The utilization of inter-subspecific indica–japonica hybrid rice has always been considered due to its stronger heterosis characteristics. However, indica–japonica hybrids face a serious problem of sterility, which hinders the exploitation of their heterosis. In the past decades, the genetic basis of indica–japonica hybrid sterility has been well studied. It was found that in sterile indica–japonica hybrids, female sterility was mainly controlled by the S5 locus and male sterility by the Sa, Sb, Sc, Sd, and Se loci. In this study, we developed wide-compatible indica lines (WCILs) by pyramiding multiple neutral (n) alleles of the hybrid sterility loci. First, we identified nS alleles of the loci in single-segment substitution lines (SSSLs) in the genetic background of indica Huajingxian 74 (HJX74). Then, the nS alleles of S5, Sb, Sc, Sd, and Se loci in SSSLs were pyramided in the HJX74 genetic background. The WCILs carrying nS alleles at the S5, Sb, Sc, Sd, and Se loci showed wide compatibility with indica and japonica rice varieties. Therefore, the WCILs will be used to develop inter-subspecific indica–japonica hybrid rice with normal fertility.Since the development of  Oryza sativa L.) is the staple food for more than half of the world’s population  . The ICJLs are compatible with indica but incompatible with japonica in pollen fertility and spikelet fertility (indica–japonica rice is to develop wide-compatible indica lines (WCILs)  . Recentlertility . Another (WCILs) , 2022. HSc gene for hybrid male sterility in their chromosome substitution segments and seven SSSLs carrying the S5 gene for hybrid female sterility in their chromosome substitution segments were selected from the HXJ74-SSSL library  carried the iS alleles, while the japonica variety Taichung 65 (T65) carried the jS alleles  iodine and 1% (w/v) potassium iodide. Pollens were divided into normal pollens and sterile pollens, which were further divided into stained abortive pollens  and empty abortive pollens   . Three pt-test was used to compare the data between the two groups. The Dunnett t-test was used to compare multiple groups with the control group. The least significance range (LSR) was used for the multiple range test among the multiple groups. The chi-square (χ2) test was performed to detect the distorted segregation of three genotypes in F2 populations according to the Mendelian ratio of 1:2:1. SPSS statistics 23.0 and Origin Pro 9.0 were used for data analysis and charting1.For statistical analysis, the percentage data were converted to the square root of the arcsine values. Student’s Sa, Sb, Sc, Sd, Se, and S5 loci associated with hybrid sterility, HJX74 was test crossed with T65, a japonica variety with jS alleles at these six loci, and GLA4, an indica variety with iS alleles at these six loci  = 34.00–62.27 in the five segregation populations of the Sc locus, while χ2(1:2:1) = 9.36–12.19 in the three segregation populations of the Sa locus  and HJX74 showed significantly higher pollen fertility in their F1 hybrids with indica testers than those obtained with japonica testers. In contrast, the other three SSSLs  did not show a significant difference in the pollen fertility of F1 hybrids between the crosses with indica and japonica testers  carried iS5, one SSSL (10-06) carried jS5, and the other three SSSLs  carried nS5 , but that of i/S5jS5 genotype from the crosses between 10-06 carrying j/S5jS5 and SSSLs carrying i/S5iS5 was only 68.34%, which was significantly lower than the spikelet fertility of the other four genotypes  with the nS5 gene were selected to pyramid the two nS genes in the HJX74 genetic background. Three SSSLs with nSc were crossed with three SSSLs with nS5, respectively. In the segregating populations, the plants carrying nSc and nS5 loci were selected. Nine pyramiding lines were developed, which carried nSc and nS5 loci from different donors and nSb, nSd, and nSe in the HJX74 genetic background  with the ckground . TherefoIn the nine WCILs, the plant type was similar to HJX74 . In addiindica testers and five japonica testers . Using the HJX74-SSSL platform, a series of WCIRLs is being developed and will be used to develop indica–japonica hybrid rice by crossing with japonica male sterile lines. Therefore, it is expected that indica–japonica hybrid rice will be the rice of next generation (It is believed that inter-subspecific hybrids have stronger heterosis than intra-subspecific hybrids . Therefoarieties . Therefoneration .The original contributions presented in the study are included in the article/GZ designed and supervised the work, analyzed the data and wrote the manuscript. JG, YL, and LX performed most of the experiments and compiled the experimental data. TY, JZ, ZD, GT, KS, XL, WY, and QT conducted a part of the experiments. HZ, RZ, and SW prepared the experimental materials and supervised some experiments. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Reports on the treatment of bleeding associated with emicizumab administration are scarce. Herein, we report the case of an eight-year-old boy with moderate hemophilia A with an inhibitor who experienced tonsillar hemorrhage while undergoing emicizumab treatment. He visited our hospital for postprandial bloody vomiting. The activated partial thromboplastin time was 20.8 s; only a small amount of hemorrhage was observed in the retropharyngeal space, and tranexamic acid was administered. He experienced hematemesis on Day 2 of hospitalization, and fiberoptic laryngoscopy confirmed hemorrhage from the posterior tonsil. Varicose vessels were observed at the soft palate, and considering thrombosis, an emergency cauterization was performed instead of bypass therapy. In small children, observing the tonsils is difficult, and the coagulation ability of the patient with hemophilia A is inferior to that of healthy people, even under emicizumab administration. Thus, active hemorrhage assessment and appropriate hemostatic control are necessary. Regular replacement therapy, which prevents hemorrhage by replacing the coagulation factor VIII, is generally common in hemophilia A. Although the frequency of replacement decreases with the development of extended half-life factor VIII, some cases are difficult to treat due to the requirement of intravenous injection and the presence of factor VIII inhibitors; this remains a problem in administering the therapy . However2 99% (room air). Bilateral second-degree tonsillar enlargement, a small amount of accumulated blood in the oral cavity, and venous distention in the right soft palate were observed. Hemoglobin concentration (Hb) was 146 g/L, platelet count (Plt) was 248 × 109/L, and activated partial thromboplastin time (APPT) was 20.8 s (reference range: 24.3–36.0 s). Pharyngeal fiberoptic findings showed a small amount of venous hemorrhage from the posterior part of the left tonsil, and varicose veins were observed at the upper right soft palate . Regular replacement of coagulation factor VIII was started; however, the patient was confirmed as inhibitor-positive one month later, and the titer was high at 31BU/mL. Afterward, regular replacement was not performed, and hemorrhage was handled with the replacement of coagulation factor VII. Four months later, the inhibitor titer was high, which increased up to 301 BU/mL. Two years and eleven months after the start of regular replacement therapy, the inhibitor titer decreased to 5 BU/mL but did not disappear. Immune tolerance therapy was also considered, but various reasons—such as the moderate severity level, difficulty in securing vascular access due to obesity, and repetition of traumatic subcutaneous bleeding in joints every one to two months—led to the induction of emicizumab. Two months before hospitalization, emicizumab induction was started with weekly administration of 3 mg/kg for four weeks, followed by biweekly administration of 3 mg/kg, and the course was satisfactory with no hemorrhage. The last emicizumab replacement was performed 12 days before hospitalization. The patient consumed sugar-coated sweet potato chips at night and was presented to the emergency room of our institution because of repeated hematemesis in the subsequent morning. He was hospitalized for detailed examination and treatment. The patient had a height of 144 cm (+3.5 standard deviation or SD), weight 50.2 kg (+4.8 SD), body temperature 36.7 °C, heart rate 110 bpm, blood pressure 126/82 mmHg, respiratory rate 20 breaths/min, and SpOt palate . 9/L and an APPT of 22.7 s, but Hb decreased to 83 g/L. Active hemorrhage from the posterior part of the left tonsil was observed on laryngeal fiberoptic findings (Considering the existence of varicose veins, the tendency of exacerbation of the hemorrhage was very low, as well as the risk of thrombosis, bypass therapy with factor VII was not performed. Tranexamic acid was administered, and spontaneous hemostasis was expected. Small amounts of melena were observed on the day after admission; however, there was no intraoral bleeding during the monitoring period. Approximately 200 mL of hematemesis was observed on day 3 of hospitalization. Hematologic tests showed a Plt of 156 × 10findings , and urgThis case revealed the following points. In hemophilia, severe traumatic hemorrhage can occur despite favorable emicizumab management. Moreover, in pediatric patients, physiologic tonsillar enlargement can be observed, and assessment of bleeding can be challenging. Emicizumab promotes coagulation reactions by bridging factors IXa and X. Due to this effect of emicizumab, APTT would be shortened and does not accurately reflect the capacity for coagulation. A cynomolgus monkey model suggested that emicizumab shortens APTT to the lower limit of normal or below ,3,6, sugIn pediatric patients, physiologic tonsillar enlargement because of repeated infections can be observed, making it difficult to perform detailed evaluations within the pharynx. Tonsillar hemorrhage is often observed following tonsil resection; however, the idiopathic type is most often because of increased blood flow associated with infections . The patIn patients with hemophilia A treated with emicizumab, normal APTT does not always accurately reflect the capacity for coagulation. Therefore, if the assessment of the source of bleeding is difficult in traumatic or mucosal bleeding, careful evaluation, including invasive tests such as fiberoptic testing, should be performed, and appropriate hemostasis should be attempted. Experience regarding emicizumab use in pediatric patients is limited, and evaluation of more patients with hemorrhage is warranted in the future.


BR is a unique, highly lipophilic substance with physiological and toxic effects in the cell membranes of organs and body tissues. The fetus excretes BR through the placenta to the maternal circulation. After birth, BR is thought to act as an antioxidant against the increase in reactive oxygen species caused by the rapid increase in oxygen concentration during the adaptation process from in amniotic fluid to in air. However, bilirubin encephalopathy is a toxic effect of bilirubin. Due to the lipophilic nature of BR, it must be bound to a carrier to be distributed to various parts of the body by hydrophilic blood. This carrier of BR is human serum albumin (HSA). In humans, BR can be excreted efficiently after undergoing photochemical reactions upon high affinity binding to HSA. HSA also plays an important role in the prevention of bilirubin encephalopathy. This review focuses on the developmental and physiological role of bilirubin metabolism during the fetal and neonatal periods.Human fetal and neonatal bilirubin metabolism is centered on  Nonetheless, their in vivo actions are not fully understood. In particular, bilirubin has been the focus of considerable attention because it causes bilirubin encephalopathy. In 1954, Bernhard et al. reported that bilirubin stabilizes and improves the absorption of vitamin A and linoleic acid, a polyunsaturated fatty acid, in the intestinal tract .For BR to be distributed throughout the body, it needs a carrier in the hydrophilic bloodstream. Its hydrophobic physicochemical properties make it suitable for distribution in lipids, mainly in cell membranes. HSA serves this purpose. BR is thought to bind with high affinity to HSA at domain IIA with a binding constant on the order of 10 effects –20. The  effects , 22. Thein vivo antioxidant activity of this cycle  to form oxidation products, and in the latter pathway, BR is oxidized by electron transfer to produce biliverdin, which can be metabolized back to BR by biliverdin reductase, a widely distributed enzyme in the body. However, it is difficult to assess the is cycle .3.4Z,15Z-bilirubin IXα in phototherapy for neonatal hyperbilirubinemia).To validate the evidence indicating that BR acts as an antioxidant, it is necessary to demonstrate both a decrease in BR and an increase in BR oxidation products resulting from the scavenging and quenching of ROS. Therefore, the identification of BR and its oxidation products is important. The oxidation products of BR are shown in in vivo. The following products have been identified: biliverdin  and the bilirubin oxidation products produced by scavenging activity (reaction with ROS) have been detected liverdin –26, biotliverdin , biotripliverdin , exovinyliverdin , endovinliverdin , hematinliverdin , Z-BOX Aliverdin , Z-BOX Bliverdin , Z-BOX Cliverdin , and a hliverdin .4.4Z,15E-bilirubin IXα, while the major product of the structural isomerization reaction is 4E,15Z-cyclobilirubin IXα (Z-lumirubin)  . 4Z,15E- is weak , and the is weak , 41–43.4E,15Z-Cyclobilirubin IXα is the most important compound formed during phototherapy because it polymerizes into a dark brown substance that causes bronze baby syndrome, an adverse reaction to phototherapy, and is ultimately excreted from the body . It. It95). morphism , UGT1A1*UGT1A1*6 –100, andGT1A1*28  as the rt energy , 39, 102t energy . The freperature . Thus, tUGT1A1 in breast milk , increased enterohepatic circulation , genetic polymorphisms (UGT1A1 mutations such as UGT1A1*6 and UGT1A1*28), dehydration, starvation, IL-1β, and α-fetoprotein (UGT1A1 activity in breast milk has also been identified recently. In neonatal hUGTI mice, UGT1A1 metabolizes bilirubin in the gastrointestinal tract to prevent the accumulation of bilirubin. Intestinal UGT1A1 is under control by IKK/NF-кB signaling. Breast milk can inhibit the NF-кB mediated transcription of UGT1A1 (The enterohepatic circulation of this bilirubin is believed to play an important role in breast milk jaundice, which is considered physiological. Reported causes of breast milk jaundice include inhibitors of hepatic oprotein , 104–106oprotein  and epidoprotein  in breasf UGT1A1 .2+, which tends to increase in the neonatal period (via a comparison of bilirubin levels with those of controls. The results did not provide sufficient evidence that bilirubin prevents the development of these diseases through its antioxidant effect (in vitro studies of phototherapy light sources for neonatal hyperbilirubinemia, the reduction in BR levels with light irradiation was thought to be mainly due to photochemical changes (When considering the antioxidant role of bilirubin in neonates, it is necessary to consider the extent to which bilirubin acts relative to many low-molecular-weight antioxidants. In terms of antioxidant concentrations, neonates have higher levels of bilirubin, uric acid, and vitamin C, but lower levels of vitamin E, carotenoids, and vitamin A compared with adults, and bilirubin is often present at the highest concentration among these antioxidants. However, albumin, haptoglobin, and hemopexin, which are proteins with antioxidant properties, are at low levels, while transferrin is high in response to Fel period . Serum bl period  and in rl period , 111. Net effect , 113. Wh changes  and also changes . In addi changes . The Umu changes .in vitro, which was attributed not to bilirubin but to ROS generated by endogenous substances (In vivo effects include those seen in a famous animal study where Gunn rats were treated with riboflavin-5-phosphate and exposed to blue light, which caused adverse reactions such as blistering and bleeding (Daylight irradiation is reported to cause DNA damage bstances , 117. Inbleeding . These rRegarding breast milk jaundice, vitamin A and unsaturated fatty acids, which were first noted for their antioxidant effects on bilirubin, may act as stabilizers in the intestinal tract –5. In ou7.Bilirubin metabolism in the fetus and neonate is centered on BR. The physiological significance of neonatal jaundice, including breast milk jaundice, which occurs only in humans and rhesus monkeys, needs to be studied in terms of antioxidant effects. Phototherapy for neonatal hyperbilirubinemia requires the development of safe and effective light sources that do not increase BR oxidation products, and it is also necessary to determine a safe threshold for the bilirubin level that does not exert bilirubin toxicity but still has antioxidant effects.SI contributed to the conception and design of this review and drafted the manuscript. HO, YK, and TI prepared the figures and table. KK, SN, and TK performed English editing and literature review. TK critically reviewed the manuscript. All authors contributed to the article and approved the submitted version.


To evaluate the role of magnetic resonance imaging (MRI) in the assessment offemoral and acetabular version in developmental dysplasia of the hip(DDH).This was a cross-sectional study of 20 consecutive patients with DDH (27dysplastic hips) who were examined with MRI. In dysplastic and normal hips, we evaluated the followingparameters: osseous acetabular anteversion (OAA); cartilaginous acetabularanteversion (CAA); femoral anteversion; osseous Mckibbin index (OMI);cartilaginous Mckibbin index (CMI); and the thickness of the anterior andposterior acetabular cartilage.The OAA was significantly greater in the dysplastic hips. The CAA, femoralanteversion, OMI, and CMI did not differ significantly between the normaland dysplastic hips. In the DDH and comparison groups, the OAA wassignificantly lower than the CAA, the OMI was significantly lower than theCMI, and the posterior acetabular cartilage was significantly thicker thanthe anterior cartilage.Our findings confirm that MRI is a valuable tool for the assessment offemoral and acetabular version in DDH. Preoperative MRI evaluation has greatpotential to improve the planning of pelvic and femoral osteotomies. It has beenpostulated that developmental dysplasia of the hip (DDH) is associated withexcessive acetabular anteversion-4. However, acetabular retroversion,due to reduced posterior coverage rather than increased anterior coverage, is seenin approximately 18% of cases of untreated DDH-8. It is also acrucial measurement in the preoperative assessment of DDH cases scheduled for pelvicosteotomy, because the type of pelvic osteotomy will be determined by the site ofacetabular deficiency (anterior or posterior). Most osteotomies, including Degaosteotomy, will correct insufficient anterior coverage, whereas the correction of insufficient posteriorcoverage, caused by acetabular retroversion, requires certain other types of pelvicosteotomies. Correction of excessive anteversion helps restore the normal anatomyand biomechanics, as well as ensuring adequate femoral head coverage,10. In contrast, undetected retroversion can lead toosteoarthritis, femoroacetabular impingement, and hip pain in adulthood-14.Acetabular version refers to the position of the acetabular cup in the axialplane,15. However, CT measures onlyosseous acetabular anteversion (OAA). In pediatric patients, the acetabulum hascartilaginous portions, and cartilaginous acetabular anteversion (CAA) is thereforemore representative of the true magnitude of acetabular anteversion. Magneticresonance imaging (MRI) is superior to CT for the visualization of acetabularcartilage and thus for the determination of CAA. In addition, MRI does not exposepatients to ionizing radiation, which has a major impact in pediatricpatients,16.Acetabular anteversion, which is easily measured by computed tomography (CT),typically ranges from 15° to 20°. Abnormal FA isa risk factor for osteoarthritis,18. There iscontroversy regarding the degree of FA in DDH, some studies having shown it to beincreased-21, whereas others have shown nosuch increase,22. That can complicate the decision to performfemoral derotation osteotomy.Femoral version is the angle between a line tangential to the chondral border of theposterior condylar axis and a line passing through the femoral neck axis. Femoralanteversion (FA) is an inward rotation of the axis of the femoral neck, relative tothe femoral condyles, in the axial plane; it can be measured by MRI or CT. It rangesfrom 30° to 40° in children and decreases with age, typically being 13° inadults,24. There are few data in the literature regarding the MI inDDH; it may be normal, decreased, or increased. High and low MIs are indicative of an increased risk ofhip instability and femoroacetabular impingement, respectively.The Mckibbin index (MI), also known as the Mckibbin instability index, is the sum ofthe angles of femoral and acetabular anteversion, that sum typically ranging from30° to 60°. A normal MI is crucial for appropriate hip biomechanicsThis was a cross-sectional study of 20 consecutive patients treated at thepediatric orthopedics and malformation clinic of our institution between July2019 and December 2020. All patients were ≥ 2 years of age, had beendiagnosed with DDH by X-ray, and were scheduled to undergo either triple pelvicosteotomy or combined femoral and Dega osteotomy. There were 27 dysplastic hips,collectively designated the DDH group, and 13 normal  hips,collectively designated the comparison group. Patients who were candidates forclosed reduction were excluded, as were those with cerebral palsy, those withtraumatic hip dislocation, and those with hip dislocation due to sepsis.All MRI examinations were performed in a superconducting, closed 1.5-T scanner. Prior to each examination,patients were sedated by an anesthesiologist. Each examination was performedwith a body coil and with the legs of the patient in the neutral position. Weacquired an axial T1-weighted fast spin-echo (FSE) sequence, with a repetitiontime/echo time (TR/TE) of 423/10 ms, and an axial intermediate-weightedfat-suppressed proton density FSE sequence, with a TR/TE of 3,928/40 ms. Forboth FSE sequences, the following parameters were employed: field of view, 220× 180 mm; matrix, 320 × 224 mm; echo train length, 16 ms; slicethickness, 3 mm; interslice gap, 0.3 mm; and number of excitations, 4. The scantime was 116 s for the T1-weighted sequence and 135 s for theintermediate-weighted sequence. We also acquired a three-dimensional (3D)spoiled gradient-echo (SPGR) sequence, with the following parameters: flipangle, 10°; TR/TE, 10/4 ms; field of view, 220 × 220; matrix, 224× 224 mm; slice thickness, 1.6 mm; interslice gap, 0 mm; number ofexcitations, 2; and scan time, 164 s.The total scan time was 453 s, with two localizers (18 s each), one for theT1-weighted sequence and the other for the rest of the sequences. For theintermediate-weighted fat-suppressed proton density FSE sequence and the 3D SPGRsequence, the scan range was from the iliac crests to the upper femurs. For theT1-weighted sequence, we used two image stacks with parallel imaging and thesame parameters: the first was also from the iliac crests to the upper femurs,and the second was at the level of the knee joint, including the femoralcondyles.We measured OAA and CAA in a slice acquired at the midaxial point of theacetabulum . The FA Data were analyzed with the IBM SPSS Statistics software package, version 20.0. Qualitative data were described as absolute andrelative frequencies. The Kolmogorov-Smirnov test was used in order to determinethe normality of distribution. Fisher’s exact test was used in order to assessstatistical significance, the level of which was set at 5%. The level ofinterobserver agreement was determined by using Pearson’s correlation test tocalculate the intraclass coefficient (ICC) and was categorized as poor (ICC <0.40), moderate (ICC 0.40-0.59), strong (ICC 0.60-0.79), or excellent (ICC≥ 0.80).p = 1.00) or mean age (p =0.955).The mean age of the patients was 2.9 ± 1.12 years . Of the27 dysplastic hips evaluated, 24 (88.9%) were in female patients, three (11.1%) werein male patients, 21 (77.8%) were completely dislocated, and six (22.2%) were foundto present only subluxation of the femoral head. All of the dysplastic hips wereanteverted. The DDH was unilateral in 13 (65%) of the 20 patients and bilateral inseven (35%). Among the 13 patients with unilateral DDH, the right hip was affectedin eight (61.5%) and the left hip was affected in five (38.5%). There were nostatistically significant differences between the DDH and comparison groupsregarding sex (p < 0.001). However, the CAA value did not differsignificantly between the two groups (p = 0.326). The mean FA valuewas slightly higher in the DDH group than in the comparison group, although thedifference was not statistically significant (p = 0.595). Therewere also no statistically significant differences between the two groups in termsof the OMI and CMI values (p = 0.418 for both). The OAA value wassignificantly lower than the CAA value in the DDH and comparison groups(p < 0.001 for both). In addition, the OMI was significantlyhigher than the CMI in both groups (p < 0.001 for both). Thecartilage was significantly thicker at the posterior rim of the acetabulum than atits anterior rim, in both groups (p < 0.001 for both). There wasno statistically significant difference between the DDH and comparison groupsregarding the thickness of the cartilage at the anterior or posterior rim. Theoverall interobserver agreement was strong . used CT to assess OAAand found it to be significantly greater in dysplastic hips, as was the case in ourstudy. Other authors have reported similar findings. In pediatric patients evaluatedby MRI, Mootha et al. alsofound OAA to be significantly greater in dysplastic hips, as did Lu etal.. In contrast, Duffyet al. found no statisticallysignificant difference between dysplastic and normal hips regarding the OAA valuesdetermined from the MRI scans of pediatric patients. That difference could beexplained by the fact that the mean age of the patients was lower in that study thanin ours—7.6 months vs. 33.0 months (2.9 years). In patients with DDH, long-standingdislocation is associated with disease severity, which increases with age. Adevelopmental defect of the anterior acetabulum, which is a recognized phenomenonafter dislocation, results in a loss of the mutual stimulation between the femoralhead and the acetabulum.Many studies have assessed the degree of acetabular anteversion in cases of DDH. Liet al. found it to be significantlygreater in dysplastic hips. That difference could also be attributed to theaforementioned difference in age between their patient sample and ours. To ourknowledge, there has been only one study assessing the progression of CAA indysplastic hips over the long term. That study, conducted by Lu et al., showed that the CAA value waslowest in infancy and increased steadily up to the age of 2 years. Those authorsalso found CAA to be significantly greater in dysplastic hips than in normal hips.The difference in significance between our findings and those of Lu etal. could be explainedby the fact that we employed a different study design, in which we used thecontralateral  hip for comparison. In addition, 22.2% of the hips in our DDHgroup were found to present only subluxation of the femoral head, rather thancomplete dislocation.Although we found CAA to be greater in dysplastic hips than in normal hips, thedifference was not statistically significant, whereas Mootha et al. also found that that theOAA value was significantly lower than the CAA value in dysplastic hips. They alsocategorized CAA as abnormal if it exceeded 21° after infancy, a value larger thanthe mean CAA value in our DDH and comparison groups.In the present study, the OAA value was found to be significantly lower than the CAAvalue, in dysplastic and normal hips. We attribute that to the fact that, in bothgroups, the cartilage was significantly thicker at the posterior rim of theacetabulum than at its anterior rim. However, there was no statisticallysignificantly difference between the two groups in terms of the anterior orposterior cartilage thickness. These results corroborate those of other authors. Luet al. found no statisticallysignificant difference between OAA and CAA in children with normal hips. Thatdiscrepancy could be explained by the difference between our two studies in terms ofthe ages of the patients, which ranged from 6 months to 16 years in the Li etal. study, comparedwith 2-5 years in our study. Albers et al. described changes in the posterior and anterior acetabularcartilage with the appearance of secondary ossification centers after the age of 9years, which led to age-related changes in acetabular version. Lu et al. also found age-related variabilityin the speed of anterior and posterior endochondral ossification. In the presentstudy, we used a 3D SPGR sequence, which has the advantage of providing a moreaccurate assessment of the cartilage thickness, thus informing decisions regardingorthotropic reconstruction.Our findings differ from those of some other authors. Li et al. whoused CT to assess FA in children between 18 and 48 months of age. Mootha etal. also obtainedsimilar results using MRI in children of similar age (12-48 months). In contrast,other studies—including those conducted by Akiyama et al. and Sugano et al.—have shown significant excessive anteversion ofthe femoral neck in adults with a history of DDH. Many authors have suggested thatFA increases with age in dysplastic hips, which could explain the variability acrossstudies,29. Such authors have stated that the primarypathology in DDH occurs at the acetabulum, and that femoral changes, such asexcessive anteversion, are secondary adaptive phenomena. Therefore, excessive FAshould not be encountered in very young individuals. These conclusions have a directimpact on management. In our opinion, derotation with the femoral osteotomy step ofa triple pelvic osteotomy should not be routine and should be decided oncase-by-case basis, as was concluded by Sankar et al..We found no statistically significant difference between dysplastic and normal hipsregarding FA. That is in keeping with the findings of other studies, such as thatconducted by Sarban et al.. Tönnis et al. studied 143 patients with various hip pathologies andfound the MI to be low in all of those patients. In the present study, we found nostatistically significant difference between dysplastic and normal hips in terms ofthe OMI. That discrepancy can be explained by differences in the patient selectionprocess, because those authors included other hip pathologies, such as protrusioacetabuli, coxa vara, and coxa valga. Similarly, we found no statistically significant differencebetween dysplastic and normal hips in terms of the CMI. That was an expectedfinding, given the lack of a significant difference between the two groups in termsof CAA and FA. Likewise, the OMI was statistically lower than the CMI in bothgroups, due to the similar relationship between the OAA and CAA values. To ourknowledge, ours is the first study to assess the OMI and CMI in cases of DDH.The MI represents the sum of the angles of femoral and acetabular anteversion, theeffects of which are thought to be additiveOur study has some limitations. First, we did not stratify the patients by age. Thatcould represent a bias, given that femoral and acetabular anteversion may vary withage. In addition, our sample size was relatively small. Furthermore, because wedeemed it unethical to recruit healthy subjects as controls, we used thecontralateral  hips for comparison purposes, which could also be interpretedas a limitation.The results of this study underscore the importance of MRI in the preoperativeassessment of femoral and acetabular version in cases of DDH. The advantage ofpreoperative MRI for surgical management is that it can preclude the need forroutine femoral derotation. In addition, MRI has the advantage of allowing thevisualization of the cartilaginous framework of the hip. The visualization of theacetabular cartilage by MRI is important in that the apparent increase in OAA is notclinically relevant and should not be taken into account, because the true CAA isnot significantly increased in dysplastic hips.


PM was probably the most effective air pollutant for studying and evaluating urban air quality in the context of tree LMTs. PM2.5 was the fraction most used in these studies. The LMTs most used for PM monitoring were leaf area (Q1) and specific leaf area (Q4). These LMTs were frequently used for their easy measurement and quantification. In urban areas, it was suggested that leaf area was directly related to the amount of PM retained on tree leaves. The PM retained on tree leaves was also used to study other f associated urban air pollutants associated .Urban trees provide different ecosystem benefits, such as improving air quality due to the retention of atmospheric particulate matter (PM) on their leaves. The main objective of this paper was to study, through a systematic literature review, the leaf macro-morphological traits (LMTs) most used for the selection of urban trees as air pollution biomonitors. A citation frequency index was used in scientific databases, where the importance associated with each variable was organized by quartiles (Q). The results suggest that the most biomonitored air pollutants by the LMTs of urban trees were PM between 1–100 µm (Q1 = 0.760), followed by O Trees in urban areas provide different ecosystem benefits such as air quality improvement, oxygen production, carbon sequestration, climate regulation, noise reduction, and ecological enrichment . Trees aSelection criteria for urban tree species are appropriate unless their great diversity is considered. For this reason, phenological, physiological and morphological characteristics, called functional traits have been identified . These dFunctional traits, and in particular leaf morphology, are fundamental aspects in the choice of urban vegetation. It has been identified in different studies that leaf morphological traits act as precise monitors to determine the effects of anthropogenic actions on ecosystems ,11. ThesFunctional traits are defined as the set of phenological, morphological, and physiological characteristics that plants possess to ensure their survival success, provide insight into ecological dynamics, and responses to changes in the environment . Leaf arThe deposition of PM and gas molecules on vegetation  is usually described in terms of a one-dimensional vertical deposition over a homogeneous layer of vegetation . The phyThe type and size of air pollutant affects the deposition on the tree leaves. Thus, variation in the different LMTs alters their effectiveness in the capture of the various air pollutants . DiffereThe main objective of this paper is to study, through a literature review, the LMTs most used for the selection of urban trees as air pollution biomonitors. In this study, the most studied air pollutants worldwide were considered in the context of their association with urban tree leaves. This literature review is relevant because it is a tool for tree species selection options for monitoring, controlling, and improving urban air quality. The paper is structured as follows. Initially, we describe the materials and methods used for this systematic literature review to collect and analyze the selected information. Subsequently, we present results and discussion concerning associated air pollutants, the most used LMTs, and applications in the context of urban air pollution. Lastly, the main conclusions are presented.In this study, a systematic literature review was conducted for documents published worldwide between 2010–2020 about tree LMTs in urban areas in an air pollution context. The LMTs were studied with respect to their use as biomonitors of urban air pollution. The databases used were Scopus, ScienceDirect, and Google Scholar.3), nitrogen dioxide (NO2), sulfur dioxide (SO2), carbon monoxide (CO), carbon dioxide (CO2), PM2.5, volatile organic compounds (VOCs), PM10, and total suspended particles (TSP). These air pollutants correspond to those most commonly reported in the literature concerning urban areas )The findings show the importance of LA as a trait that allows the study of different environmental factors, such as evapotranspiration, light interception, response to irrigation, and ecological factors such as photosynthetic efficiency and plant growth in urban green areas ,62. It w2.5 study, other leaf traits were also reported that allowed a better understanding of its retention by urban trees, including trichomes and stomatal density [Additionally, Singh et al.  reported density ,71. Prev density ,73.The results show that LMTs such as LA and SLA, and to a lesser extent LDMC, can be modified by invasive plant species. These species have leaf traits that allow them to dominate plant communities and functional structure in urban areas . Hence, 3), which supported their use in studies on urban air pollution [In relation to the order of importance in the use of LMTs in an air pollution context, a significant number of documents detected (≈80.0%) used LA to establish different environmental or ecological conditions, either of the same plant or of its ecosystem, possibly due to its ease of measurement. This trend was constant in the documents detected regardless of geographical location , and was repeated for different tree species. Lastly, LA provided information about the different air pollutants retained on tree leaves : green infrastructure (50.0%) [Our results suggest three main applications of leaf macro-morphology in the context of urban air pollution n = : green i (50.0%) ,38,67,76 (50.0%) ,70,77, a (50.0%) . This tr (50.0%) , and by  (50.0%) . In rela (50.0%) ,79,80. U (50.0%) ,81. Inde (50.0%) ,65,82. TAccording to Barwise and Kumar , the int2.5 emissions, and the implementation of green infrastructure in urban areas. These make it possible to manage air pollution levels in a practical, efficient, and economical way [The results suggest that the best way to manage air quality in urban environments is to reduce air pollutant emissions ,40. Howeical way . Vieira ical way  reportedical way . Indeed,ical way ,78.10 retention by urban vegetation [2.5, because strong wind reduced the retention capacity of PM2.5 by the urban vegetation, due to its resuspension and transport through the air masses [2.5 [Additionally, the findings suggest the importance of assessing interactions that occur between the diversity, composition, and structure of urban green areas ,90. Peargetation , but thir masses . This teses [2.5 ,96.3 (Q2) > PM2.5 (Q2) > PM10 (Q3). In in recent years, there has been a growing interest in CO2 the context of global warming. The results suggest that PM is the most effective air pollutant for studying and evaluating urban air quality in the context of the tree LMTs. This is most evident in urban areas with high concentrations of this pollutant . Specifically, PM2.5 is the most used fraction in these studies. Positive correlations between PM2.5 and PM10 (rs = 0.707), and significant correlations between PM2.5 and O3 (rs = 0.926) were observed in studies involving the LMTs of urban trees. The PM retained on tree leaves has also been used to study other types of urban air pollutants . The most used LMTs for urban air pollution biomonitoring are in order of importance LA (Q1) and SLA (Q4). These LMTs are frequently used because of their easy measurement and quantification. It is suggested that in urban areas, LA is directly related to the amount of PM retained on tree leaves. Unlike PM10, with PM2.5 it is necessary to consider the resuspension from the leaf surface of trees by the wind action.The findings of this study on the LMTs most used for the selection of urban trees as biomonitors of air pollution allow us to make the following conclusions. In order of importance, the most frequently biomonitored air pollutants by the LMTs of urban trees are the following: PM—all fractions between 1 and 100 µm (Q1) > O2.5, PM10, and O3, which are responsible for different diseases of public interest. Moreover, species should not only be selected for their ability to remove pollutants from the air, but must be chosen for their suitability to grow in urban environments, e.g., under specific climate conditions or considering invasive species. Lastly, the findings of this study are relevant to deepen knowledge regarding the use of tree LMTs to biomonitor air pollution in urban areas. This research is relevant to the design and implementation of strategies for surveillance, control, and improvement of air quality associated with urban trees .Urban applications of LMTs suggest that green infrastructure is important for improving air quality by the capture of PM


Central diabetes insipidus (CDI) is an uncommon complication of acute myeloid leukemia (AML). Patients present with polyuria either preceding or at the time of diagnosis of AML. We describe the case of a 36-year-old male who presented with a subacute onset of polyuria, polydipsia, nocturia, and fatigue. After an extensive workup, he was diagnosed with AML/CMML (chronic myelomonocytic leukemia) with a normal karyotype with DNMT3A, CBFB, and PTPN11 mutations. Further workup of the polyuria with a water deprivation test helped confirm the diagnosis of CDI along with MRI findings suggestive of hypophysitis. In this report, we analyze the clinical workup for AML and CDI and report the possibility of extramedullary leukemic infiltration associated with DNMT3A mutation, which has been reported as one of the mechanisms in the existing literature. We also discuss other theories hypothesized to cause CDI in AML patients with abnormal karyotypes. Our patient progressed to AML from CMML-2 after a cycle of decitabine, with confirmed gingival and presumed central nervous system (CNS) involvement. He is in minimal residual disease (MRD)-negative complete remission after induction with a CNS-active acute lymphoblastic leukemia-2 regimen. He also received double umbilical cord blood transplantation, conditioned with cyclophosphamide, fludarabine, thiotepa, and total body irradiation (TBI) of 4 Gy. This was complicated by engraftment syndrome for which he is currently being managed. CDI of the patient was corrected by desmopressin administration. Pituitary involvement has been reported in 0.6% of leukemia cases; however, because pituitary involvement and the presence of diabetes insipidus are not necessarily correlated, the true prevalence of leukemia-associated central diabetes insipidus is unknown . DiabeteμL with 32% neutrophils and 17% blasts in peripheral blood), anemia (hemoglobin: 8.9 g/dl), and a normal platelet count. He was admitted and started on hydroxyurea 500 mg daily, and allopurinol 100 mg daily. A bone marrow aspirate (BMA) and biopsy were performed, and he was discharged on the same day. However, because of increased bleeding from the bone marrow site, he returned to the hospital the day after. The BMA/biopsy results were consistent with chronic myelomonocytic leukemia (CMML-2)/acute myeloid leukemia (AML) with normal karyotype with DNMT3A, CBFB, and PTPN11 mutations. After the course of hydroxyurea, the patient was started on decitabine. He also received continuous intravenous hydration with isotonic fluids and was noted to have a urine output amounting to 12–16 litres per day. The polyuria and polydipsia in conjunction with hypernatremia raised concerns for DI. At baseline, he had a serum osmolality of 297 mOsm/kg, a urine osmolality of 99 mOsm/kg, and the urine sodium was less than 20 mEq/L. The patient underwent a water deprivation test along with administration of one dose of desmopressin acetate (0.05 mg) following which his urine osmolality was found to be 260 mOsm/kg establishing a diagnosis of CDI. Further workup with an MRI (magnetic resonance imaging) of the brain showed focal nodular enhancement at the proximal pituitary infundibulum with a measured value of 0.4 cm with slight effacement of the infundibular recess. The pituitary gland also demonstrated heterogeneous enhancement, and these findings were collectively suggestive of hypophysitis. Additionally, there was a loss of the normal posterior pituitary high-intensity signal on a pre-enhanced T1WI which reflects decreased storage of vasopressin that has a T1-shortening effect in patients with CDI. He was treated with desmopressin and symptomatically improved in the coming months. His urine output during his initial inpatient admission amounted to almost 13-14 liters/day (while receiving maintenance intravenous fluids). With desmopressin, fluid restriction, and diligent follow-up by endocrinologists, his urine output decreased to 5-6 liters/day. He reported improvement in nocturia and polydipsia with the treatments. He also received pituitary radiation for secondary prophylaxis.This is the case of a 36-year-old healthy male who presented with subacute onset of excessive fatigue, polydipsia, polyuria associated with nocturia, and cold intolerance. On initial workup, his urinalysis was normal with no signs of infection. His complete blood count was significant for leukocytosis , exposure to ionizing radiation, chemotherapeutic agents , certain RNA retroviruses, and secondary AML in the context of a prior history of myelodysplastic syndromes [The combination of AML and DI is unique, and the diagnosis of DI is mostly made either before the diagnosis of AML or at the time of diagnosis of AML , 6. DI wTypically, a bright spot is seen on T1-weighted MRI, due to vasopressin that is stored in the posterior pituitary. It is not necessary for all the patients with central diabetes insipidus (CDI) and AML to have MRI findings; however, patients can have a loss of the neurohypophysis (posterior pituitary) bright spot, which is suggestive of hypothalamic-pituitary dysfunction . AlthougAccording to the report of Müller et al, out of 18 cases that were evaluated cytogenetically, 89% had abnormal chromosome 7, 44% had abnormal chromosome 3, and 39% had abnormalities of both chromosome 3 and 7 .It is hypothesized that monosomy 7 may lead to abnormal expression of the neutrophil migration gene which causes neutrophil chemotaxis, in turn causing infiltration of the posterior pituitary leading to DI , 9. FurtBased on a study, 90% of ADH is bound to platelets, and only 10% is free in the plasma. This is consequential to ADH uptake by platelets from plasma , 11, 12.A study by Xu et al. explored the possibility of extramedullary leukemic infiltration mediated by TWIST1 in patients with DNMT3A mutation (which was seen in our patient); however, a definite causal relationship is still unclear .Cytogenetic abnormalities can be detected in approximately 50% to 60% of newly diagnosed AML . ClinicaAnalogously, CDI with AML is an unfavorable association and some reports have documented poor clinical outcomes , 6, 16. From a leukemia standpoint, he progressed to AML from CMML-2 after a cycle of decitabine, with confirmed gingival and presumed central nervous system (CNS) involvement. He is in minimal residual disease (MRD)-negative complete remission after induction with a CNS-active acute lymphoblastic leukemia-2 regimen with high dose cytarabine, mitoxantrone, and intrathecal methotrexate. Most recently, he received double umbilical cord blood transplantation, conditioned with cyclophosphamide, fludarabine, thiotepa, and total body irradiation (TBI) of 4 Gy. This was complicated by engraftment syndrome for which he is currently being managed.Endocrine manifestations can be seen in patients with hematologic malignancies. They can be a direct consequence of the malignancy or because of certain chemotherapeutic agents. Their recognition is crucial for prompt management. CDI can be one of the manifestations of AML and carries both therapeutic and prognostic implications. CDI can be managed with desmopressin as seen with our patient. The role of intrathecal chemotherapy and radiation therapy in the pituitary needs to be explored further in adult patients with this presentation.


Bifidobacterium longum BB68S (BB68S) on cognitive functions among healthy older adults without cognitive impairment. A randomized, double-blind, placebo-controlled trial was conducted with 60 healthy older adults without cognitive impairment who were divided into probiotic or placebo groups and required to consume either a sachet of probiotic  or placebo once daily for 8 weeks. The Montreal Cognitive Assessment (MoCA) was used as an inclusion screening tool to screen elderly participants with healthy cognitive function in our study, and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was used to assess cognitive function in subjects before and after intervention as an assessment tool. BB68S significantly improved subjects’ cognitive functions , especially immediate memory, visuospatial/constructional, attention, and delayed memory domains. BB68S intervention increased the relative abundances of beneficial bacteria Lachnospira, Bifidobacterium, Dorea, and Cellulosilyticum, while decreasing those of bacteria related to cognition impairment, such as Collinsella, Parabacteroides, Tyzzerella, Bilophila, unclassified_c_Negativicutes, Epulopiscium, Porphyromonas, and Granulicatella. In conclusion, BB68S could improve cognitive functions in healthy elderly adults without cognitive impairment, along with having beneficial regulatory effects on their gut microbiota. This study supports probiotics as a strategy to promote healthy aging and advances cognitive aging research.Probiotics could improve cognitive functions in patients with neurological disorders such as Alzheimer’s disease, but the effects on cognitive function in healthy older adults without cognitive impairment need further study. The purpose of this study was to investigate the effect of  Research in the field of aging and neuroscience reveals that the human brain shrinks with the process of normal aging, while the ventricles expand and both gray and white matter are reduced , resultiThe gut microbiota was first defined by Lederberg and McCray, accentuating the importance of microorganisms located in the human body in health and diseases . CompellProbiotics, live microorganisms that provide health benefits when administered regularly in the host, substantially affect the composition as well as metabolic output of the gut microbiome ,13,14. PBifidobacterium longum BB68S  is a potential probiotic. The 16S ribonucleic acid (rRNA) sequence of B. longum BB68S is available in the NCBI database under sequence number OP984807. Our previous in vivo and in vitro study evaluated and verified its safety [s safety . In an is safety . Conside10 CFU/sachet) or placebo  after lunch or dinner daily for 8 weeks. Throughout the intervention period, the subjects were asked to abstain from consuming any other probiotics or any dietary supplements with probiotics while they were required to be consistent with their daily diet and exercise, thus excluding their corresponding influence on the test results. To monitor the stability of their lifestyle, subjects were requested to record their daily dietary intake. The subjects received adequate training before recording in their daily diaries. In addition, any adverse events or symptoms of discomfort were also required to be recorded. On day 70 ± 1, upon the completion of the ingestion period, fecal samples were collected in a sterile tube and stored at −80 °C until further analyses. The cognitive functions of the subjects were again evaluated using the RBANS scores. The study was authorized by the China Agricultural University Ethics Committee (CAUHR-2021021) and filed under registration number ChiCTR2200062331 . Written informed permission was acquired from each subject.To investigate the effects of BB68S on the cognitive function of healthy elderly people aged 60–75 years, we designed a randomized, double-blind, placebo-controlled trial. The sample size was estimated according to Assessment of Neurological Status (ANS) scores demonstrated by Xiao et al. . We calcThe subjects’ personal information was collected, including age, sex, disease status, and drug use in the first round of screening. Experienced researchers assessed their physical conditions based on medication history and dietary habits, and patients were screened according to the inclusion and exclusion criteria.http://www.mocatest.org, accessed on 21 November 2022) to define the cognitive health of the elderly. The exclusion criteria were as follows: (i) obvious cognitive decline, or diagnosis with Alzheimer’s disease, mild cognitive impairment, etc.; (ii) hearing, visual, or communication disabilities or difficulties, incapable of living independently, or surgical history of digestive system resection; (iii) history or clinical trace of nervous system disease or psychosis; (iv) history of serious diseases, such as those of the heart, liver, kidney, or hematopoietic system; (v) use of the test-related product  within a short period; (vi) unable to eat the test product according to the regulations, and (vii) participation in other clinical studies.We selected subjects based on the following inclusion criteria: (i) aged 60–75 years at the time of screening and (ii) with healthy cognitive function judged by the Montreal Cognitive Assessment (MoCA) screening tool. The specific criteria were as follows: total MoCA scores were 19 or higher for those with 6 or fewer years of education, 22 or higher for those with 7–12 years of education, and 24 or higher for those with 12 or more years of education. In our study, we used the Chinese Beijing Version of MoCA , age , and MoCA scores . The subjects were evenly and randomly allocated to the probiotic or placebo groups. The research team members remained blind to each participant’s assigned group until all data were collected.Fecal samples were collected before and after intervention. We provided a cryogenic storage box (4 °C) and a sterile tube with a scoop inside the lid, instructing subjects to gather fecal samples into the tubes within 24 h before visiting and transporting them in the cryogenic storage box to the research site. The tubes were kept tightly sealed and stored in the cryogenic storage box until they were sent to the laboratory, following which, the samples were immediately stored at −80 °C until further analyses.Before and after intervention, we used the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) as an assessment tool to assess the subjects’ cognitive function. During the assessment, the subjects were placed in a quiet and undisturbed environment and simultaneously evaluated by two researchers experienced in using the evaluation form. One of the two researchers was required to speak uniformly and clearly to inform subjects of the description of each item, to ensure that they heard all instructions, and finally compute the average of the original scores of the 12 items recorded simultaneously by the two researchers. The twelve averages were then converted to five global domain scores as the final score for the corresponding subjects.The bacterial genomic DNA was extracted from fecal samples according to the method described by Tang et al. . Purity http://drive5.com/uparse/, accessed on 21 November 2022) was used to cluster the operational taxonomic units (OTUs) using a 97% similarity criterion [The original reads were demultiplexed and quality-filtered using the fastp 0.20.0 tool  and interiterion , and chiriterion  was usedt-test was used for the comparison of continuous variables and the chi-square test was used for the comparison of categorical variables. For the primary outcome, RBANS scores at week 8, an analysis of covariance model adjusted for baseline scores was used to examine the difference between the probiotic and placebo groups. With a significant threshold setting at p < 0.05, data analysis was performed using IBM SPSS statistics 23.0.When describing the baseline characteristics, we used the intent-to-treat dataset, comprising all subjects who underwent random assignment to a treatment group, and when analyzing the main results, the per-protocol set was adopted. Normality tests were performed on all continuous variables using the Kolmogorov-Smirnov test. We calculated means (SDs) for continuous variables and counts (percentages) for categorical variables. The independent samples p-values were greater than 0.05).A total of 167 subjects were recruited for screening, and 60 subjects were chosen based on the inclusion criteria. The subjects were randomized to give 30 subjects in each of the placebo and probiotic groups. Ten subjects withdrew their consent and dropped out, including five from each of the placebo and probiotic groups, with 50 subjects finally finishing the trial . The intp < 0.0001). As shown in Table, the BB68S group had significantly higher scores in 4 domains than the control group after 8 weeks of intervention. The score differences  between groups were 4.36  for immediate memory, 2.01  for visuospatial/constructional, 7.29  for attention, and 4.28  for delayed memory. BB68S’s effect on language was nonsignificant (p = 0.141). Changes in RBANS scores after the intervention were calculated and are exhibited in Each subject underwent RBANS assessment at baseline and at week 8, and the effects of BB68S on cognitive functioning were evaluated . BB68S iTo determine the relationship between the improvement in cognitive function and the gut microbiota, we performed gut microbiome analysis for all participants. After the amplification and cloning of bacterial sequences, purified amplicons were sequenced for a total of 50 fecal samples. Finally, 1133 OTUs from all samples were annotated, which were divided into 13 phyla, 23 classes, 56 orders, 109 families, 283 genera, and 600 species.p > 0.05)  . This inp > 0.05). These results indicated that the BB68S intervention did not have a substantial impact on the beta diversity of the gut microbiota.In At the phylum level A, the guBacteroides, Prevotella, Faecalibacterium, Megamonas, Agathobacter, Blautia, Escherichia-Shigella, Roseburia, Subdoligranulum, Bifidobacterium, Ruminococcus, Klebsiella, Dialister, Phascolarctobacterium, Lachnoclostridium, Lactobacillus, Fusicatenibacter, and Coprococcus.Solobacterium and Oribacterium decreased significantly  compared to that of controls. Among the 12 items, list learning, story memory, figure copy, line orientation, coding, story recall, and figure recall scores of the probiotic group improved significantly. Among the 5 domains, only language did not significantly improve. All of the other four domains improved significantly in the BB68S group. The scores increased as follows: 4.36 points for immediate memory, 2.01 points for visuospatial/constructional, 7.19 points for attention, and 4.28 points for delayed memory . In contrast, another study evaluating the effect of drinking lactic acid bacteria-fermented milk on memory only observed significant improvement in memory (the score increased by 4 points), with no change in total RBANS score and other domain scores [Bifidobacterium longum BB68S significantly improved the cognitive function of healthy elderly people, providing strong evidence for future research and investigation.In our study, BB68S intervention significantly improved cognitive function  are needed in the future. Despite these limitations, our study also had some advantages. This study included subjects with diverse education levels and used highly sensitive screening tools specifically for different levels of education. We strictly and effectively evaluated cognitive function and measured the significant effects of probiotics on cognitive function with a short-term intervention among the healthy elderly.Bifidobacterium longum BB68S could improve cognitive function and has a beneficial regulatory effect on the gut microbiota in healthy elderly individuals. This study provides some evidence supporting probiotics as an alternative strategy to advance cognitive aging and promote healthy aging.In conclusion, our research showed that


Multivariate analysis revealed that an opioid dose <30 mg/day  was significantly correlated with the effect of naldemedine. Diarrhea was the most common adverse event (38.2%) among all grades. The efficacy and safety of naldemedine in clinical practice are comparable to those of prospective studies, suggesting that it is effective in most patients.The efficacy and safety of naldemedine for opioid-induced constipation in patients with cancer has not been investigated in clinical practice. We conducted a multicenter, retrospective study to assess the effects of naldemedine among 10 Japanese institutions between June 2017 and August 2019. We evaluated the number of defecations 7 days before and after naldemedine administration. A total of 149 patients  with a median age of 72 years  were included. The performance status was 0–1, 2, and ≥3 in 40, 38, and 71 patients, respectively. The median opioid dose in oral morphine equivalents was 30 mg/day (range: 7.5–800 mg). We observed 98 responders and 51 non-responders. The median number of defecations increased significantly in the 7 days following naldemedine administration from three to six ( Patients with cancer routinely receive opioids for pain management. Prevention of adverse events, such as drowsiness, nausea, vomiting, and constipation, is vital for the continuation of pain management with opioids. Although drowsiness, nausea, and vomiting often occur at opioid initiation and dose escalation, they often improve with tolerance ,2,3,4. IRecently, the peripheral μ-opioid receptor antagonist naldemedine has become available for OIC. Naldemedine is a peripheral μ-opioid receptor antagonist  of δ- and κ-opioid receptors to a similar degree ,8. This The results of a post-marketing surveillance evaluation of the safety and efficacy of naldemedine in clinical practice were recently published. It was found that naldemedine was well-tolerated and effective in patients with various backgrounds and treatment factors, such as age, sex, PS, presence or absence of organ damage, complications, and use of laxatives . MoreoveWe previously surveyed naldemedine use in clinical practice ; howeverThis retrospective study assessed the clinical effects of naldemedine administration in patients with cancer receiving opioid therapy upon admission to 10 Japanese institutions between June 2017 and August 2019. Eligible patients were identified using the electronic medical charts and pharmacy databases. A total of 389 patients with cancer who received naldemedine for the first time in conjunction with opioid medication during hospitalization were identified. Of those, 158 patients who could be observed for at least 7 days before and after the start of naldemedine administration were identified. Seven patients with missing data and two with colostomy whose defecation frequency was difficult to assess were excluded. Finally, 149 patients were included in the analysis . The eliThe patients included in the current study had not previously received naldemedine. They received 0.2 mg of naldemedine orally once a day with opioids, which was continued until termination was judged necessary by an attending physician, unacceptable toxicity, or withdrawal of consent.The number of defecations (times/week) was evaluated for 7 days before and after naldemedine administration. A responder was defined as a patient with three or more defecations/week in the first 7 days after naldemedine initiation and an increase of one or more defecations/week from baseline . Adverse events were graded using the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0).We also investigated the possible association between body mass index (BMI) and the efficacy of naldemedine using a BMI cutoff of 22.0, which is the ideal BMI in the Japanese population  . BMI wasp-value of ≤0.05. All analyses were conducted using JMP software for Windows .The Wilcoxon signed-rank test was used to assess normality and equal variances and test for correspondence between the two groups. Multivariate ordered logistic regression analysis was used to identify factors that predicted efficacy, and the results are described as odds ratios (ORs) and 95% confidence intervals (CIs). Differences were considered statistically significant at a two-tailed Of the 149 patients included in the current analysis, 117 died during the study. The median time from naldemedine initiation to death was 35 days . Patient characteristics are shown in The use of opioids, laxatives, and antiemetic agents is summarized in As shown in p < 0.0001; Next, the frequency of defecation was compared for 1 week before and after naldemedine administration. Then, the change in the frequency of defecation was evaluated before and after treatment in the following groups: all patients, only those who defecated less than three times/week before naldemedine administration, those who received <30 mg/day of morphine equivalent, and those who received ≥30 mg/day of morphine equivalent  . The medp < 0.0001; Moreover, the frequency of defecation during the 7 days was compared before and after naldemedine administration in specific populations. Among patients who had <3 defecations in the week before naldemedine administration (N = 66), the median number of defecations during the 7 days before and after naldemedine administration was 1  and 5 , respectively. Thus, the number of defecations increased significantly after naldemedine administration . Among patients who received a morphine equivalent of <30 mg/day (N = 60), the median number of defecations in the 7 days before and after naldemedine administration was 3  and 6 , respectively. Thus, the number of defecations increased significantly after naldemedine administration , age (<75/≥75), PS (0–2/≥3), BMI (<22/≥22), use of concomitant laxatives before starting naldemedine, and history of chemotherapy within 21 days prior to naldemedine administration did not show statistically significant differences in the effect of naldemedine.Next, the relationship between the efficacy of naldemedine and various clinical factors was analyzed. Multivariate logistic regression analysis was performed for responders . A regulIn this study, we evaluated the frequency of defecation and adverse events in patients with cancer receiving opioids in clinical practice hospitalized for at least 7 days before and after the start of naldemedine. In addition, various clinical factors related to efficacy were examined using multivariate logistic regression analysis.Of the patients included in the study, 65.7% were responders. In other words, 98 patients with ≥3 defecations in the first 7 days after naldemedine initiation had an increase of ≥1 defecation from baseline. This value was comparable to the responder rate of the COMPOSE-4 trial (71%) and that of naloxegol (73%), the same PAMORA ,17. In aIn the COMPOSE-4 and COMPOSE-5 randomized phase III trials of naldemedine in patients with cancer presenting with OIC, those with PS ≥ 3 were excluded . MeanwhiRegarding safety, the most common adverse events of naldemedine were diarrhea 19.6–39.7%) and abdominal pain (1.7%) in Japanese prospective clinical trials of patients with cancer with OIC ,19. In t.6–39.7% Our study had several limitations. First, this was a retrospective analysis, which might have reduced the validity of the data gathered. Consequently, objective assessments, such as the Bristol stool form scale , bowel fIn conclusion, the efficacy and safety of naldemedine in real-world clinical practice, where it is often administered to patients with poor PS and the elderly, are comparable to those of prospective studies, suggesting that it is effective in almost all patients, although the opioid dose may affect its efficacy. However, this was a retrospective study, and further verification in clinical practice is necessary.


Also, their changes after 8-week antipsychotic treatment were investigated. The Positive and Negative Syndrome Scale (PANSS), Psychotic Symptom Rating Scale (PSYRATS), and MATRICS Consensus Cognitive Battery (MCCB) were administered. Receiver operating characteristic (ROC) curves were conducted to evaluate the diagnostic effectiveness of the three biological indicators. Compared to HCs, levels of endotoxin, HMGB1, and C4 were remarkably increased in FES patients after controlling for age, gender, body mass index (BMI) and education years, and the combination of the three biomarkers demonstrated desirable diagnostic performance (AUC = 0.933). Moreover, the endotoxin level was positively correlated with the severity of auditory hallucinations. After 8 weeks of treatment, HMGB1 was decreased significantly in patients but still higher than that in HCs, whereas endotoxin and C4 did not change statistically. The baseline levels of endotoxin, HMGB1, and C4, as well as their changes were not associated with changes in any PANSS subscale score and total score. Our preliminary results suggest that a composite peripheral biomarker of endotoxin, HMGB1, and C4 may have accessory diagnostic value to distinguish SCZ patients from HCs. Additionally, endotoxin might be implicated in the pathogenesis of auditory hallucinations.Innate immune components involved in host defense have been implicated in schizophrenia (SCZ). However, studies exploring their clinical utility in SCZ diagnosis are limited. The main purpose of this study was to evaluate whether circulating endotoxin, high mobility group box 1 protein (HMGB1) and complement component 4 (C4) could act as peripheral biomarkers to distinguish first-episode schizophrenia (FES,  Although the exact etiology of schizophrenia (SCZ) is still largely unknown, accumulating evidence has demonstrated that immune dysfunctions, especially innate immunity as the first line of host defense, are intimately implicated in the pathophysiology of SCZ. The complex interactions between the immune system and brain may contribute to a diverse range of changes in cognition, mood and behavior in psychiatric disorders and has received considerable attention in recent years , 2. AccuPattern recognition receptors (PRRs) and their associated ligands, as well as the complement system are essential components of the innate immunity. PRRs, such as toll-like receptors (TLRs) and receptors for advanced glycation end products (RAGE), not only detect the components of exogenous pathogens , such as Gram-negative bacterial endotoxin , but also are capable of recognizing endogenous molecules released by dying cells or damaged tissues  . High moEndotoxin has been implied in SCZ due to its harmful effect on the brain and behavior, as demonstrated in neurodevelopmental conditions such as maternal immune activation (MIA) –11. On tAdditionally, a growing body of evidence shows that the complement pathway appears to be more active in SCZ , especiaOur previous study showed that FES patients had more dampened instead of enhanced monocytic TLR4 response to LPS as compared to the HCs . We specForty-two FES patients within 2 weeks of cumulative psychotropic drugs exposure and 35 healthy volunteers, who all were Han Chinese people, were recruited from the Beijing HuiLongGuan Hospital and local community, respectively. The disease duration of all the patients was less than 2 years (16.1 ± 5.4 months), i.e., they were in an early stage of the illness. These samples were previously utilized and have been described in detail in our previous immune-psychiatry study , except 2 tubes at the time of our previous research  ml blood samples were collected in EDTAKresearch , which wn = 30). PSYRATS, a clinician-administered and semi-structured interview, were developed by Haddock et al. to evaluate the dimensionality of psychotic experiences, which consists of auditory hallucinations rating scale (AHRS) including 11 items and delusions rating scale (DRS) including 6 items scoring from 0 to 4 points, with higher scores indicating greater severity of symptoms (PANSS and Matrics Consensus Cognitive Battery (MCCB) were used to evaluate the psychopathological symptoms and cognition, respectively, as previously described . Furthersymptoms .t-test or Mann-Whitney U-test for continuous variables and Chi-square test for categorical data. Analysis of covariance with age, gender, body mass index (BMI) and education years as covariates were applied to compare the levels of endotoxin, HMGB1, and C4 between FES patients and HCs, and then partial η2 was further calculated separately to determine the effect size of the group differences. A paired sample t-test was used to evaluate paired data.Data were analyzed using the IBM SPSS Statistics for Windows version 21.0. The Shapiro-Wilkinson test was used to examine data distribution. Group comparisons were performed using independent Pearson and Spearman correlation analyses were applied as appropriate to investigate correlations of endotoxin, HMGB1, and C4 levels with clinical data at baseline. To explore the relationships between the three biological measures and clinical efficacy, we conducted partial correlation analyses controlling for baseline values.p < 0.05 was considered as statistically significant.The Receiver Operating Characteristic (ROC) curve analysis was performed to evaluate the diagnostic effectiveness of each baseline biological measure for differentiating FES patients from HCs. Then a combined model including endotoxin, HMGB1, and C4 jointly was constructed with multivariate logistic regression analysis, and its performance was compared with each substance alone by calculating areas under the ROC curves (AUC) with DeLong’s test. These analyses were performed using the pROC package in R 3.6.3. Plots were generated with ggplot2. Benjamini-Hochberg FDR (BH-FDR) was used for multiple testing correction. Two-tailed p < 0.001). As expected, FES patients showed impaired performance across all MCCB domains relative to normal controls , HMGB1 , and C4  were all significantly higher in FES patients as compared to the HCs after controlling for age, gender, BMI, and education years .For a better utilization of the three peripheral biomarkers in the clinical diagnosis of SCZ, we evaluated their respective and combined diagnostic performance between the FES patients and the HCs. ROC analysis showed that the individual AUCs of endotoxin, HMGB1, and C4 ranged from 0.741 to 0.862 (95% CI ranged from 0.631 to 0.941), and the combination model of the three indicators significantly improved diagnostic power with an AUC of 0.933 . Since our previous study had found that LPS stimulation resulted in a lower TLR4 expression on monocytes in FES patients as compared to HCs (p > 0.05). Additionally, the plasma endotoxin, HMGB1, and C4 were independent from each other in patient group . Results were the same in HC group.No correlations of the baseline plasma endotoxin, HMGB1, and C4 were observed with age, gender, disease duration, BMI, smoking status, family history of psychiatric disorder, PANSS subscale scores, and total scores, as well as all cognitive dimensions evaluated by MCCB in FES group .Regarding the PSYRATS evaluation in the SCZ patients, we found a positive association between endotoxin concentration and baseline score of AHRS .Eight-week follow up data were available for 20 patients with SCZ. There were significant improvements in PANSS positive scores, general psychopathology scores and total scores . The levels of endotoxin and C4 did not change significantly .The levels of endotoxin, HMGB1, and C4 before and after treatment, as well as their changes were not associated with any PANSS subscale score, total score at 8 weeks and changes in PANSS scores by partial correlation controlling for baseline psychopathological symptoms  to 0.862 (HMGB1), while a combination of the three parameters could improve the diagnostic efficacy to 0.933. As is well established, an AUC value > 0.9 may imply a highly accurate diagnostic performance in clinical practice, suggesting that the three innate immune-related biomarkers selected in our study may be a promising combination for distinguishing FES from HCs.In the present study, 20 patients were followed up prospectively for their clinical outcome at 8 weeks. We found the concentration of plasma HMGB1 in FES patients was significantly decreased after antipsychotic medication but still higher than HCs, whereas endotoxin and C4 were not affected by the treatment. Coupled with aforementioned cross-sectional results on the peripheral levels of the three biomarkers in SCZ patients, our finding indicates that they may be trait markers in SCZ. To date, only two studies have investigated their changes after treatment in SCZ patients, involving HMGB1 and C4, respectively , 53. IntSeveral limitations should be mentioned in our study. Firstly, due to the small sample size, we did not consolidate our findings with another validation dataset. Therefore, caution should be taken in interpreting our results. Secondly, the present study could not establish the causal associations between increased endotoxin, HMGB1, C4, and SCZ. Moreover, the FES patients in our study had short-term psychotropic drugs exposure at baseline, hence, we cannot completely rule out the possible influences of this confounder on the plasma levels of the three biomarkers. Thirdly, we only examined total C4 levels rather than two isoforms of C4 including C4a and C4b, which are two functionally distinct isotypes . It is nDespite these limitations, this study is the first to holistically explore endotoxin, HMGB1, and C4 in FES individuals with minimal exposure to antipsychotics, revealing that a combination of the three biomarkers in the peripheral blood can be used to distinguish FES patients from HCs, indicating its clinical usefulness. In addition, we found that endotoxin showed a significant positive correlation with auditory hallucinations, suggesting that endotoxin might be implicated in the pathogenesis of this important psychotic symptom, and might also be a potentially interesting target for future therapy. Future study should determine whether the immune variables measured here are specific to SCZ, in other words, whether they have the ability of differential diagnosis among various mental disorders.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 Medical Ethical Committee of Beijing HuiLongGuan Hospital. The patients/participants provided their written informed consent to participate in this study.LT and YT initiated and directed the study. SC, MG, WC, and MX were responsible of recruitment of study subjects and clinical assessments. LT, YT, and SC performed statistical analysis and interpreted results. SC and LT wrote the first draft of the manuscript in consultation with YT. HF invited in evolving the ideas, analyzing data, and editing the manuscript. All authors read and approved the final manuscript.


Among the MS classification models, the linear support vector machine achieves the highest average accuracy of 91.1%  and has a significant permutation test outcome. The proposed method can contribute to quantifying MS and establishing viewer-friendly VR by determining its qualities.Head-mounted display (HMD) virtual reality devices can facilitate positive experiences such as co-presence and deep immersion; however, motion sickness (MS) due to these experiences hinders the development of the VR industry. This paper proposes a method for assessing MS caused by watching VR content on an HMD using cardiac features. Twenty-eight undergraduate volunteers participated in the experiment by watching VR content on a 2D screen and HMD for 12 min each, and their electrocardiogram signals were measured. Cardiac features were statistically analyzed using analysis of covariance (ANCOVA). The proposed model for classifying MS was implemented in various classifiers using significant cardiac features. The results of ANCOVA reveal a significant difference between 2D and VR viewing conditions, and the correlation coefficients between the subjective ratings and cardiac features have significant results in the range of −0.377 to −0.711 (for SDNN, pNN50, and  Virtual reality (VR) using head-mounted displays (HMDs) has become increasingly popular for professional and entertainment purposes and contributed to technological advancement and increased economic activity ,2. VR teMany previous studies have attempted to understand and interpret MS from the perspectives of postural instability ; vestibuPhysiologically, heart rate variability (HRV) indicates the interaction of autonomic, intrinsic, and humoral influences on heart rate . The HRVTo this end, this study proposes a novel method for classifying MS caused by VR content from HMDs based on cardiac features. The cardiac features measured in both before and after VR viewing conditions are compared with 2D conditions using a statistical analysis method called analysis of covariance (ANCOVA); moreover, these features are analyzed using a partial correlation with a simulator sickness questionnaire (SSQ). Herein, MS (VR condition) is distinguished from the normal state (2D condition) using statistically significant cardiac features based on various classifiers, such as linear discriminant analysis (LDA), K-nearest neighbors (KNN), decision tree (DT), and linear support vector machine (LSVM). In addition, a real-time system is developed to monitor MS.Thirty participants volunteered to participate in this study. Two participants were excluded from the experiment due to premature termination caused by severe levels of VIMS, resulting in a final sample of 28 participants . Participants’ ages ranged from 21 to 34 years . All participants had normal or corrected-to-normal vision and no family or medical history of cardiovascular disease. Informed written consent was obtained from each subject prior to the experiment, and they were instructed to get a full night’s rest and to abstain from cigarettes, alcohol, and caffeine for 24 h prior to the experiment. This research complied with the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board of Sangmyung University (No. BE2018-46).VR content “Ultimate Booster Experience”  was used in this experiment to cause VIMS through the Oculus Rift S VR HMD device . This study aimed to choose VR stimuli that can sufficiently cause the MS state, and the VR content “Ultimate Booster Experience” with the highest SSQ score among the five VR contents was chosen through a pre-test of 20 subjects. None of the participants had previously experienced viewing VR content  by using an HMD. The VR stimulus in the experiment contained content including a giant swing, bungee jump, air balloon, eagle flight, and rocket mode.This study employed a “within-subject” design to compare the viewer’s cardiac activity in response to the VR contents under the 2D (non-VIMS) and VR conditions (VIMS). The participants sat on a comfortable armchair in an electrically shielded room. They were instructed to experience the VR content in 2D (viewing distance of 1 m) and VR versions using a 27-inch LED monitor  and the HMD device. The scenes in the two versions were identical. Participants experienced the VR content using either the 2D or the HMD version of the VR content for 12 min. The experiment was conducted simultaneously for two days. The order of tasks  was count-balanced randomly to minimize sequence/order effects by repeated measures design . A resting-state was provided for 5 min before and after viewing tasks, and electrocardiogram (ECG) signals were measured. The ECG signals were measured using the lead-1 method using three electrodes placed on the left collarbone , left , and right arms , see N), which comprises general discomfort, increased salivation, sweating, nausea, difficulty concentrating, stomach awareness, and burping; (2) oculomotor responses (O), which include general discomfort, fatigue, headache, eyestrain, difficulty focusing, difficulty concentrating, and blurred vision; and (3) disorientation (D), which comprises difficulty focusing, nausea, fullness of the head, blurred vision, dizziness (eyes open), dizziness (eyes closed), and vertigo. The total SSQ score is calculated using Equation (1) based on the three factors, where the values of N, O, and D are defined by summing the subjective rating values  of each questionnaire for nausea, oculomotor responses, and disorientation, respectively. In general, a five-point scale is used for the single stimulus subjective tests as recommended in ITU-T REC. P.913 . Additionally, the heart rate shows no significant result [F1,53 = 2.456, p < 0.001, with a small effect size (ηp2 = 0.044)).For the VR viewing condition, the heart rate, SDNN, pNN50, and ln VLF (x-axis) and ln HF (y-axis) values for each 2D and VR viewing condition. Considering the results, the 2D condition pattern is stabilized before and after viewing, and the 3D condition pattern can be observed to be significantly changed. As seen in The autonomic balance was plotted in nine zones of two dimensions using ln VLF, ln HF, and ln VLF/ln HF ratio) in the post-viewing condition are significantly different . Additionally, note that the heart rate is not significantly different .Partial correlation is present between the total SSQ score and significant cardiac features in the post-viewing condition, with residual covariates in the pre-viewing condition. ln VLF, ln HF, and ln VLF/ln HF ratio). The heart rate is not included in the classification features. The optimized hyperparameters are as follows: the data for all methods are standardized; the number of neighbors for KNN is 28, and Euclidean distance is applied; the split criterion for DT is maximum deviance reduction, and the maximum number of splits is 2; the box constraint level for LSVM is 0.0706. The accuracies, recalls, precisions, f1 scores, and AUCs of the four classifiers  are listed in p < 0.0001) in the permutation test. In this study, the 2D and VR viewing conditions are classified. The features for the classification are only five statistically significant indicators , a power supply (MP160), and a personal computer for analysis. It can classify an MS or normal state in a VR environment using an HMD device. This system monitors user behavior via webcam and VR scenes and confirms the results of cardiac features in both the time and frequency domains. In addition, the results depending on time for assessing MS can be confirmed using a sliding bar for each time log. The system was developed using MATLAB App designer , and signal processing is performed using the MATLAB toolbox , as shown in ln VLF, ln HF, and ln VLF/ln HF ratio, show a significant difference between the 2D and VR viewing conditions based on the ANCOVA analysis. (2) Considering the normalized HRV, the autonomic balance is located within the reference zone in the normal state. However, it moves almost into Zone 5 in MS. (3) The correlation coefficients between the total SSQ score and significant cardiac features are in the range of −0.377 to −0.711  or 0.653 to 0.677 (for ln VLF and ln VLF/ln HF ratio), indicating significant negative or positive correlations, respectively, in the range of weak to strong. (4) Among the algorithms for classifying MS, the highest average accuracy, recall, precision, F1 score, and AUC of MS classification results using the LSVM achieved 91.1, 96.4, 87.1, 91.5, and 0.96 , respectively. The ROC curve is a useful tool when predicting the probability of a binary classification. In general, skillful models reveal curves that bow up to the top left of the plot. When the curve is close to the point , it is evaluated to be the perfect model. In addition, recall and precision are defined as the ratio of correctly classified positive samples to a total number of classified positive samples (either correctly or incorrectly) and the ratio between the numbers of positive samples correctly classified as positive to the total number of positive samples. Recall and precision are metrics used to assess the performance of classification algorithms since accuracy alone is not sufficient to understand, and improving precision typically reduces recall and vice versa. A good classification model needs to strike the right balance between precision and recall [p-values are used to assess the competence of a classifier. This study confirmed that the classification model for the MS reveals a significant result in the permutation test .This paper proposes a quantitative method for measuring MS based on cardiac activity and a real-time system for assessing the same. This study confirms whether 2D and VR viewing conditions cause MS in subjects based on SSQ scores. The subjects in the VR viewing condition demonstrably experience MS but not in the 2D viewing condition, because the SSQ scores show a statistically significant difference between the 2D and VR viewing conditions. This study yields four significant findings: (1) The cardiac features, such as SDNN, pNN50, d recall . F1 scorA significant difference can be observed in the cardiac activity results of individuals with subjective symptoms of MS. In this study, both the SNS’s activation and the PNS’s deactivation are determined from the normalized HRV indices in subjects that experience MS. The normalized HRV features have been demonstrated to best reflect the SNS and PNS activities ,61. The In addition, many previous studies have reported that MS is strongly associated with the cognitive load caused by inconsistencies or conflicts among different types of sensory information  ,73,74,75This study has several limitations. (1) This study selected an SSQ questionnaire to perform the subjective measurement of MS, because the SSQ questionnaire is the best-known test for the subjective measurement for MS. However, traditional SSQ questionnaires were developed for measuring cybersickness and may differ significantly from today’s VR experience. In future studies, recently revised questionnaires need to be considered , includThis paper proposes a method for assessing MS caused by watching VR content on an HMD using cardiac features. This study demonstrates a significant difference in cardiac features between the MS and normal states, and the classification performance achieves an average accuracy of 91.1%. In addition, a real-time system was developed for continuously monitoring MS using significant cardiac features. The proposed method can quantify the level of MS severity and determine the optimal viewing factors of a VR environment  to minimize the symptoms of MS. This research will consequently help improve the viewing environment and lead to the establishment of viewer-friendly VR. However, since MS is strongly correlated with various factors, such as age and gender , further