollen limitation – was calculated using the following formula:where Ps is the number of seeds from the hand-pollination treatment, Po is the number of seeds from the control treatment, and Pmax is the larger of the two values .The PL index was calculated for each population in a given year; thus, the values are always expressed at the population level. The PL index should range from zero, when both treatments produce the same number of seeds, to one, when natural pollination (control) does not produce seeds (complete pollen limitation). In the present study, however, in 23 of the 56 cases, the PL index was below zero, and we decided to include the negative values in further analysis, as we assumed that raising only the negative values to zero will reduce the reliability of the data.P. caeruleum populations, we performed observations of insect activity on flowers. During 2015–2018, we recorded insect activity simultaneously with the experiments set up to assess pollen limitation. To determine the frequency of insect visitation to flowers, we applied the method described by −1·population−1·year−1) in each population. Observations were recorded from 10.00 to 16.00 h (peak pollinator activity) under appropriate weather conditions; we avoided recording on rainy and windy days. In the laboratory, each insect recorded visiting a flower was counted and classified into the following groups: (i) honeybees (Apis mellifera), (ii) bumblebees (Bombus spp.), (iii) solitary bees, (iv) hoverflies (Syrphidae), (v) other flies (other Diptera), (vi) butterflies (Lepidoptera), (vii) beetles (Coleoptera), and (viii) others . We only considered insects that touched the flower sex organs as potential pollinators. The frequency of insect visitation was calculated per census (15 min) relative to the number of inflorescences in a recorded patch.To assess the assemblage composition of insects that visited To determine the effects of meteorological conditions on seed production and the PL index, we collected meteorological data, including mean monthly precipitation and ambient temperature, from the nearest weather station (Institute of Meteorology and Water Management).We used R 4.0.3 for data analyses. First, data were assessed for normality (Shapiro–Wilk test) and transformed when necessary and possible. To determine the differences in seed production and frequency of insect visitation to flowers across populations and years, we applied two-way ordinal ANOVA using the “clm” function in the “ordinal” package, followed by the “Anova” function in the “car” package, because the assumption of data normality for parametric tests was not met, even when the data were appropriately transformed.To determine the significance of differences in seed set between hand-pollinated and naturally pollinated flowers among populations in a given year , we applied a nonparametric Mann–Whitney U-test.r ≥ |0.7|)   followed≥ |0.7|) . FinallyGeneralised linear mixed model (GLMM) was used to evaluate the effects of the frequency of visitation by specific insect groups and meteorological variables on seed production in control treatment. In the model log-transformed population size, the mean frequency of visits by specific insect groups, and temperature and precipitation in selected months were included as the fixed effects and population was included as the random effect. The effect of year was not included in the model, due to near-zero variance and negligible role of the random effect of the year in relation to the random effect of the population.During the selection of the variables to GLMM, characterizing meteorological conditions, we avoided rejecting variables describing precipitation and temperature during months in which the seed experiments were set, as we found them more influential. Finally, all variables were centred and scaled to adopt a similar range of values to improve model performance. As the data on seed set included many zero values and were characterised by negative binomial distribution, we applied zero-inflated negative binomial GLMM using the “glmmTMB” function in the “glmmTMB” package , as it pFurthermore, we applied a linear mixed model using the “lmer” function in the “lme4” package to analyse the possible predictors affecting the PL index, as it was characterised by normal distribution. In two models, the calculated values of the PL index for each population in each year were combined with the (i) average frequency of insect groups visiting flowers and (ii) average monthly meteorological variables for each month, including population and year as the random effects. As zero models in both cases were characterised by the lowest AIC value, we averaged the models. For this purpose, we compared the AICc values of the candidate models, and averaged those including factors with ΔAICc <2 . Finally, only one factor was included in each model: frequency of visits by honeybees and temperature in October  to a normal distribution by adding 0.5% to each score, followed by log-transformation.2 = 803.70, df = 14, p < 0.001 and χ2 = 798.79, df = 4, p < 0.001, respectively) and hand-pollinated flowers .The number of seeds produced differed among populations and years in both control  and years  per inflorescence. The frequency of insect visits significantly differed among populations  and in the population in the northeast (DRO: 15.0°C). In contrast, the lowest temperatures were recorded in populations in the north of the country .Regarding precipitation, less pronounced trends were noted. The highest precipitation was recorded in two population in the north (SPN: 63.5 mm and BOB: 61.8 mm) and one population in the northeast (ZED: 61.0 mm), and the lowest precipitation was recorded in populations in the northeast . Across years, plants that produced seeds in 2018 were exposed to the highest temperatures, whereas plants that produced seeds in 2015 were exposed to the lowest precipitation.The number of flowering shoots varied among populations, and while this number remained relatively stable in most of the populations, there were marked fluctuations in some populations  during the study period .p = 0.014), the visitation frequency of hoverflies , and average precipitation in June (GLMM = 0.046). On the other hand, the visitation frequency of honeybees, precipitation in August of the previous year, and average temperature in September of the previous year  negatively affected seed production in control treatment  in the model explained most of the variation.The linear mixed models demonstrated that the PL index was negatively affected by the visitation frequency of honeybees  and posip = 0.038; p = 0.019; p = 0.962).Overall, the PL index was negatively affected by population size , control flowers produced significantly fewer seeds than hand-pollinated flowers. Among these populations, two were small  and one was large . The presence of pollen limitation in the large population may be the result of a sudden increase in the number of flowering individuals (probably as an effect of mowing) and consequent increase in the visitation frequency of insects, particularly honeybees, collecting large amounts of pollen, which may not left enough to pollination of other flowers (for details see next subsection “Flower visitors and their effects on seed set and pollen limitation”).In contrast, in three other populations, control flowers produced significantly more seeds than hand-pollinated flowers. Among these populations, two were small  and one was medium . In these three populations, insects likely treated the profusely hand-pollinated stigma as a food source. Additionally, apiaries are present close to the two small populations; and in BIA alone, honeybees were almost exclusive flower visitors and the frequency of their visitation was also high. The medium population was surrounded by a fen, with few other co-flowering plants; thus, stigmas covered with pollen may have been an attractive food source.P. caeruleum may reduce the probability of pollen limitation in populations, as has been shown in other plant species , which rather does not predispose them to a high degree of pollen limitation.The magnitude of pollen limitation depends, among other factors, on the plant mating system; as such, self-compatible plants and generalists are less prone to pollen limitation than self-incompatible plants and specialists . The gen species . The P. P. caeruleum is described as generalist. In this plant, the cup-shaped flowers, which offer nectar and pollen, are easily accessible to a wide spectrum of insects. In the present study, we recorded visits by diverse groups of pollinators. In 3 of the 15 study populations, the assemblages of insects visiting flowers have been previously analysed. According to P. caeruleum.The pollination system of P. caeruleum flowers, and together with bumblebees, they accounted for nearly 88% of total insect visits. Other groups of insects, although present in most populations, accounted for over 12% of all visits to flowers. Among these, flies (including hoverflies) were the largest contributors, whereas solitary bees, beetles, butterflies, and other insects contributed to a lesser extent. These trends support the previous assumption of P. caeruleum populations studied. Several groups of insects willingly used the food sources offered by P. caeruleum flowers, but only when honeybees and bumblebees were sparse.Considering data across all seasons and populations, honeybees were the most frequent visitors of P. caeruleum flowers is a consequence of the widespread introduction of colonies of these insects by beekeepers. Populations distant to settlements, such as those located in national parks , were characterised by a lower frequency of honeybees visits and a more diverse composition of flower visitors assemblage. This result suggests the negative effect of honeybees on the diversity of other pollinators visiting flowers, corroborating previous reports (The high proportion of honeybees (70.5%) among insects visiting  reports . Honeybe reports . The autP. caeruleum. This result is confirmed by previous findings that honeybees, in addition to bumblebees, are the key pollinator groups based on the pollen load carried by individuals and the frequency of their visitation  of hand-pollinated flowers, or stigma damage during the hand-pollination by the experimenters. Consistently, honeybees appear to play a dual role as insects that on the one hand may in fact reduce pollen limitation, as reported previously , all morphogroups are expected to serve as efficient pollinators.We observed that bees and, to a lesser degree, flies were the frequent visitors of us study  showed tP. caeruleum, the lack of specialisation in terms of pollination biology and the spatiotemporal variations in the composition of pollinator assemblages may result in high divergence in flower traits related to pollination. Our previous study on the chemistry of P. caeruleum nectar showed high variability in these traits among populations . Higher temperatures during autumn delay the development of cold hardiness  and may help in more effective protection of endangered plant species.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.JR and MZ conceived the study. JR, KR, MZ, EB, AW, BO, PM, IT, EJ, and MS assembled field data. JR and PM analysed the data. JR and MS visualised the data. MZ acquired funding. JR wrote the draft version of paper. All authors contributed to the article and approved the submitted version.The study was financially supported by the Polish National Science Centre (grant no. 2014/15/B/NZ8/00249 to MZ) and Faculty of Biology of the University of Warsaw (grant DSM no. 110134 to KR).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.