What's more, the effect of lnc-MCEI on the chemosensitivity of ESCC was further evaluated. Bioinformatics analysis demonstrated that lnc-MCEI was involved in the tumorigenesis of ESCC and lnc-MCEI levels were significantly increased in ESCC cells and tissues. Additionally, lnc-MCEI knockdown retarded cell proliferation, colony formation of ESCC cells, but induced cell apoptosis. Moreover, lnc-MCEI knockdown significantly improved the chemosensitivity of ESCC to cisplatin (DDP) both in vivo and in vitro. Further mechanisms disclosed that lnc-MCEI functioned as a competing endogenous RNA (ceRNA) via sponging miR-6759-5p and IGF2 was a target of miR-6759-5p. Meanwhile, we found that IGF2 suppressed chemosensitivity of ESCC cells via PI3K/AKT pathway. These data suggested that lnc-MCEI was an oncogenic lncRNA and lnc-MCEI knockdown enhanced chemosensitivity of ESCC cells to cisplatin by targeting miR-6759-5p /IGF2/PI3K/AKT axis.Large amounts of long non-coding RNAs (lncRNAs) have been annotated whereas most of them have not been functionally characterized. Here we identified lncRNA ENST00000441932 as an oncogenic lncRNA in esophageal squamous cell carcinoma (ESCC) and named lnc-MCEI ( Esophageal cancer ranks eighth among all tumors and sixth among causes of cancer deaths, with at least 456,000 new cases annually worldwide Long non-coding RNAs (lncRNAs) are considered to be non-coding RNAs with >200 nucleotides (nt) in length and have no protein coding abilities in vivo and in vitro. Therefore, this study revealed that lnc-MCEI promotes ESCC tumorigenesis and chemoresistance and was a potential therapeutic target for ESCC.Thus, our study was aimed to explore the role of lnc-MCEI in the ESCC progression and chemoresistance. Bioinformatics analysis demonstrated that lnc-MCEI might participate in ESCC chemosensitivity of ESCC to cisplatin and further experiments validates this both A cohort of tumor and adjacent normal tissues were collected from 50 patients diagnosed with ESCC in the First Hospital of Jilin University from August, 2013 to August, 2018 under the approval of Institutional Review Board and Human Ethics Committee of the hospital. Patients were performed complete surgical resection (esophagectomy) prior to adjuvant chemo- or radiotherapy and ESCC samples were collected. Adjacent normal tissues were taken from the side of the tumor at least 5 cm away from the edge of the tumor. All tissues were stored at -80 ℃ until use and all the patients have signed the informed consent form.limma was used to obtain the differential expressed genes (DEGs) from the microarray data (GSE89102) which was available in the Gene Expression Omnibus (GEO) repository p value < 0.01). Probe information has been reported previously R package Human esophageal epithelial cell line (Het-1A) and ESCC cell lines  were used in the present study. Het-1A cell line was obtained from the American Type Culture Collection  and TE-1 cell line was purchased from Chinese Academy of Medical Sciences . In addition, KYSE-30 and EC109 cell lines were derived from CoBioer  and EC9706 cell line was gotten from Shanghai Huiying . KYSE-30 or EC109 cells were transfected with the small interfering RNA (siRNA) targeting lnc-MCEI (si-MCEI), miR-6759-5p mimics, miR-6759-5p inhibitor at 50 % confluence. Lnc-MCEI and negative control (NC) hairpin RNA (shRNA) sequences were purchased from GenePharma  and cloned into the pBS/U6 vector (Addgene) for lnc-MCEI knockdown. Additionally, the IGF2 expression plasmids construction and transient transfection were performed as the protocol previously described 5′-CGCCGAACCAAAGTGGATTA-3′ (forward) and;5′-GGAGAGACAGAGTGAACGTGA-3′ (reverse).The mRNA levels of target genes were examined by qPCR as the protocol previously described Cell proliferation were analyzed by MTT assays and cells colonies subjected to different treatments were stained and counted 10-14 days after seeding as previously described Wild-type (WT) or mutant (MUT) 3'-UTR of lnc-MCEI and IGF2 were cloned into the firefly-tagged pGL3 promoter luciferase vector  and then were co-transfected into HEK-293 cells with the Renilla control luciferase vector (Promega). Additionally, cells were co-transfected with miR-6759-5p mimics or miR-6759-5p inhibitor for another 48 hours. Luciferase activities were detected with a dual luciferase assay system (Promega) and results were presented as the ratio of firefly/Renilla.Total protein extraction and western blotting was performed as previously described For RIP assays, a Magna RIP™ RNA-Binding Protein Immunoprecipitation Kit  was utilized according to the manufacturer's protocols. Then the lnc-MCEI mRNA levels were determined by qRT-PCR.Immunostaining of Ki67 were carried out as previously described 6 EC109 cells of sh-control or MCEI-shRNA in 100 μL PBS were administered via subcutaneous injection into the right groin of the nude mice. The mice were intraperitoneally injected of DDP (1 mg/kg) from the second week every 3 days. The formula (volume (mm3) = (length × width2)/2) was used for the calculation of tumor volume every 3 days. Mice were sacrificed on day 18 post injection and tumors were harvested and weighed Twenty-four male BALB/c nude mice (six-week-old and six mice in per group) were randomly divided into four groups including NC, sh-lnc-MCEI, DDP and sh-lnc-MCEI+DDP. 3×10P < 0.05 was considered to be statistically significant.Results (mean ± SD) were analyzed with a one-way ANOVA or Student's t-test . The correlation between miR-6759-5p and lnc-MCEI in ESCC tissues was analyzed by using Spearman correlation analysis. P < 0.01; Figure ). Further analysis was performed and we found that lnc-MCEI was one of most significantly up-regulated genes in ESCC tissues . Moreover, the data series (GSE104958) was utilized and lnc-MCEI was also significantly increased in ESCC tissues with non-pathological complete response (non-pCR) compared to the tissues with pathological complete response (pCR) after chemotherapy . Additionally, data from The Cancer Genome Atlas (TCGA) RNA-Seq database was analyzed to support this and the lnc-MCEI levels in tumors were significantly higher than normal tissues . Next, the association of lnc-MCEI expression with patient survival was further evaluated according to the TCGA dataset. As shown in Figure , increased expression of lnc-MCEI was significantly associated with poor patient survival (P = 0.17). Based on the above bioinformatics results, the increased lnc-MCEI expression in ESCC tissues compared to the normal controls or matched normal tissues was confirmed . In addition, up-regulated lnc-MCEI expression in ESCC cell lines compared to the human esophageal epithelial cell line (Het-1A) was also observed . These results demonstrated that up-regulated lnc-MCEI was implicated in the promotion of ESCC progression and chemoresistance.To determined candidate genes involved in esophageal squamous cell carcinoma (ESCC) chemoresistance, a bioinformatics analysis was carried out based on the published microarray data (GSE89102) obtained from the Gene Expression Omnibus (GEO). Differential expressed genes (DEGs) were then examined between the 5 paired ESCC tissues and normal tissues by using the microarray information and 1747 significantly up-regulated and 1478 significantly down-regulated DEGs were finally identified . Accordingly, cells with lower lnc-MCEI levels exhibited significantly inhibited migration and invasion properties . Furthermore, lnc-MCEI knockdown significantly increased the percentage of apoptotic cells in both of the cell lines . These data suggested that lnc-MCEI knockdown significantly inhibited the malignant biological behaviors of ESCC cells.Subsequently, the role of lnc-MCEI in tumorigenesis was evaluated by knockdown strategies in KYSE-30 and EC109 cells. As shown in Figure , lnc-MCEI expression significantly increased in a time- and dose-dependent manner in KYSE-30 and EC109 cells subjected to DDP. More importantly, the results of MTT assays and colony formation assays indicated that DDP treatments combined with lnc-MCEI knockdown significantly enhanced the chemosensitivity of KYSE-30 and EC109 cells to DDP . In addition, the combination of these two strategies dramatically induced the apoptosis of KYSE-30 and EC109 cells . All these data suggested that lnc-MCEI knockdown sensitizes ESCC cells to DDP.Next, to determine the effect of lnc-MCEI on chemosensitivity, KYSE-30 and EC109 cells were treated with cisplatin (DDP) combined with lnc-MCEI knockdown or not. As shown in Figure ). In addition, the decreased lnc-MCEI expression in ESCC tissues compared to the normal controls or matched normal tissues was observed  and lnc-MCEI expression was also decreased in ESCC cell lines compared to the human esophageal epithelial cell line was also observed . Moreover, we found that there was a significant negative correlation between the expression of lnc-MCEI and that of miR-6759-5p . Subsequently, the interaction between lnc-MCEI and miR-6759-5p was confirmed via dual luciferase reporter analysis and the data suggested that miR-6759-5p mimics decreased the luciferase activity of wild-type (WT) lnc-MCEI but had no effect on mutant (Mut) lnc-MCEI . Additionally, the lnc-MCEI expression was affected by the miR-6759-5p levels in KYSE-30 cells treated with miR-6759-5p mimics or miR-6759-5p inhibitor . Further RIP assays confirmed that Lnc-MCEI functioned as a ceRNA via sponging miR-6759-5p .To further explore the underlying mechanisms of lnc-MCEI involved in chemoresistance, the proposed target genes of lnc-MCEI were examined by searching in LncBase v2.0 database. The results indicated that lnc-MCEI could act as a ceRNA by binding to miR-6759-5p . The results of dual luciferase reporter assays indicated that the luciferase activity of IGF2 with wild-type (WT) 3'-UTR was significantly decreased whereas IGF2 with mutant 3'-UTR was not influenced after miR-6759-5p mimics treatments . The mRNA or protein IGF2 expression was also affected by the miR-6759-5p levels in KYSE-30 cells treated with miR-6759-5p mimics or miR-6759-5p inhibitor . What's more, lnc-MCEI knockdown significantly decreased the protein expression IGF2 and phosphorylated AKT (p-AKT) but this effect was rescued by miR-6759-5p inhibitor in both KYSE-30 and EC109 cells . In addition, MTT assays suggested that IGF2 overexpression rescued the inhibitory effect of the combination of lnc-MCEI knockdown and DDP whereas the effect of IGF2 overexpression was then abolished by the PI3K inhibitor LY294002 in KYSE-30 cells . Further western blotting data exhibited consistent changes of IGF2 and p-AKT in KYSE-30 cells . These data indicated that lnc-MCEI mediated the chemosensitivity of ESCC by targeting miR-6759-5p /IGF2/PI3K/AKT axis.The potential target genes of miR-6759-5p were further examined by using the TargetScan Human 7.2 database. The putative binding sites of miR-6759-5p were observed in 3'-UTR of IGF2 mRNA . Furthermore, the combination of lnc-MCEI knockdown and DDP significantly induced the apoptosis of KYSE-30 and EC109 cells but the effect was abolished by the miR-6759-5p inhibitor or IGF2 overexpression . These data suggested that the miR-6759-5p inhibitor or IGF2 overexpression restores the effect of lnc-MCEI knockdown on chemotherapy.To further confirm the role of miR-6759-5p and IGF2 in the lnc-MCEI-mediated ESCC progression and chemoresistance, colony formation assays were performed and the data indicated that miR-6759-5p inhibitor or IGF2 overexpression rescued the inhibitory effect of the combination of lnc-MCEI knockdown and DDP ( in vivo. Immunodeficient nude mice were injected with EC109 cells that had been stably transfected with lnc-MCEI-shRNA (sh-MCEI) or negative control (NC). The results disclosed that tumor volume and tumor weight were significantly decreased in the sh-MCEI and DDP groups and the combination of sh-MCEI and DDP exhibited a more significant suppressive effect on the tumorigenesis . Moreover, the positive rate of Ki67 was also lower in the sh-MCEI + DDP group than the sh-MCEI or DDP group . In summary, our data suggested that lnc-MCEI inhibition suppressed ESCC tumorigenesis in vivo and lnc-MCEI mediated the chemosensitivity of ESCC by targeting miR-6759-5p /IGF2/PI3K/AKT axis.We next examined the role of lnc-MCEI in ESCC tumorigenesisThe mortality of esophageal squamous cell carcinoma (ESCC) remains high despite the rapid promotion in diagnosis and treatment of ESCC in-vivo and in-vitro biological experiments in our study confirm that lnc-MCEI promotes the malignant biological properties and inhibition of lnc-MCEI sensitizes ESCC cells to DDP. Therefore, lnc-MCEI was identified as an oncogene for the first time in our study.Lnc-MCEI has been rarely studied in previous studies and its role in cancer has never been discovered. Shi-Mei Zhuang et al. reported that lnc-MCEI was one of the candidate lncRNAs frequently amplified in hepatocellular carcinoma (HCC) but the function in HCC progression have been uncovered Studies have shown that lncRNAs may act as a competing endogenous RNA (ceRNA) sponging for miRNAs via the miRNA response elements (MREs) IGF2 was increased 1.97-fold in esophageal cancer than that in normal tissues detected by immunohistochemistry (IHC) Taken together, the beneficial effect of lnc-MCEI knockdown on the malignant biological behaviors of ESCC cells and chemosensitivity of ESCC cells to DDP was verified in the present study. Therefore, lnc-MCEI was identified as an oncogenic lncRNA in ESCC and could be a potential therapeutic target for ESCC by inhibition of miR-6759-5p/IGF2/PI3K/AKT axis.


This report describes a case involving a balloon kyphoplasty bone tamp becoming lodged inside the vertebral body and unable to be withdrawn, the first report of its kind in the literature. A board certified interventional pain management physician was performing a balloon kyphoplasty for an L3 osteoporotic vertebral compression fracture using a bipedicular approach with two bone tamps. Cannulation and cavity formation were completed without complication; however, upon removal of the balloons it was noted that one had become lodged in the vertebral body. Several attempts were made to remove the balloon. Neurosurgery and the balloon manufacturer were consulted intraoperative, and it was decided to leave the balloon fragments in situ and complete the interventional fixation of the vertebral body with bone cement. The patient followed up in the clinic several months later without neurologic complications. Postoperative radiography confirmed the presence of a retained foreign body consistent with balloon fragments. Balloon kyphoplasty and its various procedural complications will be discussed, as well as the intraoperative decision making faced when encountering a complication. Balloon kyphoplasty (BKP) is a minimally invasive, percutaneous procedure used to restore vertebral body height and repair spinal compression fractures caused by osteoporosis. BKP is indicated for acute symptomatic compression fractures with height loss of >20%. It is a type of vertebroplasty utilizing an inflatable bone tamp in the vertebral body to restore vertebral height prior to injection of bone cement. Similar to traditional vertebroplasty, BKP presents with many complications. Those complications include cement extravasation, thermal injury and post-procedural pain. However, BKP has been shown to be more effective at restoring vertebral height at lower pressures and with fewer complications than traditional vertebroplasty. BKP has some complications specific to it, such as further vertebral fracture from balloon expansion, balloon rupture, and re-collapse following balloon deflation. This report describes a BKP in which the bone tamp broke off inside the patient and was unable to be removed, the first case of which to be described in the literature.A 83-year-old male patient presented to pain management with low back pain ongoing for several weeks. The patient was previously seen by an orthopedic surgeon who recommended a conservative treatment with the thoracic lumbosacral orthosis (TLSO) brace with which the patient was non-compliant. Multiplanar multisequence non-contrast MR images of the lumbar spine were obtained Figure . FindingThe patient was offered BKP for correction of vertebral kyphosis and symptomatic relief. A BKP was performed with re-expansion of the vertebral body under fluoroscopic guidance and injection of bone cement Figure . FollowiVertebroplasty was first described in 1984 in France for the treatment of a vertebral hemangioma and involves a transpedicular approach with infiltration of polymethylmethylacrylate under pressure to stabilize the bone. Vertebroplasty has shown improved quality of life and pain scores up to one year following the procedure when compared with non-surgical management. Both traditional vertebroplasty and BKP show an improvement in kyphotic angle following the procedure with BKP maintaining results for up to three years . ComplicFollowing review of the literature, this is the first report of a retained bone tamp following BKP. There are many possible factors that may have contributed to the shearing and retention of the balloon. Examples of such factors include the pressure used in order to inflate the bone tamp , an acutBKP generally presents with fewer complications than traditional vertebroplasty. However, it is not denuded of complications such as further vertebral fracture from balloon expansion, balloon rupture, and re-collapse following balloon deflation. A retained bone tamp is now a new reported complication.


A total of 3973 documents were initially retrieved. Finally, 72 articles met the inclusion criteria, but only 26 suggested original tactical variables based on the distance variables. The distance variables can be classified into player–player, player–space, player–ball, and Geometrical Centre (GC)–GC /player/space/goal. In addition, several nonlinear techniques have been used to analyse the synchronisation and predictability of the distance variables in team invasion sports. Player–opponent distance is of special interest in those sports in which man-marking is commonly used, and in the micro-structure close to scoring situations in all sports. In addition, player–player distances are used to measure the length and the width of the team and player–GC distance to assess the dispersion of the team. Player–space distances have been measured to assess the distance of the player/team-line to relevant areas of the playing space. Several techniques have been applied to analyse the synchronisation  and the complexity and regularity or predictability  of the distance variables in team invasion sports, revealing the lack of consensus. Although the distance variables may be interesting tactical variables when considered in isolation, it would be enriching to analyse the relationship among these variables.The aim of the study was the identification, computational examination, critical assessment and future considerations of  Although all players constantly interact with one another during team invasion sports matches and tasks, the nature  of thesedistance variables) has been suggested through the measurement of the distance between both players  [distance of the players in a particular zone of the pitch; that is, they have measured several player–space distances [distance variables have been used to assess team behaviour in team invasion sports [distance variables in order to assess their practical application in team invasion sports training and matches.Based on studies of racket games , the asspponent) ,18,19,20istances ,21,22. An sports ,25,26,27distance variables [distance variables.The inherent complexity of team invasion sports  suggestsariables . These tariables . Based oariables  and periariables , Palut aariables  computedariables ). The reariables ,15,30,31ariables  have beeariables ,19,20,32ariables . Thus, iariables , and difdistance variables to assess collective tactical behaviour in team invasion sports by positional data.The aim of the present study was the identification, computational examination, critical assessment and future considerations of This systematic review was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines . The prodistance variables or modified this variable, and provided their computational criteria. The studies included in the review met all inclusion criteria. The quality of the included studies was individually assessed using a modified Downs and Black checklist by Sarmento et al. [When the referred authors had completed the search, they compared their results to ensure that the same number of articles had been found. Then, one of the authors (MR) downloaded the main data from the articles  to an Excel spreadsheet  and removed the duplicate records. Subsequently, the same authors screened the remaining records to verify the inclusion/exclusion criteria, using a hierarchical approach in two phases: Phase 1, titles and abstracts were screened and excluded by two authors  against criteria 1–5 where possible; Phase 2, full texts of the remaining papers were then accessed and screened against inclusion criteria 1–5 by the same authors . The papers that were included after these phases and met the 6th inclusion criteria were included in the systematic review. The inclusion criteria were: (1) Team sports in which the use of the mobile  is simultaneous ; (2) The main objective of the study is to assess tactical performance or dimension in team players; (3) Studies that include a tactical variable regarding the position of the players using Electronic Performance and Tracking Systems (EPTS); (4) Studies that aim to measure a tactical variable; (5) Studies that aim to analyse the position of more than one player, whether they are rivals or not; (6) Studies that measured the o et al. .Any disagreements on the final inclusion/exclusion status were resolved through discussion in both the screening and excluding phases. Moreover, relevant articles not previously identified were also screened in an identical manner and the studies that complied with the inclusion/exclusion criteria were included and labelled as ‘not identified from search strategy’.distance variables –GC/player/space/goal. Player–opponent distances are of special interest in those team invasion sports in which man-marking is commonly used and in the micro-structure close to scoring situations in all team invasion sports. In addition, player–player distances are used to measure the length and the width of the team and player–GC distances to assess the dispersion of the team. The player–space distances have been measured to assess the distance of the player/team-line to relevant areas of the playing space. Several techniques have been applied to analyse the synchronisation  and the complexity and regularity or predictability ) of the distances in team invasion sports, revealing the lack of consensus among researchers.The aim of the study was the identification, computational examination, critical assessment and future considerations of distance : GC–GC, GC–player, GC–space, GC–ball, player–space, player–ball [distance variables considered the distance between the player and the basket [The interaction between two players, assessed in e., dyad ,41), is e., dyad ,21,24,26yer–ball ,25,39,42distance of each player from the try and lateral lines. Thus, Passos et al. [distance between a defender and their opponent  for the first time. The authors compared the impact of both interpersonal distance and relative velocity on attacker–defender distances during an experimental task that was representative of a typical sub-phase of rugby union  [distance between the attacker and the defender in fixed player–opponent distances  in a basketball match and Silva et al. [distance variables continuously, and varying the opponents of the distance during play). Fixed player–opponent distance variables are of special interest in those sports in which man-marking is commonly used, such as basketball [distance variables could be more relevant in sports in which zonal marking is applied by the trainers.The measurement of distances in team invasion sports was suggested by Araujo et al. . Specifis et al.  measuredry line) . Next, Bry line)  measureda et al.  calculatsketball  and futssketball , althougsketball ,24,44. Ndistance variables, Silva et al. [distance between all players and their closest opponent and this was interpreted as the average radius of action free of opponents [distance between the opponents, Silva et al. [Based on the defender–attacker a et al.  proposeda et al. . Silva ea et al.  proposedpponents . Based oa et al.  proposeda et al. . The idea et al. . Each tea et al. . Finallya et al.  assesseddistance between two teammates, has been widely assessed in team invasion sports [distance between two teammates was assessed, Lames et al. [distance between the maximum and minimum position of the players  of the same team  in order to assess the occupation of the space in the direction of goal to goal. Soon after, several studies proposed the measurement of the range in both directions  [distance variable, but considering the distance between fixed distance variables , that is, the distance between the same teammates during a basketball match. A further study took into consideration all possible player–teammate distance variables formed by the outfield players in order to asses intra-team relations  and variability in the distance between players) [distance variables that considered the goalkeeper. Specifically, they measured the distance that remained behind the defensive line, which was a measure of the distance between the goalkeeper and the last defender. Thus, player–opponent and player–teammate distance variables were analysed independently in order to observe the positional balance between both players [distances [Another player–player distance, the n sports ,17,18,37d width) ,46. Lated width)  assessedplayers) . Moreove players , and theistances  in orderdistance variable in team invasion sports for the first time. Specifically, a player–space distance: the distance of the attacker and the defender from the try line  and distance of attacker and defender from both lateral lines  during a rugby training task. Besides presenting a 3-D analysis of interpersonal dynamics of attacker-defender distances, the authors also aimed to identify parameters to measure dynamical system properties in these distance variables [distance to the goal) in order to analyse how players coordinate their actions to create/prevent opportunities to score goals in futsal matches. Moreover, they proposed the assessment of the defender´s angle to the goal and the attacker  [distance between the ball carrier and their immediate defender  and the distance of the ball carrier to the basket  in order to assess the distance between these two points when a shot is attempted or when possession is lost during competition basketball games. Thus, player–space distances have been measured taking into account the player–opponent relative position and distance to the goal, basket, or end zone [distance variable for the first time, with several studies considering the position of the ball in the analysis of the team behaviour variables [As mentioned above, Passos et al.  measuredariables . Similarariables  suggestettacker) . Maybe fttacker)  linked tend zone ,21,22. Rend zone  measuredx and y coordinates, Frencken and Lemmink [distance between the GCs of the teams in order to assess the “pressure” between the teams. Later, several studies proposed other tactical variables [distance between all players and the GC of the team at that moment. In a later study, Barttlet et al. [cx), and because the team GC is computed from the position (ix) of all players, then the stretch index incorporates all inter-player distances.Taking into account the relative positioning of each team, expressed in single  Lemmink  measuredariables  as the Gariables  proposedariables ) of eacht et al.  picked ut et al.  but appldistance between the GC and each player to assess the coordination of each player and GC using the relative phase (this data processing technique will be discussed in the next section). In addition, these authors proposed the measurement of the maximal and minimal distance of the farthest and closest player with respect to the GC [distance from their own GC, Sampaio et al. [distance between each player and the opponent´s GC in order to assess how player movement patterns are coordinated with all their teammates’ and opponents’ positioning expressed as a single value .The radius was used to analyse the counterphase relation in which it was observed how the team with possession expanded against the contraction of the defending team . In 2012o the GC . Togetheo et al.  suggestedistance [distance variable was suggested in order to assess the collective behaviour of particular sub-groups of players involved in the creation/prevention of goal scoring [defensive line) and the distance measured between the GC and the defensive line in soccer. In the same line of research, Silva et al. [distance to the goal centre defended by a goalkeeper and to the end line where the mini-goals were placed during several soccer SSGs. Thus, the GC–space distance has been suggested for assessing the relative position of the team, expressed as a single value, with respect to different types of goals.Similarly to the player–space distance ,21,22, t scoring . Specifi scoring  implemena et al.  calculatdistance variables, Bourbousson et al. [distance variables, Bourbousson et al. [distance variables made between two players from each position, and due to the importance of the score, several studies suggested this analysis of the 1 vs. 1 distance close to the target  in order to assess the performance in these special play situations in team invasion sports [Regarding the relative phase for intra-team n et al.  suggesten et al.  and suggn et al. . On the n et al.  assessedn sports ,48.distance variables: player–ball and player–teammate distances differentiating attacking and defending teams and the player–opponent distances. In addition, Travassos et al. [distance variables by the Hilbert transform: defending team–, attacking team–, teams–ball , and defending–attacking distances . These studies suggested that ball dynamics determine the relations between players [Later, Travassos et al.  assesseds et al.  measured players ,3. In-ph players  and (b)  players , a great players .distance variables with similar levels of synchronisation. This analysis was applied to the percentage of time of distance synchronisation and they classified each distance variable into one of three groups according to its synchronisation level: the higher, intermediate and lower synchronisation groups.The above-mentioned studies used the relative phase to measure synchronisation between two oscillators. In order to evaluate the synchronisation between more than two oscillators, Duarte et al.  applied distance variable [m) and the tolerance factor for which similarity between observation windows is accepted (r). Higher values of ApEn, close to 2, signified more complexity and less regularity and predictability. After analysing the relative position between defender and attacker during the micro-structure 1 vs. 1 near to the try line in rugby, they found that system complexity increased with changes in relations between players [To our knowledge, Passos et al.  used thevariable . Based ovariable , the aut players . Moreove players , and sev players ,50,51. A players .distance values during soccer small-sided and conditioned games by means of sample entropy measures (SampEn), specifically the SampEn of distance to nearest opponent, i.e., the entropy of player–opponent distance. The use of SampEn instead of ApEn was suggested by Richman and Moorman [Silva et al.  analysed Moorman  for two distance between all player distances formed by outfield players using ApEn.Also using SampEn, Barnabé et al.  measureddistance variables have been suggested during the last two decades. According to the nature of the oscillators or points, they can be classified into player–player , player–space, player–ball, and GC–GC/player/space/goal distance variables. The measurement of the distance between players allows the assessment of the interaction between a couple of players, teammates or opponents. It is of special interest in those sports in which man-marking is commonly used, such as basketball and futsal, and in the micro-structure close to scoring situations in all team invasion sports. Moreover, player–player distances are used to measure the length and the width of the team and player–GC distances to assess the dispersion of the team. The player–space distances have been measured to assess the distance of a player (or team line) from relevant spaces, such as the target or the external borders of the playing space. Although these variables may be interesting considering each one independently, it would be worthwhile to analyse the relationship among them.Several types of relative phase, cluster method; entropy, ApEn, ApEnratioRandon, ApEnratioSuffle, SampEn, cross-SampEn, AMI). Usually, the relative phase has been used to measure the synchronisation between two oscillators , but several authors have suggested the cluster method in order to evaluate the synchronisation among more than two oscillators. This suggestion comprises a more complex analysis of team invasion sports. Regarding entropy, different types of techniques have been suggested . There is no consensus, and this makes the comparison among studies difficult.The application of the relative phase and entropy has allowed the analysis of the synchronisation and the complexity and regularity or predictability of several GC and distances tactical variables (i.e.,


Conditional logistic regression analysis was used to estimate the odds ratios (ORs) of the association between the meteorological data and Bell’s palsy. The mean NO2 and PM10 concentrations for 60 days were higher, while that of O3 was lower in the Bell’s palsy group than in the control group (both P < 0.001). The Bell’s palsy group showed 16.63-fold higher odds of NO2 for 60 days (0.1 ppm) than the control group . The ORs of PM10, and O3 for 60 days showed inconsistent results according to the included variables. Bell’s palsy was related to high concentrations of NO2.This study investigated the relationship of weather and air pollution with the onset of Bell’s palsy. The Korean Health Insurance Review and Assessment Service-National Sample Cohort (HIRA-NSC) data from 2002 through 2013 were used. The 3,935 Bell’s palsy patients were matched with 15,740 control participants. The meteorological data, including daily mean temperature (°C), daily mean highest temperature (°C), daily mean lowest temperature (°C), daily mean temperature difference (°C), relative humidity (%), spot atmospheric pressure (hPa), sulfur dioxide (SO The incidence of Bell’s palsy is approximately 11–40 per 100,000 person/year worldwide1. In Korea, approximately 0.12% of the population, regardless of age, suffers from facial palsy2. Viral infection and vascular compromise are thought to be related to Bell’s palsy3. Because both viral and cardiovascular causes might be influenced by meteorological factors, such as temperature and air pollution7, meteorological factors may have indirect effects on Bell’s palsy. In Korea, there is a traditional assumption that cold exposure causes Bell’s palsy9.Bell’s palsy is defined as idiopathic peripheral facial paralysis13. Some researchers reported a high incidence of Bell’s palsy in cold weather11. On the other hand, others demonstrated a high incidence of Bell’s palsy in warm weather or no difference in incidence based on the weather conditions13. Most previous studies based their analysis on regional incidence rates without the consideration of individual factors, and they had small study populations13. To the best of our knowledge, no previous study has evaluated the effect of air pollution on Bell’s palsy. When the PubMed and EMBASE databases were searched through November 2019 for studies using the keyword phrase ‘ AND (air pollution)’, two papers were identified; however, neither was relevant14.However, previous studies reported conflicting results regarding the association of Bell’s palsy and cold exposureThe hypothesis of the present study was that meteorological conditions, including air pollution, could increase the incidence of Bell’s palsy. To test this hypothesis, the exposures of patients with Bell’s palsy and a control group to meteorological conditions were compared.2), ozone (O3), and PM10 (particulate matter ≤10 μg/m3) showed differences  prior to the onset of Bell’s palsy was 16.63  prior to the onset of Bell’s palsy was 1.07 , while that of O3 was 0.18 . The daily mean temperature, daily mean highest temperature, daily mean lowest temperature, daily mean temperature difference, relative humidity, spot atmospheric pressure, SO2, and CO were not different between the Bell’s palsy and control groups  and Bayesian information criterion (BIC) values (The odds ratio (OR) of the 60-day NOl groups . After p) values .Table 2A2 were consistent, while those of O3 and PM10 were changed according to the variables included in the different models.In the various models  was associated with an increased risk of Bell’s palsy in young women , middle-aged men , middle-aged women , old men , and old women  groups 21.The oxidative stress and inflammatory response to NO2 might represent an indirect link between NO2 and the risk of Bell’s palsy. NO2 is known to be associated with the risk of cardiovascular diseases, such as stroke and myocardial infarction, and cardiovascular mortality23. A meta-analysis study reported that there was increased cardiovascular mortality following long-term NO2 exposure 23. Among several air pollutants, namely, CO, NO2, PM10, PM 2.5, and SO2, only NO2 was associated with an increased risk of hospital admissions for non-myocardial infarction-related cardiovascular disease  and heart failure 24. Another longitudinal follow-up study demonstrated an excess relative risk of hospital admissions of 2.8% for myocardial infarction and 4.9% for hemorrhagic stroke22. Several epidemiological studies have suggested the association of cardiovascular diseases with Bell’s palsy26. The incidence of peripheral arterial occlusive disease was 1.5 times higher in Bell’s palsy patients than in the control group25. Patients with Bell’s palsy had a 2.02-fold higher risk of stroke than the control group (95% CI = 1.42–2.86)26.The elevated cardiovascular risk due to NO10 was found to induce oxidative damage by increasing the intracellular level of hydrogen peroxide and decreasing catalase activity in human lung epithelial A549 cells27. In addition, PM suppressed the anti-inflammatory functions and innate immune neutrophils to endotoxins of lipopolysaccharides28. PM10 also had detrimental effects on cardiovascular diseases. A 10 µg/m3 increase in PM10 concentration was related to a 10.10% increase in the incidence of ST-elevation myocardial infarction29. This increase in the incidence of cardiovascular disease could be related to the risk of Bell’s palsy. However, we did not find a consistent result of association between PM10 and Bell’s palsy after adjustment for NO2 and O3. There was no previous study evaluated the relation between PM10 and Bell’s palsy, as far as our knowledge. However, possible explanations of the inconsistency in this study include the higher impact of NO2 than that of PM10 on the risk of Bell’s palsy and relatively small differences on the PM10, which could attenuate the statistical power. More studies are required to explore the relationship between PM10 and Bell’s palsy.Similarly, PM3 and Bell’s palsy, we were unable to explain their inverse association. We believe this might be affected by the negative relationship between NO2 and O3, as O3 could be created from NO2 by photolysis via ultraviolet light30. Actually, the relative concentration of NO2 is higher than that of O3 in Korea31. Therefore, the dominant effect of NO2 on Bell’s palsy might be able to conceal the effects of O3 on Bell’s palsy. On the other hand, there is a possibility that O3 might actually reduce the risk of Bell’s palsy, as ozone therapy has been reported to affect facial nerve palsy32.Because we could not find any previous study that evaluated the association between O33. On the other hand, other previous studies reported relationships between Bell’s palsy and low temperature and atmospheric pressure36. However, many previous studies did not assess individual-level factors, such as comorbidities. Instead, these studies only analyzed the regional incidence of Bell’s palsy according to seasons or months36. In addition, the effects of air pollutants could be influenced by weather conditions. For instance, the synergistic effects of temperature and air pollutants on mortality due to cardiovascular or respiratory diseases have been reported38. Thus, air pollutants should be included when evaluating the effects of weather conditions on health outcomes. However, most previous studies did not concurrently consider air pollutants and weather conditions.Other meteorological conditions, including temperature, atmospheric pressure, and humidity, did not show associations with Bell’s palsy in the present study. In accordance with our results, some prior studies demonstrated that there was no association between weather conditions and the onset of Bell’s palsy2 exposure in both the urban and rural groups  patients was relatively smaller than the number of older patients, which could be a cause of the nonsignificant association between exposure to air pollutants and Bell’s palsy in this age group . All methods were performed according the guidelines and regulations of the ethics committee of Hallym University. Written informed consent was waived by the Institutional Review Board. We describe the Korean Health Insurance Review and Assessment Service - National Sample Cohort (HIRA-NSC), meteorological data, and air pollution data in supplemental file From a total of 1,125,691 patients with 114,369,638 medical claim codes, the participants who were defined as having Bell’s palsy were selected for inclusion . The Bell’s palsy participants were matched 1:4 with participants who had never been diagnosed with Bell’s palsy (control group). Age group, sex, income group, region of residence, and past medical histories  were matched between the Bell’s palsy and control groups. In matching the region of residence , participants who lived in urban areas were matched with control participants who lived in another urban place. The same method was used for those who lived in rural areas. The control group participants were sorted using a random number generator. The matched control participants were presumed to be enrolled concurrently with each Bell’s palsy participant (index date). The Bell’s palsy participants for whom we could not identify sufficient numbers of matching participants were excluded (n = 61). Finally, 1:4 matching resulted in the inclusion of 3,935 Bell’s palsy participants and 15,740 control participants  (ppm), NO2 (ppm), O3 (ppm), CO (ppm), and PM10 (μg/m3) for 14 days, 10 days, 7 days, 5 days, and 3 days before the index date were analyzed (Table The daily mean temperature (°C), daily mean highest temperature (°C), daily mean lowest temperature (°C), daily mean temperature difference (°C), relative humidity (%), spot atmospheric pressure (hPa), sulfur dioxide . The region of residence was classified as urban and rural areas.The past medical histories of the participants were defined using the 10th revision of the International Statistical Classification of Diseases (ICD-10) codes. Hypertension (I10 and I15), diabetes (E10-E49), and dyslipidemia (E78) were acknowledged if the participants were treated ≥2 times.Bell’s palsy was defined using the ICD-10 code (G510). Among the cases with this ICD-10 code, the participants who were treated ≥2 times and who were treated with steroids were defined as having Bell’s palsy.The rate of general characteristics between Bell’s palsy and the control group were compared using the chi-square test. The mean meteorological data 14 days before the index date was compared using an independent t-test.To analyze the ORs of meteorological data for Bell’s palsy, conditional logistic regression was performed. The crude (simple) and adjusted (multiple) models were analyzed. The models were stratified by age, sex, income, region of residence, hypertension, diabetes, and dyslipidemia. The 95% CI was described. We describe the independent variables and the methods used to reach the final model in Supplemental Tables 2, O3, and PM10. Additionally, we calculated a combined model.We estimated a single pollutant model for NOThe participants were sub-grouped according to age and sex . An identical model was used in these analyses.Two-tailed analyses were performed. and statistical significance was defined as P values less than 0.05. SPSS version 22.0  and SAS version 9.4  were used to conduct statistical analyses.supplementary tables.


The historical use of constant hit rates for determining chance performance has been based upon the assumption that random hits are distributed evenly across multiple trials. For any closed-set, forced-choice task with 2 to 10 alternatives and 2 to 100 trials, we calculated the probability of obtaining any given hit rate due to random guessing alone according to the binomial distribution. Hit rates with probabilities p > 0.05 were interpreted as being likely to occur due to random chance alone, whereas hit rates with probabilities of p ≤ 0.05 were interpreted as being unlikely to occur due to chance alone. For sound localization experiments with speakers at fixed positions, the expected probability of a random hit was also calculated using the binomial distribution. The expected angular root mean square (rms) error in sound localization resulting from the random selection of sound sources was investigated using Monte Carlo simulations. A new aspect in the interpretation of test results was identified for situations in which the observed number of hits is much lower than would be expected due to chance alone. For test methods incorporating a relatively low number of alternatives and a sufficiently high, yet clinically feasible, number of trials, both upper and lower thresholds for chance-level performance could be identified. This lower threshold represents the lowest hit rate which can be expected through random chance alone. Extending interpretation of results to include this lower threshold affords the ability to not only identify performance significantly superior to that of chance, but also that significantly poorer than chance and thereby represents a simple method for the objective detection of malingering.The primary aim of this study was to extend existing theory on the relationship between chance-level performance and the number of alternatives and trials in closed-set, forced-choice speech audiometry and sound localization methods. When calculating chance performance for closed-set, forced-choice experiments with multiple trials, the binomial distribution should be preferred over the simple 1/ Audiometry involves the use of listening tasks to assess a person’s ability to detect, discriminate, localize or recognize various aspects of acoustic stimuli. Though comprising some of the most ecologically valid methods within the standard audiological test battery, both speech audiometry and sound localization tasks are nonetheless affected by a number of factors independent of the listener’s hearing status. One factor, which despite its relevance has received relatively limited attention, is the likelihood that the listener might correctly perform a given task by chance alone. This test characteristic is especially influential when implementing closed-set, forced-choice methodologies, such as is routinely done in both clinical and research capacities for patients of all ages. In contrast to open-set speech audiometry, where the listener is tasked with producing one response out of effectively unlimited alternatives, in closed-set, forced-choice speech testing, possible responses are limited to a small number of known response options. As the number of response options  is limited and the listener is required to provide a response for every trial (forced-choice), the probability of randomly guessing the correct response (hit) may become significant.a). However, the nature of this relationship is more dynamic than is commonly assumed. Only in instances of a single trial or infinitely many trials does chance-level performance equal the reciprocal of the number of alternatives. This is due to variation in the distribution of random hits across multiple trials. Rather than being constant, the number of hits achieved by guessing will change from multiple trial assessment to multiple trial assessment, varying around the chance-level probability of a single trial (1/a). It is of some concern, then, that in the overwhelming majority of publications using closed-set, forced-choice methods with multiple trials, the chance level hit rates are misinterpreted to be constant and identical with the probability of success in a single trial (1/a), irrespective of the number of trails conducted in the test. Examples of well-cited papers accepting this assumption are [As the number of alternatives falls, the probability of correctly performing a task by chance alone rises. A test result can be interpreted as being superior to chance performance if the proportion of hits (hit rate) is higher than the chance level. Traditionally, chance level has been defined as a fixed probability, calculated from the reciprocal of the number of alternatives 1//a. Howevtion are , to nametion are .The primary aim of this study was to extend existing theory on the relationship between chance-level performance and the number of alternatives and trials in closed-set, forced-choice speech audiometry and sound localization methods through recognition of the random nature of guessing across multiple trials. This extension is grounded in the mathematics of the binomial distribution, wherein its standard deviation describes the inherent scatter of hit rates achieved by chance in multiple trial measurements, which occur with certain probabilities based of the binomial distribution. Applying the binomial distribution, the influence of chance on the test results can be calculated to get an exact probability of chance occurrence for each test result. It is applicable to all closed-set, forced-choice assessments with binary outcomes  and multiple trials.Leveraging properties of the binominal distribution to interpret speech audiometry results is not entirely new. Hagerman was the first to use the binomial distribution in modeling the reliability of speech audiometry  and Thorp = 1/a, where a is the number of available response options. As such, the probability of hits by random guessing remains constant for all single trials within a multiple-trial, closed-set, forced-choice test, as long as a does not change and unless there is a systematic influence of effects such as learning or fatigue across assessments (which in this work we assume will not occur). The probability distribution of such a binary random variable which takes the value 1  with probability p and the value 0  with probability q = 1 − p is subject to the Bernoulli distribution, which is a special case of the binomial distribution for a single trial .The following sections provide a brief introduction to the theory and application of the binomial distribution in closed-set audiometric procedures. Generally, the probability of randomly selecting a correct answer (hit) from a given set of alternative response options in a single trial has been defined as 1 < n < ∞), the binomial distribution results in probabilities of hits due to chance which depend on the number of alternatives (a) and the number of trials (n). Even if the probability of a hit by chance is constant in every single trial and the inherent probability of hits due to chance does not vary, the measured number or proportion of hits (hit rate) due to chance certainly varies across many multiple-trial assessments. This variation is a fundamental property of chance. Hence, in multiple-trial assessments, the number of hits or the hit rate by chance should not be assumed to be constant, calculated according to the probability of success in a single trial (1/a). This holds only for a single trial or an infinite number of trials , but not for small data sets with a limited number of trials. Rather, in multiple-trial measures, the single-trial probability 1/a is the mean (expected) hit rate by chance p of success due to chance for a single trial asTo calculate the probability of observing a given hit rate due to chance alone as a binomial variable, the hit rate P(k) of observing a hit rate H of k hits in n trials purely by chance is given by the probability mass function of the binomial distributionk = 0, 1, 2, …, n, withThe probability μ) of the binomial distribution isHμ is equal to the single trial success probability p:The mean number of hits (kP(k) for k observed hits by chance of assessments with different numbers of alternatives a and trials n can be calculated.Using Eqs a and n, in one-sided testing the largest hit rate by chance with p > 0.05 is defined as the upper threshold of random guessing (U). Usefully, for certain combinations of a and n, an additional lower threshold (L) for hit rates by chance, for which p > 0.05, can also be identified. In the case of two-sided testing, the critical value of p will be p > 0.025, because the probability of p > 0.05 is divided into the upper and lower tail of the binomial distribution. In single-sided testing, only observed hit rates outside one side of the interval between upper or lower boundaries are of interest, which occur with chance probabilities of p ≤ 0.05, so that they deviate significantly from the expected hit rates on the basis of purely random guessing. In two-sided testing, observed hit rates outside either the upper or lower boundaries are relevant and p ≤ 0.05 is the sum of the probabilities for significantly deviating hit rates outside the interval divided into p ≤ 0.025 each for hit rates above the upper or below the lower boundary.With the calculated probability of the random occurrence of a given hit rate, both one-sided and two-sided tests of significance can be performed to identify results with low-likelihood of having occurred due to chance alone. In this study, for any combination of U, the result can be interpreted as being significantly better than chance. Second, if the proportion of observed hits is lower than L, the result will be significantly lower than chance and malingering or systematic errors on the part of the equipment, the examiner, or the listener, might be suspected. Sometimes, a listener is not willing to perform correctly in a closed-set, forced-choice task and deliberately selects. This behavior can be detected by the fact that, with a sufficiently high number of trials and a small number of alternatives, a certain number of hits can be expected by chance with a probability > 0.05. In this way, the lower threshold L meaningfully increases the interpretative power of closed-set methods because malingering or aggravation of hearing loss can be detected with the precision of statistical significance.In this way, two clinically relevant observations are made possible by single-sided testing of significance: First, if the observed hit rate is above U and L are calculated for chance-level hit rates for typically used numbers of alternatives and trials in closed-set, forced-choice audiometric methods and for root mean square (RMS) errors in closed-set, forced-choice sound-source localization experiments. In the second part, the proposed method of significance testing for malingering will be presented.In the first part of this paper, k) is transformed into hit rates H by For any closed-set, forced-choice task with 2 to 10 alternatives and 2 to 100 trials, we calculate the probability of hit rates due to random guessing using P(k) > 0.05 will be interpreted as significantly influenced by chance in single-sided testing. Hence, hit rates with chance probabilities of P(k) ≤ 0.05 will be interpreted as significantly free of chance. For certain combinations of number of alternatives (a) and number of trials (n), the lower threshold (L) of random guessing is the smallest hit rate H for which the chance probability is P(k) > 0.05. The upper threshold (U) is defined as the largest hit rate with P(k) > 0.05. Single-sided testing is used when the observed results may differ from those expected by chance in only one direction. For example, single-sided significance testing would be appropriate if one were only interested in cases with hit rates either larger or lower than U. This is the case in the vast majority of clinical issues. In this example, the probability for randomly guessed hit rates either higher than U or lower than L would be P(k) ≤ 0.05 in each case.The decision as to whether observed hit rates were significantly free of chance can be based either on single-sided (one-tailed) or two-sided (two-tailed) tests of significance. Hit rates with chance probabilities U or smaller than L. For two-sided statistics, the total probability of randomly guessed hit rates both above U and below L is P(k) ≤ 0.05, which yields P(k) ≤ 0.025 for each threshold. The higher and lower thresholds, U and L, are therefore the largest and smallest hit rates which can be achieved by chance alone with a probability of P(k) > 0.025 for each of the thresholds. Observed hit rates higher than U or lower than L, thereby occurring with a probability of P(k) ≤ 0.05 for each threshold in the case of single-sided testing and P(k) ≤ 0.025 in the case of two-sided testing, will be defined as being significantly independent of chance.Two-sided testing can be conducted when results in both possible directions are of interest. That is to say, when one is interested in both hit rates larger than U and L will also be calculated for RMS errors by pure chance in sound-source localization experiments applying Monte Carlo simulations. In the first step, one speaker will be set as the target sound source out of the number a of available speakers. Then a random selection is made from the available loudspeakers, which is simulated by the binomial distribution , an incorrectly selected loudspeaker is determined by a random number distribution with uniform probability of 1/a in a second selection run (response). Now it has to be checked that the set and the randomly selected loudspeaker (response) are actually different, otherwise a new random selection will be made. Only in case of a wrong random selection, the angle between the set and the wrong selected speaker will be determined as angle error. This loop is repeated until the given number of n trials with false responses has been reached. In the end, the simulated random angle errors will be averaged as RMS error over the number of trials. Different Monte Carlo simulations were carried out for typical combinations of numbers of speakers, angles between them and numbers of trials. For each configuration of speakers and number of trials, the number of simulated subjects was 100,000 to calculate a reasonable exact forecast of random RMS errors. U and L were calculated from the parameter of the resulting distribution of RMS errors to get the upper and lower thresholds of RMS errors for single- and two-sided tests of significance. The Monte Carlo simulation was performed with PTC Mathcad Prime 5.0 .ribution  with theAn example calculation of single-sided and two-sided probabilities of hit rates by pure random guessing for a test with four alternatives and 20 trials is given in U and L of hit rates by chance for tests with 2 to 10 alternatives and 2 to 100 trials for single-sided testing is presented in n (rows) and alternatives a (columns) is either higher than U or lower than L, the result can objectively be interpreted as being significantly different from results which would be expected due to chance alone. The probability of observing hit rates either higher than U or lower than L by chance alone is P(k) ≤ 0.05. U and L for two-sided testing are presented in L and higher than U can be considered valid and meaningful. For example, a given participant’s hit rate can be lower than, higher than, or between the thresholds for random guessing. In those measurements, the sum of the probabilities for hit rates by chance less than L and greater than U is P(k) ≤ 0.05. Hence, the overall probability of P(k) ≤ 0.05 for hit rates outside the expected range for chance results is divided between the upper and lower thresholds, resulting in P(k) ≤ 0.025 for any threshold. Two-sided testing increases the range of hit rates possible through chance alone (e.g. (1/a) of the probability distribution for increasing numbers of trials. At the same time, L increases from zero and opens a range for results below L that deviate significantly from the hit rates by chance.The complete set of one e.g. , as compone e.g. . In geneL), which represent the dividing lines separating results high enough to be potentially due to chance from those so poor that they are likely independent of chance, only occurred in cases where the number of alternative responses was low and the number of trials was high. a) and the U and L. For a closed-set speech audiometry assessment consisting of 20 words  and 2–10 alternative responses possible per trial, the probability of no hits (hit rate = 0) due to chance was P(k) ≤ 0.05 in single-sided testing when 2–7 alternatives were provided. As the number of alternatives decreased, the probability of random hits increased and results with no or very few chance-related hits became less common. Even in the absence of audibility, a listener is required by the nature of forced-choice testing to select a response. If this selection can be assumed to occur randomly, the listener should successfully complete the task at p > 0.05. A complete lack of hits is to be expected only in instances of technical malfunction, misunderstanding of the task, or intentionally poor performance on the part of the listener. The range of significant results below the lower threshold can be increased for the same number of alternatives by increasing the number of trials. Lower thresholds (a), was evaluated by a re-evaluation of published data describing the localization abilities of children with bilateral cochlear implants [The potential clinical benefit of incorporating the hit rates’ true scatter with the binomial model presented in this study, as opposed to the commonly used constant hit rate by chance model  model. The binomial limits for significantly better results (single-sided testing) were found to be 0.433 for U and 0.233 for L. Therefore, only results outside these limits can be considered significantly independent of chance. The conventional model resulted in a single, constant threshold of 0.33, with results above this threshold being described as significantly better than chance.In the re-evaluation, the proportion of test results significantly better or worse than would be expected by chance alone was determined for each condition . The criThe proportion of children with results which could be described as significantly better than chance was lower for the binomial model than the conventional model for all 3 listening conditions, a difference which suggests that clinical interpretation of the dataset depends in large part on the manner in which random chance is modelled. For example, of the 18 children who completed testing when using the most recently implanted cochlear implant monaurally (mono 2nd CI), 16 performed better than the conventional chance threshold of 0.33. More precise results obtained using the binomial model and single-sided testing reveal performance significantly better than chance in only 13 ears. Therefore, the individual probability of a child to significantly improve localization with a second implant was 16/18 (89%) in the instance of constant chance level modelling and 13/18 (72%) using the more precise binomial model. It is possible then, that use of the conventional model resulted in an overestimation of the localization abilities and the probability of individual improvements of the children in this test condition. The finding that the most commonly used calculation method overestimates the number of better than chance results in comparison to the interval of hit rates by chance of the binomial distribution can be generalized.L and U for random RMS errors were calculated for popular loudspeaker arrangements and one-sided and two-sided testing  angle errors. Here, the angle between the target and the incorrectly selected loudspeaker is determined and the RMS error is calculated over several trials. In the Monte Carlo simulation, the angle error expected by random guessing is calculated with the hit probability from the binomial distribution. If the test runs are repeated several times in multi-trial experiments, this results in an interval of angle RMS errors with defined probabilities. From this,  testing . These la alternative targets in any given trial is subject to the Bernoulli distribution. For measurements with multiple trials (n > 1), however, the Bernoulli distribution changes into the binomial distribution and the observed hit rates guided by chance alone vary randomly from assessment to assessment. The conventional use of the constant hit rate 1/a, independent of the number of trials, is only accurate for instances in which either only 1 or infinitely many trials are conducted. In the latter case, the binomial probability converges to 1/a. In assessments with a limited number of trials, such as is common to clinical audiometric testing, the random hit rate is not constant, but rather varies according to the standard deviation of the binomial distribution. An advantage of recognizing the influence of the binomial distribution is that it provides an exact probability for observed hit rates in cases of pure random guessing. Thus, significance testing can be performed to determine whether a result is objectively better or worse than would be expected by chance alone. In the majority of closed-set, forced-choice audiometry studies with multiple trials, all hit rates above the single trial chance level of 1/a have been erroneously considered significantly free of random effects and thus valid. In this study, however, recognition of the variable effectiveness of random guessing allowed for the definition of thresholds (U and L), which allow for a precise objective, test-specific distinction between results significantly affected by chance from those significantly different from the results expected by chance alone.Randomly selecting 1 of U and L, beyond which the results deviate significantly from hit rates by pure guessing. The upper threshold U determines the maximum hit rate. However, the lower threshold L, which determines the minimum hit rate to be expected solely from random guessing, is of particular importance. This is a new aspect in the interpretation of chance-level performance that leads to more information through the application of the binomial distribution. For a clinical trial, it would therefore be advisable to use test conditions where both U and L can be used to interpret the test results. Doing so offers a clinically useful advantage, as the lower threshold can be applied as a means of assessing results for malingering or systematic technical or procedural errors. For instances in which closed-set speech audiometry is used for the purpose of determining the extent of hearing damage for a work-related injury case, for example, this method provides an objective means for the clinician to better interpret both good and poor results. Obtaining results significantly poorer than would be expected due to chance alone (below L) might be an indication that a patient is simulating a complete loss of speech understanding by intentionally selecting incorrect answers. The method would also be beneficial in differentiating between patients with poor speech understanding abilities and those performing poorly due to lack of understanding of the task. Irrespective of the cause of the poor performance, for closed-set, forced-choice tests with the optimized characteristics of low alternative and high trial numbers, the lower threshold of guessing (L) represents a valuable, new source of information for the statistically valid interpretation of speech audiometry results.The investigation and interpretation of hit rates better than chance probability is common practice. However, it is often neglected to interpret hit rates that are lower than those that can be expected by chance. Application of the binomial distribution allows for a new significance test-based method for the objective interpretation of results below chance levels. With the binomial model, it is possible that a carefully balanced combination of number of trials and alternatives provides two thresholds for hit rates, The following example illustrates the benefit of the lower threshold for significant different hit rates from random guessing. During the localization tests, one child stood out due to severe fatigue. He had to be especially motivated for the last test . His test result was then so low that it was well below the lower limit of the hit rate by chance, L . This gia model (13/18 vs. 16/18). This finding suggests that the effect of sequential cochlear implantation on lateralization performance might have been substantially overestimated if the unrealistic constant hit rate equal to the chance probability 1/a of a single trial is assumed for multi-trial measurements.In addition to clinical use, utilization of the binomial model also influences interpretation of research results. The use of constant hit rates to define chance-level performance in multi-trial closed-set, forced-choice testing is based upon the untenable assumption that randomness does not apply to hit rates across trials. By accounting for the random distribution of success and failure across trials, the clinician is provided with a simple, objective tool to further support decision-making.The conventional handling of random guessing in closed-set, forced-choice testing as a constant variable should be limited to single-trial methods. In conventionally multi-trial methods, like speech audiometry or localization experiments with many words or sound directions per assessment, the probability of hits by pure guessing varies randomly. This results in an range of possible hit rates by chance that can be calculated from the binomial distribution and which depend upon both the number of alternatives and the number of trials. The use of the binomial distribution adds more exact probabilities for hit rates or RMS localization errors by random guessing. Using certain combinations of low numbers of alternatives and sufficently high, yet clinically practical, numbers of trials leads to a lower threshold of hit rates or RMS localization errors than is likely to be achieved by guessing alone. Hit rates or RMS localization errors smaller than these lower limits can be interpreted as significantly free of random guessing. This may allow the simulation of a severe hearing disorder to be detected with the precision of tests of significance. In this way the application of the binomial model extends the interpretation of multi-trial, closed-set methods.


There is insufficient knowledge about the functional and medical recovery of older people infected with SARS-CoV-2. This study aims to gain insight into the course of functional and medical recovery of persons who receive geriatric rehabilitation (GR) following SARS-CoV-2 infection across Europe. Special attention will be paid to the recovery of activities of daily living (ADL) and to the GR services offered to these patients.A multi-center observational cohort study.This study will include several European countries (EuGMS member states) each providing at least 52 comparable routine datasets (core dataset) of persons recovering from a SARS-CoV-2 infection and receiving geriatric rehabilitation. The routine data will be anonymously collected in an online CASTOR database. The ethical regulations of each participating country will be followed.ADL functioning.Length of stay, discharge destination, hospital readmission and mortality. Other variables that will be collected are quality of life, treatment modalities, complications, cognition, frailty, mood/anxiety, BMI, nutrition and pain. All variables will be reported at admission and compared with follow-up scores .This study will explore the effect of geriatric rehabilitation on post-COVID-19 patients, especially on ADL recovery, and the variety of geriatric rehabilitation services across Europe. Information from this study may help improve recovery of older persons infected with SARS-CoV-2 and improve geriatric rehabilitation services in the ongoing COVID-19 pandemic. The COVID-19 pandemic is hitting the world hard. Older people over the age of 70 years are more likely to get very ill when infected with SARS-CoV-2. The majority of patients admitted to the hospital with COVID-19 are in this age group. They have the highest morbidity and mortality all infected people. Some of them need intensive care, including ventilatory support. COVID-19 is often associated with prolonged hospitalisation and sequelae include multi-organ failure, pulmonary dysfunction, physical deconditioning, chronic fatigue, sarcopenia and pressure ulcers. There is also a high incidence of mental problems following COVID-19 including cognitive decline, Post-Traumatic Stress Disorder (PTSD) and Post-Intensive Care Syndrome (PICS).  To regaiBecause COVID-19 is a new illness, with unique constellations of symptoms affecting multiple body systems , we do nGeriatric rehabilitation is a multidimensional approach of diagnostic and therapeutic interventions, the purpose of which is to optimise functional capacity, promote activity and preserve functional reserve and social participation . PatientIt is known that infections are associated with deterioration in performance of activities of daily living (ADL) among vulnerable older people who had no ADL restrictions before the infection . So, it A number of COVID-19 patients have required intensive care admission, therefore rehabilitation experiences from other ICU patients may be useful as we learn how to rehabilitate those with COVID-19 –14. RehaThe members of the Special Interest Group for Geriatric Rehabilitation of the European Geriatric Medical Society (EuGMS) designed this study to get insight into the course of functional and medical recovery in older persons affected by SARS-CoV-2 receiving geriatric rehabilitation across Europe.Therefore this study aims to: 1) explore the course of ADL recovery and influencing factors; 2) describe other outcomes after geriatric rehabilitation in post-COVID-19 patients and; 3) describe geriatric rehabilitation services provided to post-COVID-19 patients across Europe.An international multi-center observational cohort study. During one-year (October 2020 – October 2021), patients will be enrolled in the study in geriatric rehabilitation facilities of EuGMS members across Europe.The study will be conducted according to the principles of the Declaration of Helsinki (2013 version) and in accordance with the General Data Protection Regulation (GDPR) and in full conformity to any applicable state or local regulations in the participating countries.The study population will consist of older people rehabilitating after a SARS-CoV-2 infection in a geriatric rehabilitation setting in one of the participating European countries.Recovering from a SARS-CoV-2 infection, confirmed with Polymerase Chain Reaction for viral RNA, serology for antibodies against SARS-CoV-2, or alternative tests as they become established and nationally mandated by individual governments.Accepted into a geriatric rehabilitation service, either institutionally-based or provided at home.Presence of severe cognitive impairment, which leads to insufficient decisional capacities to participate in the study.Subjects who did not give informed consent, or who have opted out of using their anonymous data for research purposes where opt-out is an option.Eligible participants will be recruited in sites for geriatric rehabilitation in several countries, of which Germany, the Netherlands, Belgium, Switzerland, United Kingdom and Russia have already expressed intention to participate. In these sites, post-COVID-19 patients admitted for geriatric rehabilitation will be informed about the study and asked if they object to the use of their anonymized regular care data for research purposes to improve geriatric rehabilitation after COVID-19 infection. If they do, the data will not be used (optout procedure). In some countries this will be conducted under the guidelines for service evaluation and audit, as it uses routine data, held entirely by the clinical care team. Where this is not possible because of local legislation or guidelines, informed consent will be obtained. We propose to exclude participants who lack the mental capacity to consent to participation in research or service evaluation, as arrangements for inclusion of such participants are highly variable between countries. Such participants are unlikely to be common in geriatric rehabilitation facilities in most countries and we do not think, therefore, that our sample will be significantly biased by their exclusion.The settings in which geriatric rehabilitation is provided are heterogenous across EuGMS countries. In the Netherlands geriatric rehabilitation is mainly provided in, or run by, nursing homes, in the United Kingdom it can be provided in intermediate care facilities or community hospitals, and in Germany, Belgium, Switzerland and Russia it takes place in geriatric rehabilitation facilities or in special rehabilitation/geriatric wards in the hospital. In several of these countries it can also be provided in the home environment with the support of specialist teams.Participants will receive standard rehabilitation treatment according to the discretion of clinical teams, which will likely be adapted to the specific needs of post-COVID-19 patients. This treatment includes physical therapy, occupational therapy, and medical treatment by an advanced nursing practitioner, geriatrician or medical specialist. Additional ad hoc input by other therapists, including but not limited to speech and language therapists, dieticians, orthotists and podiatrists, will be captured. This study will not influence any therapy provided or decisions about the medical treatment or treatment programs already used in the participating geriatric rehabilitation setting.The primary outcome measure is: ADL functioning.ADL functioning will be assessed with the Barthel Index, Utrecht Scale for the Evaluation of Rehabilitation (USER) or Functional Independence Measure (FIM), depending on use in the participating country. The USER  and FIM The secondary outcomes are separated into functional and medical outcome measures and rehabilitation descriptors .Additional functional and medical outcomes include: complications, nutritional status (including Body Mass Index), performance of mobility/balance, muscle strength, fatigue, dyspnea, cognition, mood, pain, quality of life, post-traumatic stress syndrome and mortalityGeneral rehabilitation descriptors are length of stay, discharge destination, and hospital readmission. GR service descriptors are kind of professionals involved, and kind of treatment given.For each participating geriatric rehabilitation facility in Europe one instructed local care professional will complete an online CASTOR database  in whichDemographic data: Year of birth/age, gender, comorbidity, and premorbid residency of the participants.Prior information from hospital or general practitioner (GP): number of days of hospital admission, number of days at the ICU, complications during hospital stay or at home , and SARS-CoV-2 diagnosis confirmed by PCR or Serology.At admission and discharge in geriatric rehabilitation: in all participants, a core dataset, which includes the primary and secondary outcome parameters, will be collected. See table Follow-up: at 6 weeks, 6 months following regular care in the participating countries: ADL functioning, quality of life, and post-traumatic stress syndrome.As shown in Table The primary outcome is ADL functioning (Barthel index or derived from the USER or FIM). The Barthel index is recommended to be used as ADL measure for research and care practice in older populations . In our Descriptive statistics will be used to give an overview of characteristics of the participants in the participating countries for all primary and secondary outcomes.A paired sample student t-test will be used to test the difference between ADL functioning at admission and follow-up per participating country.Multivariable analyses will be used to evaluate the influence of individual factors  sample student t-tests and Mann-Whitney U-tests will be used for parametric and non-parametric continuous or ordinal variables respectively, whilst or chi-square tests will be categorical variables.No imputation will be used for missing data. We will report the proportion of missing data for each variable. The level of significance will be set at p < 0.05.Post-acute care, including rehabilitation, is an important aspect of the recovery of COVID-19 survivors in many countries around the world . While mIn contrast to many other current COVID-studies , 32, theBecause geriatric rehabilitation structures are heterogenous in Europe , the basThis study will focus on a prospective observation of routine medical and therapeutic care adaptions in post-acute geriatric rehabilitation of the new patient group «post-COVID-19 survivors», excluding patients without COVID-19.The study will identify specific requirements for and barriers to successful rehabilitation of older COVID-19 survivors. This will help in the future to better prepare and triage these persons for geriatric rehabilitation and to focus on special therapies during COVID-19 geriatric rehabilitation. We will also gain a sense of how geriatric rehabilitation services work across the continent in times of pandemic.This is the first study examining COVID-19 rehabilitation on a European level. It uses routine care data and therefore requires minimal time investment of care providers. This study will provide knowledge about the effect of routine post-acute geriatric rehabilitation care on recovery of ADL in older post-COVID-19 persons. In addition, it will provide insight into the variety of geriatric rehabilitation services offered in different European countries during the SARS-CoV-2 pandemic. Differences in routine post-acute geriatric rehabilitation care results and structures between different European countries will be assessed.A limitation of this study is the observational study design and the likeliness of missing data due to the use of routine care data. Another limitation is that the study does not cover all post-acute geriatric rehabilitation patients. Patients with severe cognitive impairment, which leads to insufficient decisional capacities to participate in the study, will be excluded. Observational studies can measure correlation between exposures and outcomes but cannot imply causality because of the absence of control data. We will, however, be able to make important inferences because of the likely size of the sample and the expected variation in practice between European countries. Due to the use of routinely collected data, inferences from this study will be restricted to the variables collected in routine practice. The choice of the Barthel Index (ADL functioning) as the primary outcome will be affected by the usual limitations of this measure, including ceiling effects (the inability to measure improvements beyond the maximum threshold) and the fact that the Barthel Index is an ordinal, rather than a continuous scale. However, we expect that the Barthel Index is sensitive enough to capture the change in ADL among post-COVID-19 patients.This study will explore the effect of geriatric rehabilitation on post-COVID-19 patients, especially on ADL recovery, and the variety of geriatric rehabilitation services across Europe. Information from this study may help improve recovery of older persons infected with SARS-CoV-2 and improve geriatric rehabilitation services in the ongoing COVID-19 pandemic.This study evaluates the course of functional and medical recovery during routine geriatric rehabilitation care in older people affected by SARS-CoV-2.This multi-center observational cohort study will include facilities in several European countries and observe functioning in Activities of Daily Living, length of stay, discharge destination, hospital readmission and mortality as outcomes.Information from this study may help improve recovery of older people infected with SARS-CoV-2 and the geriatric rehabilitation services offered to them, and also inform development of services beyond the pandemic.