This study examined the association of whole-body composition and segmental bioimpedance variables with cold pattern (CP) in different sexes.n = 488) and a non-CP group (n = 179) by using an eight-item self-administered questionnaire. Seven body composition variables and three pairs of segmental bioimpedance variables for the upper and lower extremities, which were obtained from a segmental multifrequency bioimpedance analyzer, were employed to investigate their association with CP. Participants’ characteristics were first described. Then we compared the selected body composition and bioimpedance variables between the CP and non-CP groups. Finally, their association with CP was investigated using univariate and multivariate regression analyses. All analyses were performed separately for women and men.We assigned 667 older individuals to a CP group  of 1.72 (1.16–2.57), 1.69 (1.18–2.48), 0.60 (0.40–0.89), and 0.57 (0.39–0.82), respectively. However, these results did not emerge in men.Abnormal cellular water distribution and deterioration in body cell mass and/or cell strength are associated with CP prevalence, regardless of age, height, weight. These findings are similar in the upper and lower extremities and are more pronounced in women. The abovementioned patterns may be considered effective indicators for identifying CP in the older adult population. Cold pattern (CP) is a medical term commonly used to describe cold sensitive symptoms, including aversion to cold, feeling of cold on the extremities or body, feeling comfortable in warm conditions, having a pale face and colorless urine, and relevant characteristics of pulse and tongue . These cFrom traditional medicine perspective, CP is one of the two fundamental principles that are related to the nature of diseases that manifest from yin-yang transformations  and is aFrom modern medicine perspective, these symptoms reflect the subjective thermal sensations , thermoregulation , and behavioral adjustments  of a person when subjected to a given climatic stimulus . The humIn relation to the resting metabolic rate, the other body composition variables such as body weight, body mass index (BMI), skeletal muscle mass, intracellular water (ICM), extracellular water (ECM), and body water ratios have been investigated in relations with CP or cold hypersensitivity –20, 21. Evidently, information on body cellular health and its hydration status can be demonstrated based on resistance (R), reactance (Xc), and phase-angle (PA) variables obtained from the bioelectrical impedance analysis (BIA) technique. This technique, which is simple, portable, and inexpensive, can be used effectively to evaluate R, Xc, and PA and estimate body composition variables . The BIAIn addition, segmental BIA evaluates the body segmentally by considering the arms, legs, and trunk as five separate cylinders, and provides R, Xc, and PA measurements for each segment independently  . PreviouHowever, to our knowledge, only one relevant study in the community of Jeju Haenyeo has investigated and reported a significant association between the whole-body PA and non-CP with an odds ratio (OR) and 95% confidence interval (CI) of 2.40 (1.16–4.97) . Thus, tn = 18) and extreme results (sparse data points above or below three times the interquartile range were considered extreme points) for any parameter (n = 8) were excluded from the analysis. According to the principle of multifrequency bioelectrical impedance analysis, correct impedance measurements should have lower values for higher frequencies ; therefore, observations that did not follow this pattern were excluded (n = 91)  were recruited at Chonnam University Hospital . Individuals were excluded from the study if they met one of the following criteria: had obtained less than 3 years of education; had a medical history or ongoing acute or chronic illness that interfered with the intended study design such as neurological diseases, infections, or mental health instability; had a cognitive disorder; or had an abnormal skin condition at the location of the measurement probe. In addition to a general medical examination, the participants underwent a precise clinical assessment to obtain information on demographics and medical history. In the data preprocessing, participants who had non-random missing data ((n = 91) . All of (n = 91) . The stuA segmental multi-frequency BIA device was utilized to measure whole-body composition and segmental bioimpedance variables in this study  . The dev2). With regard to segmental bioimpedance variables, the R, Xc, and PA were measured separately for each body segment, including the two arms, two legs, and trunk. As peripheral regions such as the arm and leg have appreciable variances, whereas the vital central organs are strongly resisted by thermoregulatory mechanisms  and weight (kg) were automatically measured using the same BIA device to the nearest 1 mm and 100 g, respectively. BMI was then calculated , 362). WA list of eight questions related to cold syndromes was utilized to recognize CP and non-CP as described in Several factors were considered as covariates in the multivariate regression analysis model in this study. First, age can influence the change in body composition  and the t-test was used to compare the continuous variables between the two groups and Pearson’s chi-square test or Fisher’s exact test was used to check the independence of each categorical variable with CP and non-CP. Cohen’s d test was employed to examine the effect size of differences of each continuous variable between CP and non-CP groups.Information on the participants’ demographics and body composition parameters are summarized as the mean and standard deviation (SD) and median and range  for continuous variables, and as frequency and proportions for categorical variables in the CP and non-CP groups. As women are more susceptible to CP  and havep-value of less than 0.05 was considered statistically significant. R version 4.1.2  was used for all statistical analyses.Univariate and multivariate regression analyses were applied to investigate the association between CP and body composition variables using the estimated ORs and its 95% CI. Three models were constructed before and after controlling for covariates, including the crude model, first adjusted model, and the second adjusted model. In the crude model, no covariate was adjusted for. Age, systolic blood pressure, diastolic blood pressure, educational years, and osteoarthritis were included as covariates in the first adjusted model. The second adjusted model controlled for those in the first adjusted model, as well as height and weight. All of the continuous parameters were standardized to a mean of zero and a standard deviation (SD) of one before applying these regression analyses. Finally, a two-sample z-test was used to compare these associations between women and men. A 2 in both women and men, respectively.d = −0.38).d = −0.39 and −0.44, respectively) while Ri_Re_upper and Ri_Re_lower were higher in the CP group compared to the non-CP group (d = 0.40). In men, only Ri_Re_upper and PA_upper differed significantly between the CP and non-CP groups .With regard to the segmental bioimpedance variables, R ratios and PAs in the upper or lower extremities differed significantly between women with and without CP. Particularly, PA_upper and PA_lower were lower  ranging from 0.27 to 0.67 (0.16–0.89). One unit decrease in one of these variables corresponded to 33–73% increase the odds of CP. After adjusting for age and comorbidities, these associations remained significant at approximately the same magnitudes. Additionally, when including height and weight in the third model, the associated magnitudes achieved even greater values of OR (95% CI) and range from 0.14 to 0.59 (0.05–0.84). Furthermore, FM, which was not significantly associated with CP in the crude and first adjusted models, was positively associated with CP with OR (95% CI) of 4.21 (1.91–9.63). Among the segmental bioimpedance variables, the R ratios and PAs in the upper and lower extremities were significantly associated with CP in all three models, regardless of age, height, weight, and the other covariates. Particularly, in the last model, PA_upper and PA_lower produced negative associations with CP, with ORs (95% CI) of 0.60 (0.40–0.89) and 0.57 (0.39–0.82), Ri_Re_upper and Ri_Re_lower yielded positive associations with CP, with ORs (95% CI) of 1.72 (1.16–2.57) and 1.69 (1.18–2.48), respectively.In men, before adjusting for the covariates, FM, FFM, BCM, ICW, and ECW showed approximately similar negative associations with CP, with ORs (95% CI) ranging from 0.66 to 0.69 (0.47–0.98). One unit decrease in one of these variables corresponded to 31–34% increase the odds of having CP. When taking age and other covariates into account in the second model, these associations remained significant at a slightly greater magnitude of OR. However, none of them showed a statistically significant association with CP after incorporating height and weight in the last model. For the segmental bioimpedance variables, only Ri_Re_upper and PA_upper were shown to be linked to CP in the crude model. After controlling for covariates in the second and the last model, all the segmental variables failed to produce an association with CP.Differences in the associations with CP were reported between women and men . Among tIn this study, seven whole-body composition variables including FM, FFM, BCM, BMR_m, ICW, ECW, and ICW_ECW and three pairs of segmental bioimpedance variables consisting of R ratios, Xc results, and PAs in the upper and lower extremities were used to examine the associations with CP. Regarding the whole-body composition variables, we found that individuals with CP had significantly smaller body sizes, lesser body lean mass and water volume as expressed by a decrease in weight, FFM, BCM, ICW, and ECW than those with non-CP in both women and men. With respect to the segmental bioimpedance variables, we found significant increase in R ratios and decrease in PAs in the CP group compared with the non-CP group. After controlling for age, height, weight and the other covariates, these variables continued to significantly associate with the CP prevalence, especially in women. From previous studies, some of these variables have been investigated in people with cold hypersensitivity symptoms. Particularly, they reported significantly lower body lean mass indices, FM indices, or ICW_ECW ratios in the cold group when compared with the non-cold or heat group , 19, 21.First of all, in terms of the whole-body composition variables, we found significant reductions in BMI, FFM, and BCM in both women and men. In women, the lower BMI might be due to a decrease in FFM or BCM mainly, rather than a decline in FM as indicated by the significantly lower FFM and BCM and indifferent FM when compared with those of the non-CP participants . After cThe abovementioned observations between lower body lean mass and CP prevalence might be explained by the human thermoregulation and thermal equilibrium mechanisms. Evidently, our human body generates heat internally and maintains a core temperature of approximately 37°C, regardless of the environment . The heaIn addition, BMR which is highly correlated with the body lean mass variables was also decreased in the CP group , 57. In Another variable was included to investigate the changes in body volume in relation to the body surface area, named as the volume-to-body surface area, between the CP and non-CP groups. From the above discussions, the CP individuals have a smaller body size as expressed by the lower weight and height and lesser body lean mass; thus, they produce less heat compared to the non-CP individuals. As revealed by the significantly lower body volume per surface area, our results suggested that the CP individuals not only have a smaller body size but also a relatively higher body surface area compared to the non-CP individuals. According to Bergmann’s rule, individuals with small body volume and higher body surface area are unlikely to be able to withstand cold temperature due to the imbalance between the lesser heat production and greater heat loss , 60. TheBased on the water-related variables, we found that individuals with CP had a reduced total body water volume as indicated by the decrease in both ICW and ECW. ICW reflects the BCM, whereas, ECW is associated with the nutritional status of the individual , 62. NevRegarding the segmental bioimpedance variables, the R ratios and PAs in the upper and lower extremities differed significantly between the CP and non-CP groups, especially in women, after controlling for the covariates; however, the results were not significant in men. The R ratios were calculated to reflect the changes in ICW/ECW between the upper and lower extremities, such that its positive association with the CP incidence suggested a decrease in ICW compared to ECW , 36. ThiFrom the perspective of sex differences, the associations obtained from the whole-body composition and segmental bioimpedance variables with CP prevalence differed significantly between women and men. Previous studies have suggested that women have a lower metabolic heat production and greater insulative response during cold stress experiences than men . A smallAccording to age, thermal sensations in relation to CP susceptibility vary across different age groups . A commoWomen in the CP group had slightly lower systolic and diastolic blood pressure than those in the non-CP group. Similarly, although the difference did not reach the significant threshold of 0.05, men with CP exhibited a trend of lower systolic blood pressure than those without CP. Previous studies reported a lower level of blood pressure in the individuals with cold extremities syndromes, especially in women , 80. TheThis study provided an insight into how whole-body composition and segmental bioimpedance change in relation to CP incidence for different sexes. The results suggest that individuals with abnormal cellular water distribution, insufficient BCM and/or body cell strength might be susceptible to cold hypersensitivity symptoms. An increase in BCM or overall health status induced by a well-balanced diet and regular physical activities might help protect the body from CP.In this study, the prevalence of CP was approximately 73% 448/667), which is higher than the 60% proportion of cold hypersensitivity in the general population in Korea or Japan 48/667, w–42 may bThis study investigated the association between CP and seven whole-body compositions with three pairs of segmental bioimpedance variables. Lean mass was significantly lower, whereas FM was relatively higher in individuals with CP than in those without CP, regardless of age, height, weight, and other covariates. Correspondingly, body volume with respect to the surface area and BMR_m were lower in the CP group than in the non-CP group. Segmental bioimpedance analysis revealed that individuals with CP have abnormal cellular water distributions as well as a significantly lower BCM and/or cell membrane strength in both upper and lower extremities. These findings emerged only in women but not in men. The behaviors in these body lean and segmental bioimpedance variables may be considered as potential markers for identifying CP, especially in women.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by the Institutional Review Board of Chonnam National University Hospital . The patients/participants provided their written informed consent to participate in this study.DD analyzed the data and wrote the manuscript. KK handled the Institutional Review Board approval and managed the data. SK assisted in the data analysis. SL developed and validated the cold pattern identification questionnaire. KL took care of the data collection and curation. JK designed the study and wrote the manuscript. All authors revised and approved the contents of the manuscript, contributed to the article, and approved the submitted version.


Background: In 2014, the World Health Organization (WHO) launched the “post-2015 End TB strategy”, that aims to end the global tuberculosis (TB) epidemic by 2030. However, the COVID-19 pandemic has severely impacted global public health and the strict measures to control the coronavirus spread can affect the management of other diseases, such as TB. Herein, we aimed to assess the impact of the COVID-19 pandemic on the diagnosis of TB in Brazil, during 2020.Methods: We carried out an ecological and population-based study, using spatial analysis techniques. The variables used were the new cases of TB, pulmonary tuberculosis (PTB), and also baciloscopy-positive (BP) cases in Brazil between 2015 and 2020. The percentage of changes (% change) was calculated to verify if there was an increase or decrease of TB cases in 2020, along with time trend analyses given by Joinpoint regression model. Also, interrupted time series analyses were used to assess the trend of TB diagnosis before and after the onset of the COVID-19 in Brazil. Spatial distribution maps were elaborated, considering the % change of each Brazilian state.Findings: Data analyses showed a reduction in the diagnosis of TB (−8.3%) and PTB (−8.1%) in Brazil after the irruption of the COVID-19 pandemic. Likewise, 22 states depicted a reduction in TB diagnosis. An expressive reduction of BP cases (−17.1%) was also observed. Interestingly, interrupted time series analysis showed decline in TB and PTB diagnoses from March 2020. Spatial analyses revealed that all states had a progressive reduction of TB, PTB and PB cases, from March on, with the highest percentages of reduction in December (−100% to −75%).Interpretation: Taken together, our analyses demonstrated a reduction in TB diagnosis after the irruption of the COVID-19 pandemic in Brazil and its regions, signaling a serious impact on the WHO “End TB Strategy” global plan. The world is currently facing major public health challenges due to the pandemic caused by the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) . The firMycobacterium tuberculosis   . Importais (PTB) . Despiteis (PTB) .TB is a constant threat to public health and according to WHO estimates, approximately 10 million new TB cases are reported worldwide annually . RegardlBrazil is among the 22 countries with a high TB burden . In 2017The COVID-19 pandemic has led almost all countries to implement unprecedented public health measures . As a reAn ecological and population-based study was conducted using temporal and spatial analysis techniques, using the following data: new cases of TB, and pulmonary tuberculosis (PTB), and baciloscopy-positive (BP) cases, representing Alcohol-Acid Resistant Bacillus (AARB+), in Brazil, between 1 January 2015, and 31 December 2020. The period from 2015 to 2019 was used to obtain the expected values of the events analyzed, and the year 2020 was used for comparison purposes. The expected number of cases for 2020 was assessed by calculating the average TB cases during the last 5 years prior to the pandemic (2015–2019) and compared to those detected in 2020. Herewith, it was possible to evaluate the influence of the COVID-19 pandemic on the notification of TB in Brazil during 2020.http://portalsinan.saude.gov.br/dados-epidemiologicos-sinan). SINAN uses standardized forms by the Brazilian government to collect information on compulsory notifiable diseases as TB—this forms does not include personal information such as name and address , an open access data platform of the Brazilian Ministry of Health:  and one Federal District, comprising 5,570 municipalities. Additionally, the FU are grouped into five geographic regions . The estimated population was 211,755,692 inhabitants for the year 2020 . Notably, Brazil is 12th largest economy of the world, with an estimated gross domestic product (GDP) of US$ 1.434 trillion for 2021. Notwithstanding, the country exhibits serious social inequalities, as people living in extreme poverty, illiteracy, household clusters, and areas with no access to safe-drinking water and sewage system, mainly in slums . Hence, Brazil is endemic for many neglected diseases as Chagas disease  was calculated based on the following variables: 1) new TB cases; 2) new PTB cases; 3) baciloscopy-positive cases.The % change was primarily designed to assess disparities in the mortality rate of different health problems . Howeverommended .® software 2017 (©Microsoft) was used for % change analyses and graphs elaboration.The results are expressed as percentages: 1) positive values indicate an increase; 2) and negative values indicate a decrease in the number of cases compared to the expected values . The % cp-value < 0.05 and their CI 95% did not include zero. Importantly, a positive and significant MCP values indicate an increasing trend; alternatively, a negative and significant MPC indicates a decreasing trend; and non-significant trends are described as stable, regardless of MPC values  new TB cases; 2) new PTB cases; and 3) baciloscopy-positive cases in Brazil and its regions, between 2015 and 2020. The Monte Carlo permutation test was applied to select the best model for inflection points (applying 999 permutations), considering the highest residue determination coefficient (R2). Firstly, a temporal trend of all variables between 2015 and 2019 was elaborated, to verify the behavior of TB in Brazil and its regions before the COVID-19 pandemic. Afterwards, the data of the year 2020 was added and a new time trend analysis was done to identify the impact of the pandemic on TB diagnosis. Furthermore, to describe the temporal trends, we calculated the monthly percentage change (MPC) and its respective confidence interval (CI 95%) . Time trC values .We conducted an interrupted time series analyses to assess whether the TB diagnosis in 2020 in Brazil, after the irruption of the COVID-19, differ from the trend between 2015 and 2019. The variables evaluated were the monthly detection of TB, PTB, and baciloscopy-positive. The intervention model was the onset of the COVID-19 pandemic in Brazil in March 2020. First, the graphs of residue and sample and partial autocorrelation function  were used to identify autocorrelation in the residue and properties of stationarity and normality, to select the most appropriate and statistically parsimonious models . Thereafhttps://portaldemapas.ibge.gov.br/portal.php#homepage, was used.Choropleth maps showing the spatial distribution of the % change values per state, during the months of 2020, were elaborated. The cartographic base of Brazil, divided by regions and states, made available by the IBGE on address The following parameters were used to create the maps: 1) the % change related to new TB cases per month; 2) % change in the number of PTB cases per month; 3) and % change in the number of baciloscopy-positive cases per month. Furthermore, choropleth maps were stratified into nine categories of equal intervals, according to P-score (positive or negative) percentages: −100 to −75%; −75 to 50%; −50 to −25%; −25 to −0.1%; 0%; 0.1 to 25%; 25 to 50%; 50 to 75%; >75%. QGis software version 3.18.3  was used to prepare the maps.In Brazil, 83,678 cases of TB were reported in 2020. Nevertheless, according to the average number of cases in the last 5 years (2015–2019), approximately 91,225 cases were expected in 2020, depicting a reduction of 7,547 cases (% change: −8.3%) . LikewisAs for pulmonary tuberculosis, 70,855 cases were reported in 2020, in contrast to the 77,090 estimated cases for this period  . SimilarInterestingly, a marked reduction in the number of baciloscopy-positive (AARB+) cases was noted in Brazil during 2020. Considering the average of the last 5 years (2015–2019), it was estimated 45,898 AARB+ cases. However, 38,027 AARB+ were reported in SINAN, representing a reduction of 7,871 AARB+ cases (−17.1%) . LikewisFrom March to December 2020, the % change curve showed a progressive reduction in monthly notifications of new TB cases in all Brazilian regions after the beginning of the pandemic in the country . The NorLikewise, there was a reduction in the number of baciloscopy-positive cases in all Brazilian regions . From Ma). Besides, time trend analyses in the years prior to the COVID-19 pandemic (2015–2019) confirmed increasing trends in TB and PTB diagnosis in Brazil  and across all regions. The North, Northeast and South regions had the highest MPC. Regarding the baciloscopy-positive cases, there was a stable trend in Brazil, but an increasing trend in the North and Central-West regions. Subsequently, the interrupted time series analysis was applied to verify whether the irruption of the COVID-19 affected the diagnosis of TB in Brazil in 2020. Corroborating the joinpoint analyses, we observed a not stationary and a decreasing trend in the diagnosis of TB in Brazil  increased from 2015 to 2019 in Brazil and all the regions. Impressively, all coefficients in 2020 were lower than the ones reported in 2015 . Besiden = 23) showed negative % changes in December, and the highest reduction  were located in five states.Regarding the spatial distribution of new TB cases , from MaTo the best of our knowledge, this is the first study to assess the impact of the COVID-19 pandemic in the number of TB cases in Brazil. The performed analyses showed a reduction in the notifications of TB (−8.3%), PTB (−8.1%), and baciloscopy-positive (−17.1%) cases in Brazil after the onset of COVID-19 pandemic. Likewise, this reduction was also observed in all regions and most of Brazilian states. Importantly, time trend analyses showed a progressive increasing number of new TB and PTB cases in the years prior the pandemic, becoming stable in 2020. Taken together, the compiled data demonstrate the negative effect that the pandemic can cause on the WHO “End TB strategy” program in a country considered a priority for the control of the disease in the world, pointing out an insidious scenario regarding the evolution and dissemination of tuberculosis in the next years.It is known that TB mainly affects poor and most vulnerable populations around the world, aggravating current inequalities . DespiteNotably, the irruption of the COVID-19 pandemic has caused several health problems globally, but higher impacts are seen in specific countries who had a worse coping with the disease, such as Brazil . ConsideThe % change curve demonstrated a progressive reduction in monthly notifications of new TB and PTB cases and also baciloscopy-positive cases in all regions throughout the country after the onset of the pandemic in Brazil (from March to December 2020). TB is not a seasonal disease and can affect different age groups, so new cases are expected during the whole year and in all states of Brazil. Despite being a mandatory notifiable disease in Brazil, the obligation of immediate notification is probably being compromised by the COVID-19. As expected, the negative effects of the pandemic on the diagnosis of other diseases are being reported globally .Also, due to the COVID-19 pandemic, the Brazilian health system directed its efforts to face the spread of the virus throughout the country, by building temporary hospitals and expanding the number of intensive care units . AdditioIn this sense, time trend analyses demonstrate that TB diagnosis in Brazil was increasing until the year before the pandemic. Probably, due to the onset of the pandemic and the changes in the routine of health services, such as the relocation of health professionals to face COVID-19 and the reduction in the care provided to patients with other diseases , there wM. tuberculosis transmission to close contacts  increased together with the case numbers reported in 2014 . NonetheTB and COVID-19 are both airborne infectious diseases that primarily attack the lungs. They have similar symptoms such as cough, fever, and dyspnea. Hence, differential diagnosis between COVID-19 and TB should be carefully conducted, observing all clinical characteristics , but eveWHO conducted a survey among officials that worked at different Ministries of Health, located in a total of 165 countries, and reported that after the first 3 months of the COVID-19 pandemic, 42% of countries reported partial disruptions in TB case detection and treatment . LikewisEstimates of the impact of the COVID-19 pandemic on TB care suggest that a 3-month lockdown and a 10-month protracted recovery could result in 6.3 million additional TB cases between 2020 and 2025 . More imImportantly, the intensive use of face masks and home confinement may also have reduced TB transmission during the pandemic . ConversThis study has some limitations that deserve to be mentioned. First, an ecological study using secondary data was conducted, therefore, there is a risk of bias, mainly regarding to the quality of information. Additionally, TB diagnosis may be underreported in some states, or even a registration delay in the SINAN might be present. Also, data on COVID-19 may not be accurately notified, for instance there might be registration delays altering the diagnosis date.Taken together, our analyses demonstrated that the emergence of the COVID-19 pandemic negatively impacted the diagnosis of TB in Brazil. Time trend analyses showed an increasing trend in disease diagnosis between 2015 and 2019. However, trends became stable after adding the data of 2020, the COVID-19 pandemic year. Hence, the progress made over decades of efforts to fight TB, trough the National Plan for Ending Tuberculosis, a disease considered a public health problem in Brazil, can be compromised, putting at risk the global goal of “End TB strategy”. Hereupon, public health authorities and police makers should implement emergency actions to control TB.It is essential to train and prepare health care professionals, especially from basic health units, in order to accurate detect cases, to rapid commencement of and adherence to treatment and also to active-case finding, even in adverse times such as the pandemic. Priority should be given to the poorest populations and risk groups , that are usually more affected by the disease. Notably, the pandemic is already showing a greater impact on areas of greater social vulnerability, and consequences can be disastrous for other diseases such as TB. In this context, global support must be provided to enable the countries and communities most affected by TB to respond to the pandemic, ensuring that TB services are maintained uninterrupted.


There are individual differences in rehabilitation after cochlear implantation that can be explained by brain plasticity. However, from the perspective of brain networks, the effect of implantation age on brain plasticity is unclear. The present study investigated electroencephalography functional networks in the resting state, including eyes-closed and eyes-open conditions, in 31 children with early cochlear implantation, 24 children with late cochlear implantation, and 29 children with normal hearing. Resting-state functional connectivity was measured with phase lag index, and we investigated the connectivity between the sensory regions for each frequency band. Network topology was examined using minimum spanning tree to obtain the network backbone characteristics. The results showed stronger connectivity between auditory and visual regions but reduced global network efficiency in children with late cochlear implantation in the theta and alpha bands. Significant correlations were observed between functional backbone characteristics and speech perception scores in children with cochlear implantation. Collectively, these results reveal an important effect of implantation age on the extent of brain plasticity from a network perspective and indicate that characteristics of the brain network can reflect the extent of rehabilitation of children with cochlear implantation. The cochlear implant (CI) is used worldwide as a rehabilitation method for children and adults with severe hearing loss , 2. HoweBrain plasticity (BP) is an intrinsic, general and important property of the brain , which rPrevious studies have mainly measured the BP in specific regions  of CI users by manipulating experimental stimuli or tasks. Studies have consistently found that visual stimuli activated the auditory cortex, and the auditory cortex activation induced by visual information was related to language processing –32. AlthTask-induced neural activity can often provide evidence of BP in CI users. However, as these CI users are usually very young, specific tasks may not be appropriate for them, which means that it is not easy to carry out relevant research. Fortunately, previous studies have shown that in addition to task-evoked neural activity, spontaneous neural activity in the resting state can also reveal intrinsic brain functional structures that reflect behavioral patterns –43. FurtIn electroencephalography (EEG) studies, the acquisition of resting-state data typically includes eyes-closed (EC) and eyes-open (EO) conditions. These two conditions are thought to reflect different states of brain activity , 48. SpeA brain network usually consists of a set of nodes  and links  , 55. AltThere is accumulating evidence that MST analysis can capture subtle changes in brain networks during human development , 60, andIn the present study, EEG resting state data were collected from children with early CI reception (eCI) (age of implantation <3.5 years old), children with late CI reception (lCI) (age of implantation > 3.5 years), and NH children in both EO and EC conditions. Phase lag index (PLI) and MST analysis were used to calculate connectivity strength and brain network topology, respectively, and we compared the differences in these metrics among the three groups in different resting states. Finally, the MST metrics were correlated with speech perception scores. These analyses attempted to answer the questions of how BP is reflected in network characteristics in eCI and lCI children, and how brain network characteristics are related to speech rehabilitation outcomes of CI users. Specifically, we focused on the following aspects.(1) The effects of implantation age on the resting-state functional connectivity of brain regions. We examined the differences among groups in terms of the PLI values of auditory and visual regions, and auditory and parietal regions in two resting states, respectively.(2) The effects of implantation age on topological characteristics of brain networks. We investigated the differences among groups in the metrics describing brain networks in different resting states, which reflect the efficiency of information transfer. (3) The relationships between brain network metrics and speech perception scores. (4) Whether brain network characteristics of three groups differed under the two resting-state conditions.To summarize, if implantation age had an effect on the extent of BP, then we would expect to observe that the connectivity patterns and network characteristics of the eCI children were similar to those of NH children; if not, there would be no difference in brain network characteristics between eCI children and lCI children. Finally, if speech perception scores were correlated with network characteristics, then the metrics derived from brain networks using MST analysis could reflect rehabilitation.F = 4.876, p = 0.010, η2 = 0.107]. The NH group had higher IQ scores than the lCI group (p = 0.008), but there was no significant difference between the NH group and eCI group (p = 0.672), or the eCI group and lCI group (p = 0.150). There was no significant difference in duration of rehabilitation between the eCI and lCI groups . There were significant differences in age between the eCI and lCI groups , the lCI group was older than the eCI group (p = 0.017), and the lCI group was marginally older than the NH group (p = 0.054). Nonverbal IQ and age were used as the covariates for further analysis. Written parental informed consent was obtained for all the participants. All participants were recruited and tested in accordance with the Human Research Ethics Committee for Non-Clinical Faculties of South China Normal University (reference no. 158) and the Ethics Committee of Sun Yat-sen Memorial Hospital of Sun Yat-sen University.Fifty-five prelingually deafened Mandarin-speaking children with CIs who had sensorineural hearing loss were recruited. Their implants were on the right side. Among them, 31 had received their implants before 3.5 years old, whereas the other 24 had received their implants after 3.5 years old. Hence, these children were divided into two groups: eCI group (age of implantation <3.5 years old) and lCI group (age of implantation >3.5 years old). Another 29 Mandarin-speaking children with no history of hearing loss or neurological disorders were recruited as the NH group. Each participant completed speech perception tests including tone, vowel, and consonant discrimination. All materials were prepared in reference to Auditory Function Evaluation Criteria and Methods . All soukΩ during the recording. In previous studies using this EGI system, electrode impedances were kept below 50 or 60 kΩ . All children were seated in a chair where the height and seating position could be adjusted to give comfortable support. In the EO condition, participants were requested to focus on a black fixation on a gray background to minimize glare on the screen. The impedance of channels was kept below 40 or 60 kΩ , 67, so We calculated the mean accuracy for the tone, vowel, and consonant perception tests. Analysis of variance (ANOVA) was used with mean accuracy as the dependent variable, with group  as a between-subject factor.The continuous EEG data were analyzed offline using EEGLAB 2019b, a MATLAB-based  open toolbox  for proctk) by the following equation: PLI = | < sign[sin(Δϕ(tk))] > | , where “sign” indicates the signum function. The PLI ranges between 0 and 1. A PLI value of 0 indicates no coupling or coupling with a phase difference centered around zero (mod π), whereas a PLI value of 1 indicates perfect phase locking at a value of Δϕ different from zero (mod π) (The phase lage index (PLI) was used to determine the functional connectivity between all pairs of 120 electrodes for each epoch and each frequency band. The PLI is a measure of the asymmetry of the distribution of instantaneous phase differences, determined using the Hilbert transformation, between two signals . The PLI (mod π) , 46. PLI (mod π) . In the In addition, we characterized the average PLI between the sets of electrodes in each group. For the analysis of connectivity strength, electrodes were divided into several regions of interests: left temporal region  ; right tnodes1). For each epoch, the MST was constructed using Kruskal algorithm  was constructed from the matrix containing the PLI values for each epoch. An MST is a unique subgraph based on a weighted matrix that connects all nodes (120 EEG electrodes were used in the present study) of the network without any loops or cycles . Thus, tlgorithm , which hlgorithm , 61. Thed a loop . TherefoMST analysis provides information about the topological characteristics of the tree , 58, whip > 0.05 was guaranteed. After obtaining the interaction results, we performed post-hoc tests with Bonferroni correction of p−values. Overall, the results obtained from the non-parametric analysis were similar to those from the parametric analysis, with the pattern of significant results remaining the same. Finally, correlation analyses were performed to determine any associations between behavioral scores and network metrics that differed among groups. Permutation tests were also performed on the correlations, and the Bonferroni-corrected p-values are reported.The PLI and MST metrics were log-transformed in an attempt to to obtain the statistical assumption of a normal distribution. To further verify that the data conformed to a normal distribution, the Shapiro-Wilk test was conducted separately for different metrics in each frequency band of each subject group. The results of the Shapiro-Wilk tests revealed that a few metrics did not conform to a normal distribution, including strength (mean), strength (maximum), and degree in the theta band; diameter and radius in the alpha band; and PLI values in the connection between right occipital region and right temporal region in the beta band. Therefore, for these non-normally distributed data, non-parametric repeated measures ANOVA was conducted using the Aligned Rank Transform Tool (ARTool) , 79, wheF = 52.69, p < 0.001, η2 = 0.604], with the NH group having higher scores than the eCI and lCI groups (ps < 0.001), and the eCI group having higher scores than the lCI group (p < 0.001) (see The results are reported in 001) see .F = 4.076, p = 0.021, η2 = 0.094] and theta band . Compared with the lCI group, the NH group showed weaker connectivity strength in the delta band (p < 0.001), whereas eCI and NH showed weaker strength in the theta band (ps < 0.003). For the right temporal and the right occipital cortex, marginally significant interactions were found in the delta band  and theta band . Compared with the lCI group, NH showed weaker strength in the delta band (p = 0.011), and eCI showed weaker strength in the theta band (p = 0.011). There were no other statistically significant group differences in the temporal cortex and parietal cortex for any of the frequency bands  = 5.070, p = 0.008, η2 = 0.114], diameter , kappa , Th , and CC median ; all differences among groups were in the EC condition. More specifically, compared with the lCI group, the NH and eCI groups had higher leaf (ps < 0.009), kappa (ps < 0.064), and Th (ps < 0.043) values and lower diameter (ps < 0.006). Moreover, the lCI group had a higher CC median than the eCI group (ps = 0.016).In the theta band, there were significant interactions for leaf , mean strength , degree , leaf , diameter , Th , and kappa ; differences among groups were only found in the EC condition. More specifically, compared with the lCI group, the NH group had higher max strength (p < 0.001), mean strength (p = 0.027), degree (p < 0.001), leaf (p < 0.001), Th (p < 0.001), and kappa (p < 0.001). In addition, compared with the lCI group, the eCI group had higher max strength (p = 0.027), degree (p = 0.017), leaf (p = 0.002), Th (p = 0.009), and kappa (p = 0.016). The NH group had higher max strength (p = 0.028) and degree (p = 0.043) than the eCI group. The lCI group had larger diameter than the eCI (p = 0.003) and NH (p < 0.001) groups. Notably, in the NH group, differences between the EC and EO conditions were found (ps < 0.006). Compared with the EO condition, the EC condition in the NH group had larger max strength (p < 0.001), mean strength (p < 0.001), degree (p < 0.001), leaf (p = 0.006), kappa (p < 0.001), and Th (p = 0.005), and lower diameter (p = 0.004).In the alpha band, there were significant interactions for max strength [Finally, for the delta and beta bands, there were no significant interactions or main effects of group or condition.r = 0.53, p = 0.032) and lCI group , a significant positive correlation with leaf in the eCI group , and a trend of negative correlation with diameter in the eCI group . However, we did not find a significant correlation for the NH group (ps > 0.099) in any frequency band.Correlation analysis was performed to examine the associations between functional backbone characteristics in the EC condition and the accuracy of speech perception (ACC). Speech perception was related to MST characteristics in the theta band; the most pronounced effects were found in the CI groups . More spThe aim of the present study was to examine the effects of implantation age on the extent of BP from a brain network perspective using EEG resting states, and to further investigate the relationships between network characteristics and speech perception scores. Inspired by previous studies, PLI and MST analysis were used to calculate the resting-state functional connectivity and network topology characteristics, respectively. It was found that the connectivity between the occipital and temporal regions was stronger in lCI children than in eCI children and NH children. In addition, the lCI group had lower information transfer efficiency than the NH group, whereas the efficiency of the eCI group was similar to that of the NH group. However, the effect of group differences was only found in the EC condition. More importantly, correlations were found between some MST metrics and speech perception scores.The present study found enhanced resting-state functional connectivity between visual and auditory regions in lCI children compared with both eCI children and NH children. These results are similar to those of previous studies, in which new and stronger connectivity between visual and auditory areas was found in deaf animals –82, and However, no group differences were found in the resting-state functional connectivity of the temporal and parietal regions in this study. Previous studies have reported that enhanced functional connectivity between auditory and parietal regions might be related to sign language processing , 86; thiMore importantly, based on the results of MST analysis, differences were found between the characteristics of eCI children and those of lCI children in the EC condition. Moreover, lCI children showed reduced global efficiency compared with other groups. Specifically, higher diameter values and lower leaf, kappa, Th, and degree values were found in lCI children compared with eCI children and NH children. For each metric, a smaller diameter indicates lower connectivity strength between brain network nodes ; a largeThe results of the MST analysis also revealed that the brain network of eCI group had higher integration than that of the lCI group. Although some metrics in the early implantation group were lower than those in the NH group , the overall results showed that the brain network characteristics of the eCI group were similar to those of the NH group. Subjects in our study were prelingually CI children, and there was no difference in duration of rehabilitation as we controlled the age factor. Therefore, it is reasonable to assume that the group effects stemmed from implantation age, which influenced the extent of BP, as reflected in the characteristics of the brain network.These results demonstrate that auditory deprivation has a long lasting effect on brain networks, mainly resulting in reduced brain network efficiency in children with CI , 88, 89.Notably, the present study only found differences in brain network characteristics among groups in the theta and alpha frequency bands, suggesting that BP is not reflected in all frequency bands. We therefore hypothesized that the effects of auditory deprivation on BP would also be limited to specific frequency bands. A study found that the effects of auditory deprivation were only evident in the alpha and beta frequency bands . This miThe results of speech perception tests showed that NH children performed better than those in the two CI groups. Furthermore, the eCI group performed better than the lCI group. These results suggest that implantation age has an important role, consistent with previous behavioral results –100.Interestingly, correlations were found between MST metrics and speech perception in the theta band in children with CI. Specifically, speech perception scores were positively correlated with kappa and leaf number and negatively correlated with diameter; this suggests that in CI children, lower efficiency of brain networks was associated with worse speech perception scores. The integration of brain networks is often related to efficiency of information transfer . DeficitHowever, the present study did not find any correlations in the alpha band, probably because neural oscillations in the alpha band are associated with working memory and visual attention . As audiIn the present study, differences between the EC and EO conditions were found only in the NH group, not in the eCI and lCI groups. In the NH group, degree, kappa, and Th in the alpha band were higher whereas diameter was lower in the EC condition than in the EO condition. These results are consistent with those of previous studies that found less integration in the EO condition and more integration in the EC condition , 54, 104However, the present study did not find any differences in MST metrics between the EC and EO conditions in CI children. This is inconsistent with a previous study, where increased differences in functional network topology were found between the EC and EO conditions under the influence of auditory deprivation . We specThe present study had several limitations. First, there are different aspects of language processing, such as phonological processing, lexical processing, and sentence processing. However, this study only focused on tones, vowels, and consonants; it did not fully examine the language skills of CI children. Therefore, future studies need to investigate the associations between MST metrics and different elements of the language hierarchy to better understand the effects of implantation age. Second, although this study examined CI children speech perception, it did not explore how speech perception could be improved. In future studies, the effects of different training methods on speech perception could be investigated. Third, in the present study, we focused primarily on resting-state functional connectivity between the auditory and visual regions and neglected other potentially meaningful inter-regional connections. Therefore, to better understand the impact of age at implantation on brain connectivity, a comprehensive and careful analysis of inter-regional connectivity will be necessary in the future. Fourth, EEG network modularity is also a proxy of cognitive plasticity, and is considered to be a reliable neural marker of the development of language . This seUsing resting-state EEG data and MST analysis, the present study investigated the effect of age of CI reception on BP, and the associations between brain network characteristics and speech perception scores. The results showed that the eCI group had higher brain network efficiency compared with the lCI group. The findings demonstrated the significance of implantation age in terms of various metrics derived from MST analysis. In addition, the correlations between network characteristics and speech perception scores suggest that brain network metrics can reflect the extent of rehabilitation after reception of CI.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 the Ethics Committee of Sun Yat-sen University and South China Normal University.KL and SW contributed to conception and design of the study and wrote the manuscript. KL, YZ, JW, and JL performed the experiments. KL and ML performed the data analyzes. SW, JL, and ML provided supervision and funding supports. All authors contributed to the article and approved the submitted version.This work was supported by the project of the National Natural Science Foundation of China  provides personnel and materials support and the publication fee, the project of the National Natural Science Foundation of China Youth Science Foundation  for instruments, and the Youth Science Foundation Project of the National Natural Science Foundation of China  provides the support of personnel and sites.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.


Neuromuscular training and strength training have been recommended in CAI management interventions. However, there are contradictory findings on results when comparing neuromuscular training, strength training, and the control group. The objective of this study was to compare the effectiveness of 8 weeks of neuromuscular intervention training, strength training, and no intervention in a sporting population with reported CAI. (2) Methods: Sixty-seven athletes with CAI were randomly assigned to a neuromuscular training group (NG), strength training group (SG), or control group (CG). Participants completed 8 weeks of neuromuscular training (a combination of static and dynamic exercises), strength training (resistance band exercises), or no training. Outcome measures were assessed at baseline and after 8 weeks and included selfs-reported instability feeling (CAIT), dynamic balance (SEBT), ankle dorsiflexion range of motion (WBLT), and functional status (FAAM and FAAM-SPORT). (3) Results: There were significant differences between strength and control groups in the posteromedial direction of SEBT, FAAM, and FAAM-SPORT after 8 weeks of intervention. (4) Conclusions: Neuromuscular training and strength training based on resistance bands exercises showed significant improvements in ankle dorsiflexion, subjective feeling of instability, functional status, and dynamic balance in patients with CAI. An ankle sprain is the major ankle injury in sport, with an incidence of 76.7% of ankle injuries  and an eAn initial ankle sprain is the principal risk factor for developing chronic ankle instability (CAI), with a prevalence ranging from 0% to 73% ,4. The tn = 13) and length of intervention (6 weeks). Thus, a follow-up study with a larger sample size and longer duration of the intervention could be a benefit in determining the superiority between neuromuscular training (NTP) and strength-training protocols (STP).A large body of evidence suggests that neuromuscular training or strength training is an effective intervention to improve postural control ,10, funcWe hypothesized that both intervention groups would obtain significant improvements, with a possible superiority of NTP over STP because it is an integral treatment that includes more elements susceptible to being affected in patients with CAI. Theoretically, patients with CAI may present with a unique set of symptoms resulting from the interactions of the pathomechanics, sensory–perceptual, and motor-behavioral impairments that are also influenced by personal and environmental factors . In ordeParticipants in a sporting population between 18 and 60 years were recruited via social media, posters in different university locations, and by word of mouth. They were enrolled if they met the inclusion criteria. Inclusion criteria were consistent with recommendations made by International Ankle Consortium  and wereEnrolled participants were randomly assigned to one of 3 groups: neuromuscular training group (NG), strength training group (SG), and control (no intervention) group (CG). The intervention sequence was randomized by an independent investigator who used a random number generator and sealed the treatment sequence in opaque envelopes which were opened before performing the first intervention.This study was approved by the University of Jaen’s Human Ethical Committee and registered as NCT05250739 on Clinicaltrial.gov. The intervention was conducted following the Declaration of Helsinki, good clinical practices, and applicable laws and regulations and met the CONSORT guidelines standards . We obtaAll participants underwent eight weeks of an intervention program in their assigned groups. Participants allocated to experimental groups were instructed to be focused on maintaining a proper and controlled form during the exercise performance. Although the pain was not initially included as a study variable, participants were told to avoid pain during exercise performance by adapting the level of difficulty of the exercises.Participants in this group received no intervention during the 8 weeks.Patients allocated to NG completed 16 training sessions divided into 8 weeks. The intervention consisted of 6 neuromuscular exercises, increasing the difficulty progressively as the participants controlled the execution, and they did not start the next progression until performing a complete circuit in the level before with proficiency . ParticiParticipants in this group performed ankle exercises with resistance bands . In ordeThe following outcomes were measured before and after 8 weeks of intervention.Participants completed the Spanish version of the CAIT , a validWe used FAAM scales for estimating self-reported ankle function. There are two subscales: FAAM-activities of daily living (ADL) and FAAM-sport (S), assessing self-reported ankle functions separately during daily and sports activities. FAAM is a valid outcome instrument for detecting self-reported functional deficits in patients with CAI .The premise of using SEBT is to determine if, while standing on the injured limb to maintain stability, a deficit is produced in the reaching distances, indicating a deficiency in postural control or balance that might be associated with the pathologic condition in the stance limb .The SEBT is valid and useful in demonstrating outcomes from neuromuscular and strengthening exercise interventions . In our There is strong evidence for good inter- and intra-clinician reliability of the WBLT to assess the Dorsiflexion Range Of Motion (DFROM) ,23. The n < 50). One-way analysis of variance (ANOVA) tests for continuous variables  and Kruskal–Wallis tests for categorical variables  were performed to examine baseline differences between three groups.All analyses were performed using IBM SPSS 24.0 statistical software . The Shapiro–Wilk test was employed to confirm normal distributions of continuous variables  was verified using the Levene test. If this hypothesis was verified, we used the HSD Tukey method. Otherwise, it was necessary to apply the Games–Howell test.p < 0.05.In order to assess within and between groups’ effect sizes, Cohen’s d effect sizes were calculated. The strength of effects was interpreted as weak (≤0.2), small (0.2 to 0.5), moderate (0.5 to 0.8), and large (>0.8) according to Cohen’s benchmarks . Alpha lA required number of 21 participants with CAI per group was estimated to ensure a power of 0.80 at a significance level of 95% based on a minimal detectable change of 4.28 cm in the posterolateral direction of SEBT , but 24 A total of 67 participants were enrolled in the study . No grouAs shown in p = 0.000), SEBT_PL (p = 0.003), FAAM-ADL (p = 0.001) and FAAM-SPORT (p = 0.000), were observed.As shown in p = 0.001) and between the strength group and the control group (p = 0.000). The 95% CI for NG vs. CG is , indicating that the mean SEBT-PM score in the neuromuscular group is higher than that of the control group, and the 95% CI for SG vs. CG is , indicating that the mean SEBT-PM score in the strength group is higher than that of the control group. Regarding post-intervention scores in SEBT-PL, significant differences were detected between the neuromuscular group and the control group (p = 0.031) and between the strength group and the control group (p = 0.003). The 95% CI for NG vs. CG is , indicating that the mean SEBT-PL score in the neuromuscular group is higher than that in the control group. The 95% CI for SG vs. CG is , indicating that the mean SEBT-PL score in the strength group is higher than that of the control group. In the FAAM-ADL, significant differences were detected between the neuromuscular group and the control group (p = 0.004) and between the strength group and the control group (p = 0.003). The 95% CI for NG vs. CG is , and  in SG vs. CG indicating mean scores in both intervention groups are higher than the control group. In the FAAM-SPORT, significant differences were detected between the neuromuscular group and the control group (p = 0.001) as well as the strength training group and the control group (p = 0.000) with a 95% CI for NG vs. CG of , indicating higher scores in the NG, and 95% CI for SG vs. CG , indicating in both cases higher scores in comparison with CG.Significant differences post-intervention were detected between the neuromuscular group and the control group (The present study aimed to determine the influence of neuromuscular training and strength training on functional status, subjective feeling of instability, dynamic balance, and ankle DFROM in patients with CAI. After the literature review, there was no consensus about the superiority of one intervention over another in this population group, and there was heterogeneity in the study population; thus, the objective of the study was to contribute to a better understanding of the management of CAI .Both neuromuscular training and strength training groups improved all variables, with no differences between groups on dynamic balance, functional status, subjective feeling of instability, and ankle DFROM. In contrast with previous research ,27,28,29d = 0.23. Wright et al. [The subjective feeling of instability is possibly the most common characteristic in those with CAI, and the influence on functional status and quality of life has been widely addressed ,18,26. NSelf-reported physical function is reduced in subjects with CAI and could be measured with FAAM-ADL and FAAM-SPORT to determine the influence of CAI in daily living activities as well as sport-related activities . Kim et The obtained results in this manuscript showed that both NG and SG had improvements after intervention on dynamic balance when measured with SEBT in all directions. Previous studies reported that neuromuscular training improved dynamic balance when compared with baseline, and it could be an effective intervention for secondary prevention for recurrent ankle sprain in sporting populations with CAI . Our resReduced DFROM is a frequent characteristic in individuals with CAI ,4,11. DeIt was not possible to control the daily life activities of participants, and our study population was physically active, which could influence obtained outcomes, especially on CG, because of their usual physical activities. Further research regarding the effects of different CAI-based interventions in active populations is required;Target intensity control to calculate the training volume for each patient is difficult;Influence of the patient’s previous beliefs and expectations about CAI and the treatment usually received and how popular belief may influence satisfaction with the treatment received, and the results of the variables studied;Monitorization of ankle joint muscle strength could provide additional information.Our results suggest there are improvements in NG and SG when compared with baseline, obtaining significant differences regarding CG on functional status and posteromedial direction on dynamic balance in SG patients. Although some differences were observed between the intervention groups, it is not possible to establish a relationship of superiority between any of them in an active population with CAI.


Three studies reported 30-d mortality, and the pooled odds ratio for surgery compared with medical treatment was even lower , with low heterogeneity . With studies on fewer than 30 patients excluded, the sensitivity analysis revealed a low odds ratio of in-hospital mortality for surgery versus medical treatment , with moderate heterogeneity . Subgroup analysis revealed no significant differences between any two comparator subgroups. Based on a very low strength of evidence, compared with medical treatment, surgical treatment for IE in patients on dialysis is not associated with lower in-hospital mortality. When studies on fewer than 30 patients were excluded, surgical treatment was associated with better survival.Infective endocarditis (IE) is a serious infection and causes significant morbidity and mortality. However, the benefit of surgery for endocarditis besides antibiotic treatment in dialysis patients remains controversial. We performed a systematic review of studies published between 1960 and February 2022. Meta-analysis was conducted with a random-effects model to explore the in-hospital, 30, 60, 90, 180-d, and 1-year mortality rates in adult dialysis patients with IE. Sensitivity analysis, subgroup analysis, and meta-regression were performed to explore potential sources of heterogeneity. Confidence of evidence was evaluated by the GRADE system. Thirteen studies were included. The pooled odds ratio of in-hospital mortality was 0.62 (95% confidence interval [CI]: 0.30–1.28,  Patients who have chronic kidney disease or are receiving dialysis therapy are at high risk of infection, related hospitalization, and mortality . InfectiThis study systematically reviewed literature on the outcomes of patients with IE undergoing dialysis and compared the short-term and long-term mortality rates associated with surgical treatment in this population.We performed online literature searches of the PubMed, Embase, Medline, Cochrane, and ClinicalTrials.gov databases. In addition, we searched the OpenGrey, APA PsycNet, HMIC, and MedRxiv databases for gray literature. The most recent search was performed on 14 February 2022. The population, intervention, comparison, and outcome (PICO) framework of this study was as follows: The population was patients with acute IE on dialysis, the intervention was surgical treatment, the comparison was medical treatment alone, and the outcome was in-hospital mortality. The search strategy was designed to target published articles or conference abstracts containing ‘end stage renal disease’ and ‘infective endocarditis’ or related words. The protocol was registered in PROSPERO under the approval number CRD42021240700.Supplemental Tables 1–3.Two independent investigators (SW Ting and JJ Chen) performed a comprehensive search of the aforementioned sources for studies published through 14 February 2022. The details of the search strategies and the search results are summarized in After eliminating duplicated studies, we used filters in EndNote and Excel software to screen titles and abstracts. Then, the studies were independently reviewed by two investigators (SW Ting and JJ Chen). Review articles, case reports, case series, and editorials were excluded, as well as articles with topics irrelevant to our PICO. We identified and excluded reports that used the same patient population used by another already included report and those published before 1960. To be eligible for this study, a study must (i) include an adult, chronic dialysis population with acute IE, (ii) and report in-hospital mortality separately for surgically and medically treated patients. Any disagreement between the two investigators was resolved through discussion with a third investigator (G Kuo) to reach a consensus. Studies were excluded if they had only a single treatment arm or if outcome information could not be retrieved from the full text.http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp). We rated the risk of bias in each study as high, moderate, or low following a similar rationale in previous study [low if it got 3 or 4 stars in the selection domain, 1 or 2 stars in the comparability domain, and 2 or 3 stars in the outcome domain. Moderate risk of bias was determined if 2 stars in selection domain, 1 or 2 stars in comparability domain, and 2 or 3 stars in outcome domain. Eventually, if there was only 0–1 star in the selection domain, or 0 star in comparability domain or 0–1 star in the outcome domain, the risk of bias would be rated as high. Disagreements between the two initial investigators (SW Ting and JJ Chen) were resolved through consensus with the third author (G Kuo). The quality of evidence for the overall meta-analysis was assessed based on the guidelines of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group methodology [The data were extracted from each study independently by two investigators and included the publication year, study design, and whether patients with Duke criteria–based possible IE, prosthetic valve endocarditis, or recurrent IE or patients on peritoneal dialysis were excluded. The risk of bias of nonrandomized studies was assessed with the Newcastle–Ottawa Scale (NOS) in accordance with the suggestion of the Cochrane Group for Systematic Reviews  exclusion of patients with Duke criteria–based possible IE, (ii) exclusion of patients on peritoneal dialysis, (iii) exclusion of patients with prior IE, (iv) exclusion of patients with prosthetic valve IE, and (v) study design (prospective vs. retrospective). Publication bias was assessed with a funnel plot and Egger’s test, with a p value of <.1 for Egger’s test indicating potential publication bias. Statistical analyses were performed with R version 4.1.0  [Meta-analysis of the mortality rate was performed with a random-effects model because the criteria of patient selection differed among studies. The odds ratios (ORs) for mortality at the various time-points were analyzed with the age in R . HeterogAustria) .The included studies were published between 1997 and 2021 and comprised data from a total of 1679 patients. No randomized, controlled, or blinded trials were assessed. Only two studies were prospective cohort studies ,16; the versus nonsurgical intervention was 0.62 , with moderate heterogeneity , with low heterogeneity . No study reported 60-d mortality. Only one study reported 90-d mortality, and another one reported 180-d mortality. The OR for 90 and 180-d mortality of surgical versus nonsurgical intervention was 0.56  and 1.07 . Three studies reported 1-year mortality, and the pooled OR of surgical versus nonsurgical intervention was 1.41 , with low heterogeneity .Four studies reported 30-d mortality, and the pooled OR for surgical Supplementary Figure 2). Egger’s test of funnel asymmetry indicated no significant publication bias . We also tested funnel plot asymmetry with the trim and fill method. Using the trim and fill method did not eliminate any studies but did impute two hypothetical studies. The OR for in-hospital mortality with the trim and fill method was 0.84 , indicating that our effect size may be slightly overestimated toward the direction of lower mortality because of the small study effect . Risk of bias was assessed using the NOS because all of the included studies used nonrandomized designs. Only two studies employed adequately representative exposed cohorts; their data were derived from a nationwide or multinational database [Potential publication bias was visualized with a funnel plot . The p value for interaction in above groups was all above .1  the exclusion of modified Duke criteria–based possible IE, (ii) the exclusion of patients undergoing peritoneal dialysis, (iii) the exclusion of patients with prior IE, (iv) the exclusion of prosthetic valve IE, and (v) study design  than was medical treatment alone, and the heterogeneity was moderate . Because all of the included studies have high risk of bias, we could not conduct a sensitivity analysis by including only those studies with low or moderate risks or excluding those with a high risk. Meta-regression of in-hospital mortality on the basis of study size and year revealed no significant correlations .After studies with fewer than 30 patients were excluded, surgical treatment was associated with lower OR of in-hospital mortality  [versus nonsurgical treatment.The major difficulty in comparing surgical and medical treatment in retrospective studies is the confounding factor of surgical indications; that is, patients might have undergone surgery simply because they had surgical indications, whereas those who did not receive surgery might have simply had no surgical indications. Such a potential imbalance of surgical indications makes unbiased comparison difficult. Second, the presence of multiple comorbidities could reduce the likelihood of surgical treatment. In a large study using a nationwide database in the United States, Bhatia et al. reported a lower probability of valve replacement surgery  in patients with IE undergoing dialysis than in the other patients with IE; however, compared with the general population, the patients undergoing dialysis also had more comorbidities [ < .001) . ContraiAnother challenge is that the volume of cardiac surgery in each study hospital may be associated with different outcomes. The mortality rate after cardiac surgery in general and pediatric populations is closely linked to the surgery volume of the hospital . This voversus medical treatment alone do not differ for dialysis patients with IE.This study has several limitations. First, there are no randomized, controlled studies of the outcomes of surgical and medical treatment for IE in patients undergoing dialysis. In addition, all included studies were not primarily designed to compare the outcomes of surgical and medical intervention. Thus, outcomes were all extracted from the text, and proper matches between the two treatment arms were not performed in any of the included studies. Therefore, comparison between the two treatments was not adjusted adequately for possible confounding factors. Second, none of the included studies provided hospital or surgical volume data, which crucially affect cardiac surgery outcomes. The importance of this study, however, is its highlighting of the inadequacy of current literature on this topic and its identification of crucial information that should be included or adjusted for in future studies. In conclusion, based on a very low certainty of evidence, we found that in-hospital mortality after surgical intervention Click here for additional data file.


The survival benefit of primary and metastatic resection for patients with colorectal cancer with liver metastasis (CRLM) has been observed, but methods for discriminating which individuals would benefit from surgery have been poorly defined. Herein, a predictive model was developed to stratify patients into sub-population based on their response to surgery.We assessed the survival benefits for adults diagnosed with colorectal liver metastasis by comparing patients with curative surgery vs. those without surgery. CRLM patients enrolled in the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015 were identified for model construction. Other data including CRLM patients from our center were obtained for external validation. Calibration plots, the area under the curve (AUC), and decision curve analysis (DCA) were used to evaluate the performance of the nomogram compared with the tumor–node–metastasis (TNM) classification. The Kaplan–Meier analysis was performed to examine whether this model would distinguish patients who could benefit from surgery.A total of 1,220 eligible patients were identified, and 881 (72.2%) underwent colorectal and liver resection. Cancer-specific survival (CSS) for the surgery group was significantly better than that for the no-surgery group . Five factors were found associated with CSS and adopted to build the nomograms, i.e., age, T stage, N stage, neoadjuvant chemotherapy, and primary tumor position. The AUC of the CRLM nomogram showed a better performance in identifying patients who could obtain benefits in the surgical treatment, compared with TNM classification . The calibration curves revealed excellent agreement between the predicted and actual survival outcomes. The DCA showed that the nomogram exhibited more clinical benefits than the TNM staging system. The beneficial and surgery group survived longer significantly than the non-beneficial and surgery group , but no difference was observed between the non-beneficial and surgery and non-surgery groups .An accurate and easy-to-use CRLM nomogram has been developed and can be applied to identify optimal candidates for the resection of primary and metastatic lesions among CRLM patients. Colorectal cancer (CRC) is the third most common cancer worldwide, and 50% of patients develop liver metastasis during the course of the disease , 2. AmonMore precise categorization is needed to identify those who may benefit more from surgery. Thus, it is necessary to stratify patients based on their preoperative features to provide more individualized treatments. All kinds of prediction models have been developed and validated to overcome the drawback of the TNM classification system . Among tAlthough some studies –16 have For this study, the data we analyzed were extracted from the Surveillance, Epidemiology, and End Results (SEER) database , which covers approximately 28% of the US population . The SEEThe inclusion criteria for patients were as follows: 1) patients came from the database of “Incidence—SEER Research Plus Data, 18 Registries, Nov 2020 Sub (2000-2018)”. 2) The International Classification of Diseases for Oncology (ICD-O-3) was used for the CRLM definition. “Site recode ICD-O-3/WHO 2008” was used to record tumor location information, including ascending colon, hepatic flexure, transverse colon, splenic flexure, descending colon, sigmoid colon, rectosigmoid junction, and cecum. 3) Liver metastasis. 4) Single primary site. 5) The TNM stage was stated as “M1a”. “M1a” was confined as “Metastasis limited to a single distant organ except for peritoneum” , and “YeThe exclusion criteria were as follows: 1) less than 20 years old; 2) diagnosed with no positive histology and not only from a death certificate or autopsy; 3) the information about the surgery to the primary site and metastatic lesion was missing; 4) clinical pathological information , T stage, N stage, histologic type, and neoadjuvant chemotherapy) was missing; and 5) survival information  was missing.CRLM patients treated in the Shanghai Cancer Center, Fudan University (FUSCC) from 2016 to 2017 were enrolled as an independent external validation set for this study. The included criteria are as follows: 1) over 18 years old; 2) single primary site; 3) diagnosed with positive histology; 4) the TNM stage was stated as “M1a”; and 4) complete demographic data, clinical parameters, TNM stage information, and full follow-up results.The analyzed data included age , sex , primary site , tumor size (>5 and ≤5 cm), CEA , T stage , N stage , differentiation grade , histologic type (adenocarcinoma and others), neoadjuvant chemotherapy (yes and no), marital status , surgery to the primary site (yes and no), and surgery to the metastatic lesions (yes and no). Overall survival (OS), CSS, and survival month were extracted from the SEER database. OS time was defined as the time from diagnosis to death or to the time of data analysis. Living patients were excluded at the time of the last recording. The CSS duration can be calculated from the date of diagnosis to a documented CRC-related death. According to the published papers , we idenThe research group was separated into two groups based on therapy, surgery versus non-surgery. Clinical differences  were represented as a number with percentage and compared by using the chi-square test and Fisher’s exact test. The Kaplan–Meier (K-M) method and the log-rank test were analyzed in two groups to confirm the influence of surgery on the survival of patients. To identify independent predictors, univariate and multivariate Cox proportional hazards regression analyses were performed. Hazard ratios (HRs) were calculated with 95% confidence intervals (CIs). Statistical data were analyzed with SPSS 24.0 . All statistical tests were two-sided, and only p < 0.05 could be regarded as statistically significant.The eligible people receiving surgery were randomly divided into the training and validation cohorts. Patients who survived longer than the median CSS time of those who received no surgery were defined as benefiting from the surgical treatment. According to the univariate and multivariate Cox analyses, the factors independently affecting the CSS were indicated in the training cohort. Based on the multivariable logistic analysis, the nomogram to identify the patients who may obtain benefits from primary and metastasis resection was developed. The areas under the receiver operating characteristic (ROC) curve (AUCs) were applied to quantify ROC performance to assess the discriminative and calibration capacity of the nomograms. Calibration curves were utilized to demonstrate no deviations from the reference line, indicating a high degree of dependability. What is more, the decision curve analysis (DCA) was also used to evaluate the clinical application value and clinical practicability of the models. Overall, we used ROC, calibration plots, and DCA to graphically describe the performance of our model. What is more, we attempted to assign all CRLM patients undergoing surgery to two groups—beneficial and surgery group and non-beneficial and surgery group—in terms of probability of benefit of 50%. The Kaplan–Meier analyses and the log-rank test were employed to test whether this model could identify individuals who could indeed benefit from the resection of primary and metastatic lesions.From the SEER database, 1,220 patients with M1a CRLM who met inclusion criteria were identified from 2004 to 2015. The flowchart is illustrated in In total, 12 variables were incorporated in the least absolute shrinkage and selection operator (LASSO) regression, and all of them were included: age, sex, race, differentiation grade, histology type, T stage, N stage, tumor size, marital status, neoadjuvant chemotherapy, CEA, and primary tumor position Figure 2According to the K-M analysis and log-rank test in the SEER cohort  of non-surgical patients was considered as the reference line. Patients who underwent curative surgery yielded better CSS than this reference line and were identified to be beneficial in the operation. Conversely, surgical patients whose CSS was lower than 14 months were considered non-beneficial patients. A total of 708 (80.36%) patients were categorized as “beneficial”. The characteristics of patients are presented in We randomly assigned 881 patients who underwent curative surgery in a 4:1 ratio to the training cohort (n = 705) and the validation cohort (n = 176). The median CSS time of the training cohort and validation cohort was 41 [36.74–45.26] and 40 [31.34–48.66] months, respectively.Nine independent predictors including age, race, differentiation grade, T stage, N stage, neoadjuvant chemotherapy, marital status, CEA, and primary tumor position were collected into the multivariate logistic regression. We identified five effective factors and developed a nomogram to predict the stage M1a CRLM patients who could benefit from the surgical treatment based on the training cohort Table 3.ROC analysis demonstrated the AUCs of the training and validation cohorts reached 0.826  and 0.820 , respectively, outperforming the American Joint Committee on Cancer (AJCC)–TNM classification of 0.649  and 0.635 , respectively Figure 5In this study, external validation was performed in the FUSCC cohort. The AUC of the CRLM nomogram was 0.763 , outperforming the AJCC-TNM classification of 0.626  ) was constructed at According to the Kaplan–Meier analysis and log-rank test, the beneficial and surgery group had a considerably longer survival time than the non-beneficial and surgery group . However, no significant difference was found between the non-beneficial and surgery and non-surgery groups Figure 6In the present study, a nomogram including age, T stage, N stage, neoadjuvant chemotherapy, and primary tumor position was constructed and validated to identify optimal candidates for the primary and metastatic resection. In clinical practice, our nomogram can aid clinicians in the process of making decisions as a convenient and accurate predictive model.Five factors were considered into account in our model in this study and were attached to different risk scores, which could indicate the impact they did on the decision. Present results supported our hypothesis and revealed some significant discoveries. Our nomogram shared several parameters with previous studies on CRLM survival prediction. Some factors marked with a high-risk score in our model, like T stage, age, neoadjuvant chemotherapy, and primary tumor position, were also generally recognized in other studies , 19, 20.For the first time, age was indicated to correlate with the potential of benefit strongly. A growing body of evidence suggests that the elderly have a poorer prognosis, which is consistent with our result –23. The In our nomogram, the T1 stage had the least risk scores, indicating that patients with T1-stage tumors are unlikely to benefit from surgery. This distinct phenomenon went against common sense. However, the research of Lupo Wu also noticed this phenomenon and attributed it to the distinct genetic profile of the T1 stage tumors . This fiThe primary tumor sites served as a high-ranking risk factor, which could affect the potential surgery benefit in our models, and other studies have also confirmed this observation , 25, 26.The tumor size and grade demonstrated a correlation to CSS based on LASSO regression. Nevertheless, the strength of correlation cannot meet the criteria for multiple variable Cox and logistic regression. Therefore, they were excluded from our prediction models. A similar outcome was found in other CRLM studies , 15, 16.Additionally, our research demonstrated that carcinoembryonic antigen (CEA) was associated with OS and CSS in LASSO regression. Some studies have indicated that preoperative serum CEA level plays a significant role in the prognosis of CRC patients as an independent risk factor for prognosis –37. HoweDuring the study, we were puzzled by the differences between surgical and non-surgical patients Table S1Compared with the nomogram currently published about predicting the prognosis of CRLM patients , our modWhat is more, CRLM patients diagnosed between 2004 and 2015 from the SEER database were collected for model construction and internal validation. An independent dataset was obtained from China for external validation. As a well-known database, the SEER database has larger and multi-center data compared with the limited data of our own center, which can improve the model’s predictive performance. However, these are two datasets covering highly different epidemiological, genetic, molecular, and cultural backgrounds, which are not free from potential selection bias.However, there are still several limitations in the present study. Firstly, some factors reported to be significant for the prognosis of CRLM patients such as the number and size of liver metastasis were not investigated in this study because of the lack of relevant information , 15. DesIn summary, we have provided a novel and simple model to identify stage M1a CRLM patients who could indeed benefit from surgery. This predicting model could output individualized results with good accuracy, availability, and applicability. This nomogram might influence the clinician’s decision making in the process of treatment.https://seer.cancer.gov/.Publicly available datasets were analyzed in this study. This data can be found here: Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.XJ and YW designed the study. XJ, YW, YF, and ZL collected the data and analyzed the data. XJ and YW drafted the manuscript. TZ, BY, and NZ reviewed the manuscript. WZ and LW were responsible for the whole project and supervised the study. All authors contributed to the article and approved the submitted version.This work was funded by the National Natural Science Foundation of China , Shanghai Natural Science Foundation Project (22ZR1413300), the National Key Project of China (2017ZX10203204-007-004), the Public Health Bureau Foundation of Shanghai , and 2019 clinical science and technology innovation project (SHDC12019X19).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. 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