This study aims to review the evidence for the optimal regimen of probiotics for the prevention of necrotizing enterocolitis (NEC) in very low birth weight infants.Through searching PubMed, EMBASE, Cochrane Library, and Web of Science till September 30, 2022, only randomized controlled trials were included to evaluate the optimal regimen of probiotics for the prevention of NEC in very low birth weight infants. The methodological quality of the included studies was assessed by the Cochrane risk of bias assessment tool (RoB 2), and the collected data were analyzed accordingly using Stata software.Twenty-seven RCTs were included, and the total sample size used in the study was 529. The results of the network meta-analysis showed that Bovine lactoferrin + Lactobacillus rhamnosus GG , Lactobacillus rhamnosus + Lactobacillus plantarum + Lactobacillus casei + Bifidobacterium lactis , Bifidobacterium lactis + inulin  were superior to the control group (Bifidobacterium lactis + Bifidobacterium longum) in reducing the incidence of NEC. The reduction in the incidence of NEC were as follows: Bovine lactoferrin + Lactobacillus rhamnosus GG (SUCRA 95.7%) > Lactobacillus rhamnosus + Lactobacillus plantarum + Lactobacillus casei + Bifidobacterium lactis (SUCRA 89.4%) > Bifidobacterium lactis + inulin (SUCRA 77.8%).This network meta-analysis suggests that Lactobacillus rhamnosus GG combined with bovine lactoferrin maybe the most recommended regimen for the prevention of NEC in very low birth weight infants. Clinically the infant presents with feed intolerance, increased gastric aspirates, vomiting, blood in the stool which may progress to very severe illness including shock and perforation. It is a disease that has plagued neonatal care for a long time and is still relatively common in very low birth weight infants . NEC is NEC, once established, is challenging to stop and has limited and expensive treatments. Treatment methods for NEC include antibiotics, gastric decompression, parenteral nutrition, etc. . It is nMultiple research studies have explored various interventions for prevention of NEC including the provision of human milk and microbial therapeutics, with probiotic therapy garnering the most attention. Shiloh R. Lueschow et al. found that Bifidobacterium infantis EVC001 can prevent NEC in mice through anti-inflammatory and epithelial barrier-restoring properties . The stuMost studies in the past decade have suggested that probiotics can significantly reduce the risk of NEC; However, it is unclear which probiotic or combination of probiotics is more effective  and what2.2.1.This network meta-analysis was conducted following the PRISMA statement, and the protocol for this study was registered in the International Platform of Registered Systematic Review and Meta-analysis Protocols (number INPLASY2022110001).P) Population: very low birth weight infants; (I) Intervention: probiotics; (C) Comparator: control group with only placebo or another probiotic usage; (O) Outcomes: necrotizing enterocolitis. (S) Study type: RCTs. The detailed search strategy is shown in  Study designed as RCT; (2) Neonates with birth weight <1500 g; (3) Interventions included probiotics; (4) Reported outcomes included NEC stage ≥ II (Bell staging criteria); (5) The incidence of outcomes given by the study.2.3.(1) Studies from non-randomized controlled trials, including quasi-randomized controlled trials, non-human subjects, case reports, protocols, correspondence, or conference abstracts; (2) Studies with incomplete or unreported data.2.4.Literature was screened and excluded using the literature management software Endnote. Two researchers first screened papers by title to exclude duplication, non-randomized controlled trial studies, correspondence, review papers, and conference papers. Two researchers then read the abstracts to determine which studies to include and exclude. Finally, two researchers performed full-text readings to further identify the included literature. During this process, two researchers independently screened the literature and compared the remaining literature to determine whether they could be included in the study. Any conflicts were resolved by discussion with a third author.2.5.A nine-item, standardized, and pre-selected data extraction form was used to record data from included studies under the following headings: (1) author, (2) year of publication, (3) country, (4) sample size, (5) mortality, (6) number of people progressing to NEC, (7) mean age, (8) details of the intervention, (9) overall risk of bias.2.6.Two researchers independently assessed the risk of bias (RoB 2) according to the Cochrane Handbook version 6.1.0 tool for assessing RoB 2 in RCTs. Five items were considered: (1) randomization process, (2) deviations from intended interventions, (3) missing outcome date, (4) measurement of the outcome, and (5) selection of the reported result. The risk of bias for each domain can be classified into three levels: low risk, some concerns and high risk. If the risk of bias assessment for all domains is “low risk”, then the overall risk of bias is “low risk”; If the risk of bias assessment in some domains are “some concerns” and there is no “high risk” domain, then the overall risk of bias is “some concerns”; As long as the risk of bias assessment in one domain is “high risk”, the overall risk of bias is “high risk”.2.7.In studies using probiotics as an intervention, outcome variables were dichotomized and expressed as risk ratios (RR) and 95% confidence intervals (CI). Due to potential differences between studies, we decided to use a random-effects model rather than a fixed-effects model to analyze the data.P-value was > 0.05.Data were compiled and analyzed using Markov chain Monte Carlo simulation chains of Stata software (version 15.1) based on a Bayesian framework according to the PRISMA NMA instruction manual. To quantify and demonstrate the agreement between indirect and direct comparisons, we used the nodal method calculated according to the instructions in Stata. The consistency test was passed if the We presented and described network diagrams for different probiotic usage using Stata software. In the presented network diagrams, each node represents a different probiotic usage, and the lines connecting the nodes represent a direct comparison between interventions. The size of each node and the width of the connecting lines are proportional to the number of trials.P score. The P score was considered as a frequency analog to surface under the cumulative ranking curve (SUCRA) values, a measure of the degree of certainty that one treatment is superior to another. The P score ranges from 0 to 1, with 1 representing the best treatment without uncertainty and 0 the worst treatment without uncertainty. The P score or SUCRA could be effectively expressed as a percentage of intervention effectiveness or acceptability, but this score should be interpreted with caution unless there is a genuine clinically meaningful difference between interventions. Small-scale studies could lead to publication bias in NMA, for which we created network funnel plots and checked them visually using symmetry criteria.The evaluation of the intervention was summarized and presented in the form of a 3.3.1.A total of 3,159 documents were retrieved from the electronic database, and an additional three documents were manually searched. After eliminating duplicates, the remaining 2,153 documents were read for titles and abstracts, and 1,994 documents were again excluded. The remaining 159 documents were read in full, and 132 documents were again excluded , leaving a final remaining 27 documents to be included in this study. .3.2.Seventeen studies were defined as low risk, eight as some concerns, and two as high risk. Only three of these studies did not achieve simultaneous blinding of subjects and measures. Specific details are presented in .3.3.In total, we included studies from 27 randomized controlled trials, which included 529 patients diagnosed with NEC. Interventions included Bovine lactoferrin + Lactobacillus rhamnosus GG (2 studies) , 16, Bov3.4.P-values for indirect and direct comparisons between all studies were tested for consistency and inconsistency, and most P-values were greater than 0.05, indicating that the effects of consistency between studies were acceptable. Details were shown in  , these r5.This network meta-analysis also has some limitations. This study only discussed the selection of probiotics for the prevention of NEC in very low birth weight infants, while the questions of the dosage, the timing of the intervention, and when to start the intervention remains unresolved. Most interventions were evaluated in only one or two trials, and only a few options were tested in four randomized controlled trials. Therefore, most probiotic interventions were evaluated in small experimental populations. In conclusion, the results of this study should be interpreted with caution, as the number of included trials was insufficient, so there was limited evidence for direct comparisons of some interventions, and further related studies are needed.6.Our analysis suggests that Lactobacillus rhamnosus GG combined with bovine lactoferrin is the most effective and recommended regimen for preventing NEC in very low birth weight infants. However further studies are required to confirm this and also answer questions about probiotic dosage, timing and duration of therapy.


The patients with MDD were divided into three groups according to Hamilton Depression Rating Scale 17 (HAMD-17), including mild (n = 24), moderate (n = 72) and severe (n = 42) individuals, respectively. We found that microbial diversity was closely related to the severity of MDD. Compared to HCs, the abundance of Bacteroides was significantly increased in both moderate and severe MDD, while Ruminococcus and Eubacterium depleted mainly in severe group. In addition, we identified 99 bacteria species specific to severity of depression. Furthermore, a panel of microbiota marker comprising of 37 bacteria species enabled to effectively distinguish MDD patients with different severity. Together, we identified different perturbation patterns of gut microbiota in mild-to-severe depression, and identified potential diagnostic and therapeutic targets.Disturbed gut microbiota is a potential factor in the pathogenesis of major depressive disorder (MDD), yet whether gut microbiota dysbiosis is associated with the severity of MDD remains unclear. Here, we performed shotgun metagenomic profiling of cross-sectional stool samples from MDD ( Major depressive disorder (MDD) is the most common form of psychiatric and emotional disorder, affecting >350 million people . MeanwhiBacteroides is the hub of perturbed gut microbiota in unipolar depression, while enriched Prevotella is the characteristic of bipolar depression [Alistipes and Anaerostipes as well as completely depleted Dialister, while mild symptoms (r-MDD) had higher abundance of Bilophila [Bacteroidetes, Proteobacteria, and Actinobacteria were strongly increased in a-MDD and r-MDD, whereas Firmicutes was significantly reduced [n = 138), including mild (n = 24), moderate (n = 72) and severe patients (n = 42), and healthy controls . Firstly, we sought to explore whether the whole microbial signature of MDD patients with different severity was significantly different from that in HCs. Next, we integrated the microbiota and related functional information through network analysis and correlated it with disease severity to further reveal how the signature of these disturbances changed as the disease worsened. Finally, we identified potential microbial markers related to severity of depression, and further tested their discriminative performance, thus making our findings a useful resource for the study of microbiome perturbations in depression.Recently, growing evidence indicates that gut microbiota plays an essential role in the development and progression of mental disorders . Alteratpression . In addiilophila . However reduced . These sn = 24; age, 29.34 ± 7.64; BMI, 22.56 ± 3.99), moderate group , severe group . All patients provided written informed consent to participate. Patients that were excluded from this study were those who (1) had bipolar disorders, schizophrenic, schizoaffective, or other Axis I psychiatric disorders; (2) had the serious chronic somatic disease ; (3) alcohol and substance abuse, acute intoxication; (4) were pregnant or breastfeeding; (5) changed diet habit or used antibiotic within one month before sampling.The subjects included in this study were derived from our previous clinical cohort . The stuAll samples were collected from the clinical center. Briefly, fresh stool samples were collected and contained in sterile tubes in the morning (7–10 am) and stored at 4 °C, then transferred to a −80 °C refrigerator for subsequent processing within 6 h. According to the manufacturer’s instruction, we extracted the whole genomic DNA from fecal samples with the E.Z.N.A. Soil DNA Kit . Determination of the extracted DNA’s concentration and purity was performed on the TBS-380 and NanoDrop2000 separately. Then, we checked the quality on 1% agarose gel. DNA was fragmented randomly to an average size of about 300 bp by Covaris M220. Construction of paired-end library was accomplished by NEXTFLEX Rapid DNA-Seq . Library was subjected to paired-end sequencing on Illumina NovaSeq . To avoid batch effect, all samples were assayed in the same batch.https://github.com/najoshi/sickle). Metagenomic data were aligned to the human genome using Burrows-Wheeler Aligner (http://bio-bwa.sourceforge.net), and the host genes were removed. Clean data were assembled to contigs by MEGAHIT, and the contigs with a minimum length of 300 bp were kept. Metagene was used to predict open reading frames from each assembly contigs [Low-quality sequences  in raw FASTQ files were filtered by Sickle ( contigs . All gen contigs . After c−5 [The gene set was annotated for bacteria based on the NCBI database using Diamond (version 0.8.35). For assessing the gut microbiota species of MDD patients, each gene was assigned to the highest-scoring taxonomy based on a unified database. Non-redundant gene set was aligned against the KEGG database with an e value cutoff of 1 × 10−5 , and abu−5 . Permuta−5 . Optimalhttps://huttenhower.sph.harvard.edu/galaxy/). The diagnostic performance was quantified by Random Forest classifier and tested by 5-fold cross-validation. Receiver operating characteristic (ROC) curve was plotted to estimate the diagnostic efficacy.High relative abundance bacteria were selected for following analysis at species level , then unclassified species was excluded. Linear discriminant analysis effect size (LEfSe) analysis was used to identify the differentially enriched bacteria and KOs among HCs and 3 MDD subgroups  [Based on abundance data of metagenome, Sparse correlations for compositional data (SparCC) algorithm was used to calculate the correlations between all the differentially enriched bacteria and KOs which defined by LEfSe analysis (cn:8081) . The resp values of pairwise comparisons of the Kruskal–Wallis sum-rank test were corrected by Holm-Bonferroni method. Categorical variables were performed by chi-square test. Statistical significance level was set at p < 0.05.Statistical analysis was performed using SPSS (version 22.0). Continuous variables were analyzed by one-way ANOVA test (mean±SD) followed by LSD′s multiple comparison or non-parametric factorial Kruskal–Wallis sum-rank test (mean±SEM), p = 0.71; Chi-square test), age , and body mass index  among HCs and 3 MDD subgroups  [Blautia and Faecalibacterium. Faecalibacterium (31.6%) were significantly more abundant in HCs, whereas 2 types of Bacteroides  were more abundant in 3 MDD subgroups . 3 MDD subgroups shared a similar trend that Bac and Bac 2 were the major enterotypes in microbiota  bacteria of HCs and the 3 MDD subgroups at family and genus levels. Overall, at the family level, axa Fig. . At genuaxa Fig. . Here, woup Fig. . Next, wvotella) –28, we dota Fig. .p < 0.05). Three groups of bacteria were identified through three pairwise comparisons of LEfSe analysis (Table S2–4). Compared with HCs, mild group had less differentially enriched bacteria at the set threshold. We found 14 differentially enriched bacteria in mild group, 60 in moderate group, and 74 in severe group  and Eubacterium (3 species). Blautia (5 species), Clostridium (4 species) and Eubacterium (4 species) were decreased in moderate group, while Bacteroides (16 species) were remarkable increased in moderate group. Consistently, Blautia (5 species), Clostridium (7 species) and Eubacterium (8 species) were also decreased in severe group, Ruminococcus (7 species) were decreased too. The increased bacteria remained Bacteroides (18 species) in severe group  analysis was performed pairwise on bacteria between HCs and MDD subgroups . In genus level, Bacteroides enriched markedly in every MDD subgroup , Eubacterium (6/7), Blutia (5/7) and Clostridium (5/7)  . Overall, Bacteroides were positively correlated with KOs and Blautia, Eubacterium, Ruminococcus were negatively correlated with KOs  Fig. , while t/7) Fig. . The enrium Fig. . This phKOs Fig. . Obviouscus Fig. . Compare572 Fig. .Fig. 4ThThe differentially enriched bacteria of HCs and 3 subgroups were trained separately by random forest classifier (RF) for binary classification. According to Gini importance, 37 bacteria were screened out from 3 pairs of differentially enriched bacteria to construct the biomarker panel for discriminating different groups . Ultimately, we identified 38 species differentially enriched bacteria in female group , Eubacterium (7 species), Clostridium (4 species) and Blautia (4 species); and 68 species differential enriched bacteria in male group , Eubacterium (6 species), Clostridium (4 species), Blautia (6 species) and Ruminococcus (4 species).LEfSe analysis was performed to screen out the differentially enriched bacteria . In female group, there were 3 hub clusters, the Bacteroides showed a negative correlation with Eubacterium and Blautia  and K12373 (HEXA) may be key node connecting Blautia and Bacteroides, showing completely opposite correlation with these two microbial clusters. susD is an outer membrane protein. It is the main starch binding protein on the surface of Bacteroides, and can effectively use polysaccharides as a source of carbon and energy [Blautia and Bacteroides could elucidate its role in MDD severity. K12373 (HEXA) is a hexose kinas, play an important role in sugar metabolism in Bacteroides fragilis [rpoE) is an important part of transcription activation factor that binds to RNA polymerase complex to regulate gene expression in bacteria [Bacteroides, the increased expression of K03088 might indicate the function enhancement of Bacteroides.It is generally believed that high diversity of gut microbiome is a sign of healthy status , 32. Some of MDD . Bacteroicroglia –40. Bact disease , 42. Becesponses , 44. Sim colitis –47. In sbacteria –50. Alsoresponse , 52. In d energy . Furtherfragilis . Likewisbacteria . In sighMotivated by the results that showed that there were alterations in the gut microbiota in moderate and severe MDD, we constructed a random forest model with 37 bacteria species. The AUC value of the classification of MDD subgroups were 0.992 to 0.998; suggesting a high diagnostic value. Overall, this finding provided evidence that gut microbiota-targeted biomarkers may become potential non-invasive tools for MDD stratification.Bacteroides and Prevotella had higher abundance in male [Bacteroides. Further research was required to figure out if this was related to gender differences in MDD. In order to obtain consolidation evidence, it is necessary to further expand the study cohort to determine the gender bias of gut microbiota in MDD.Additionally, we initially explored the gender bias in the structure of gut microbiota. The prevalence of MDD in women was twice of in men , 57, we  in male . In our The limitations of this study are: (i) The sample size of the three MDD subgroups is relatively small, and the samples were collected from a clinical center, therefore regional variations cannot be ruled out; (ii) All patients were not under medication; therefore, follow-up studies are required to explore whether this biomarker panel can be used to monitor treatment response; (iii) Given that fecal bacteria transplantation could transfer depressive phenotypes from humans to mice, it will be important to determine the correlation between the disturbance of gut microbiota and disease severity in animal models, and uncover the underlying mechanisms.Taken together, we analyzed and found the unique and common alterations in gut microbiota across different disease severities. Microbiota may affect physiological functions through mutual synergy or antagonism, and the status may shift from balance to imbalance as symptoms get worse. Furthermore, we identified a novel combined biomarker that could discriminate different severity subgroups with high accuracy. In conclusion, our study provides a new direction for understanding the progression of MDD, and a potential promising strategy for developing a novel method for objectively assessing the severity of MDD.Supplemental tablesSupplementary materialsStorms checklistaj-checklistsupplementary figure 1supplementary figure 2supplementary figure 3supplementary figure 4supplementary figure 5supplementary figure 6supplementary figure 7supplementary figure 8


Infections with human papillomaviruses (HPV) are sexually transmitted and can cause cancer. In Germany, vaccination against HPV is recommended for girls and boys aged 9–17 years. We aimed to investigate HPV DNA prevalence, genotype distribution and vaccine effectiveness (VE) in women aged 20–25 years 10 years after the introduction of HPV vaccination in Germany (2018–2019), and compared these data to an equally designed study from 2010–2012.t-test and proportion t-test, and calculated crude and adjusted prevalence ratios (PR) and 95% CIs.Seventy six geographical clusters were randomly selected, followed by random selection of 61 women aged 20–25 years per cluster. Participants performed cervicovaginal self-sampling and answered questions on demographics, sexual behaviour and HPV vaccination. Samples were tested for 18 high risk and nine low risk HPV genotypes. We performed chi-square tests, Fisher’s exact test, unpaired Student’s p < 0.0001) in unvaccinated participants.Of 7,858 contacted women a total of 1,226 agreed to participate. Of these, 94 women were positive for HPV types 16 and/or 18. HPV16 prevalence was 7.0% (95% CI 5.6–8.6) and HPV18 prevalence was 0.8% (95% CI 0.4–1.5). HPV6 and HPV11 were rare with only five  and one  positive tests. Seven hundred fifty-seven women (62%) had received at least one HPV vaccine dose and 348 (28%) were vaccinated as currently recommended. Confounder-adjusted VE was 46.4% (95% CI 4.2–70.1) against HPV16/18 infection and 49.1% (95% CI 8.2–71.8) against infection with at least one HPV genotype covered by the quadrivalent HPV vaccine. Compared with the 2010–2012 study results, HPV16/18 prevalence dropped from 22.5% (95% CI 19.0–26.3) to 10.3%  HPV DNA positivity. Infections with human papillomaviruses (HPV) can cause dysplasia and cancer . They arThe HPV prevalence differs according to HPV genotype and highly depends on the site of sampling and test method , 8. In aEffective prophylactic vaccines against HPV are available since 2006 and since 2016 the nine-valent vaccine has been mainly used in Germany , 12. CurTo determine the baseline HPV prevalence, genotype distribution and risk factors for HPV-infection in 20–25 years old women in Germany, the Robert Koch Institute (RKI) and the HPV laboratory at the Clinic for Gynecology of Charité—Universitätsmedizin Berlin conducted an HPV prevalence study (baseline study) in the years 2010–2012 . This stThe present study aimed to repeat the 2010–2012 baseline study with a similar study design in 2017/2018  by collecting data on HPV infections in a nation-wide sample of 20–25 years-old women in Germany, which allows direct comparison between these two time points. We investigated the prevalence and vaccine effectiveness (VE), and compared the results to the baseline study in order to contribute to the evaluation of the vaccination program in Germany.De novo random sampling of 76 clusters was followed by random sampling of 40 women per cluster and 501 women in the city of Berlin.This population-based cross-sectional study was carried out by the RKI in collaboration with the Clinic for Gynecology, HPV research lab at Charité—Universitätsmedizin Berlin. The recruitment strategy for the population-based random sample was developed by GESIS Leibniz Institute for Social Sciences . Recruitment of participants was carried out from June 2017 to January 2018 using a two-stage sample design. Seventy six geographical clusters  were randomly selected, followed by the random selection of 61 women aged 20 to 25 years in each of these clusters. Clusters were formed according to region  and number of inhabitants . An additional cluster was selected in the city of Berlin with 400 women. Registration offices were asked to provide randomly drawn addresses of women in the age group 20–25 years with primary residence in their municipality. In order to meet the required sample size  of 1,173 participants, we initially contacted 5,029 women. As response rate was low, a second recruitment wave was started in 2017. ® Brush, Rovers Medical Devices, Oss, Netherlands) with a detailed description and illustrations for the self-sampling procedure, a paper-based questionnaire or login-data for an online-questionnaire which was developed using the software Voxco . The questionnaire was based on the questionnaire of the 2010–2012 baseline study and was divided into four chapters: (1) general demographic information; (2) information regarding cancer screening and history of HPV-associated dysplastic lesions and cancer; (3) information on sexual behaviour; and (4) information on received HPV vaccination. Invited participants were excluded from the study if they did not sign the consent form, were pregnant, or if no samples were provided. As an incentive, participation in a lottery was offered to all women who completed the study.An invitation letter was sent to each potential participant including study information and consent form. Study material package was sent to those participants who returned the signed consent form. Study material included a cervicovaginal self-sampling collection kit  and the German Federal Commissioner for Data Protection. Informed written consent were obtained from all participants.Pseudonymised self-collected dry samples were submitted at ambient temperature via postal mail to the RKI. Samples were immediately stored in a fridge at −20°C and were forwarded once per week to Charité HPV laboratory for HPV DNA extraction and testing. Extracted DNA was further stored at −20°C until use. Samples were tested for 18 HR-HPV genotypes  and nine LR-HPV genotypes  by multiplexed genotyping (MPG) with Luminex readout  schedule completed before first sexual intercourse, (b) schedule completed before the age of 18 years, and (c) dosing schedule and intervals as recommended by the vaccine manufacturer .®) and genotypes HPV6/HPV11/HPV16/HPV18 included in the quadrivalent vaccine (Gardasil®). Group-specific prevalence was calculated as the proportion of participants who were DNA-positive for at least one of the HPV-genotypes included in one group. Prevalence was reported as percentage with 95% confidence interval (CI). We performed chi-square tests and Fisher’s exact test for categorical variables, and unpaired Student’s t-test for continuous variables. We performed a proportion t-test to test for prevalence differences between the results of the baseline study and the present study. We calculated crude and adjusted prevalence ratios (PR) and 95% CIs. To measure the association between HPV positivity and vaccination status and to allow for adjustment, we included all potentially relevant variables  and performed Poisson regression with backward selection based on a p-value <0.1 to obtain the final model. Prevalence results were further compared descriptively with findings of the baseline study. For a detailed description of the baseline study design, see .HPV prevalence was calculated for all 18 HR-HPV genotypes separately and, in order to assess the effects of the most often used quadrivalent and bivalent vaccines in the study population, for the following groups of HPV genotypes: genotypes HPV16/HPV18 included in the bivalent vaccine  . A non-rn = 1,226) are provided in n = 128), the study included about 200 participants per predefined age group. Although recruitment targeted only 20–25 year-olds, few women (n = 16) who turned 26 between recruitment and participation were included in the study. Participants came from all regions of Germany and were evenly distributed between rural and urban regions as well as eastern and western parts of Germany. The majority  of participants had a German citizenship. In total, 2.4% (n = 29) of participants had a low education status .Demographic characteristics of participants (n = 245) were active and 8% (n = 101) former smokers. Thirty women (2.4%) had some form of immunodeficiency and were taking respective medication. Thirty-four percent (n = 420) of participants had never previously participated in cervical (pre-)cancer screening. Five percent (n = 55) of the participants were previously diagnosed with a cervical lesion and 15 (1.2%) reported having received genital warts treatment in the past.Of the participating women, 20% (p < 0.001).Demographic characteristics were additionally stratified by HPV16/18 positivity . While 1We further analysed participants according to sexual behaviour and vaccine uptake . In totan = 63), Gardasil (n = 632) or Gardasil9 (n = 9). In total, 348 (28%) of the women were vaccinated according to current STIKO recommendations. Nearly half (48%) of the participants who provided information on their age at the time of the first vaccine dose were vaccinated when they were older than 14 years (n = 36) had their first vaccine dose in the same year as their sexual debut or after their sexual debut.Regarding vaccination history, 62% had received at least one dose of either Cervarix , had a higher lifetime number of sexual partners  as well as a higher number of sexual partners in the past 12 months . Moreover, they reported using condoms less often during sexual intercourse in relationships . Regarding vaccination history, HPV16/18 positives were less likely to have an HPV vaccination history .We found statistically significant differences between HPV16/18 positive and HPV16/18 negative participants regarding sexual behaviour and vaccine uptake. HPV16/HPV18-positive participants were less likely to be living in a current relationship . Analyzing the HPV type-specific prevalence by age of first vaccination dose before and after the participants’ 15th birthday showed no significant differences (data not shown).The prevalence of the vaccine-covered HPV genotypes ranged from 0% (95% CI 0.0–0.5) for HPV11 to 7.6% (95% CI 6.2–9.2) for HPV52 . HPV preConfounder-adjusted VE was 46.4% (95% CI 4.2–70.1) against HPV16/18 infection . VE agaip-value <0.0001). For the vaccine-covered genotypes HPV16/18, prevalence dropped from previously 22.5% (95% CI 19.0–26.3) to 10.3% . Interestingly, we observed an increase in HR genotypes that are not included in the bivalent and quadrivalent HPV-vaccines  when comparing the results of the baseline study with the present study results.Compared with the baseline study results, overall HPV16/18 prevalence significantly decreased from 20.2% (95% CI 17.5–23.2) in 2010–2012 to 7.7% (95% CI 6.2–9.3) in 2017/2018 in the study populations . While HThis study reports population-based data on HPV genotype-specific prevalence based on self-sampling among young women 10 years after initiation of routine HPV vaccination in Germany. With these analyses, we were able to evaluate the impact of the vaccination program in terms of reduction of HPV infections at population level 10 years after its initiation and to estimate vaccine effectiveness of HPV vaccines.HPV vaccine coverage in adults is not routinely measured and reported in Germany, but data on coverage in adolescents are available: In 2008, shortly after endorsement of the HPV-vaccination recommendation, HPV vaccine uptake in 12–17 years-old girls in Germany was around 32% . In 2011In our investigated cohort of 20–25 year-old women from 2017/2018, vaccine uptake was substantially higher compared to the above described data on vaccine uptake in the respective birth cohorts. The majority (63%) of the participating women aged 20–25 had initiated and 55% completed an HPV vaccine series. In terms of comparison of these studies, it is important to mention that we investigated an older age group compared with the age groups of the previously described studies. Besides this circumstance, the possible bias of voluntary responses  could also be the cause of this difference in vaccine uptake. Our results—gained from a study population with a higher vaccine coverage than the general population—might overestimate the reduction of HPV prevalence in the population and, thereby, the estimated effect of the vaccination program. However, the higher vaccine coverage in our study population has neither an effect on the VE estimates nor on the results regarding the reduction of HPV prevalence since 2010–2012 in vaccinated women as well as in unvaccinated women.When our study population was eligible for vaccination, the vaccination program targeted only 12–17 years-old girls. Earlier vaccination  was introduced in Germany in 2014 as a recommendation to prevent HPV infections more effectively. Still, 28% of the women in our study had been vaccinated according to the current recommendation, so that we were able to evaluate the difference in prevalence among vaccinated and non-vaccinated participants as well as the VE according to the current vaccination scheme.A high number of women started their vaccination series after their 15th birthday (48%) or initiated the vaccination series before turning 15 years but after sexual debut or at least in the same year (10%). Since the time of vaccination of this study population, recommended age limits were lowered by STIKO in Germany. Retrospectively, these findings strongly support the decision of STIKO in 2014 to lower the recommended HPV vaccination age from 12–17 years to 9–14 years ensuring a timely vaccination before sexual debut. Still, it has to be emphasized that vaccination should be completed before sexual debut irrespective of age as >16% of our study population had their sexual debut prior to their 15th birthday.Vaccine-covered HPV genotypes were rare in our study cohort, and overall the majority of HPV genotypes had a prevalence of ≤2.5%. Only HPV16 and HPV52 had a higher prevalence of 7.0 and 7.6%, respectively. With an overall HPV16/18 prevalence of 7.7%, the prevalence was approximately 50% lower in vaccinated (4.9%) than in non-vaccinated women (10.3%) showing the direct effect of vaccination. With the exception of HPV58, all HPV genotypes were less prevalent in the group of vaccinated participants. We observed an increase in prevalence of non-vaccine HPV genotypes in HPV vaccinated women as compared to unvaccinated women and the baseline study. A possible explanation could be the differences of the induced immune responses during spontaneous resolution of an HPV infection, leading to a broad poliantigenic response also against the more conserved viral E proteins, while L1-based virus like particle (VLP) vaccination induces exclusively L1 genotype-specific neutralizing antibodies and L1-specific T cell responses in the absence of other HPV antigens. These more diverse immune reactivities against more conserved early proteins will comprise cross-protective immunity against related HPV genotypes that in turn will not be able to establish an infection. However, after L1 VLP vaccination this cross-protection is not present and not protecting against related HPV genotypes that now can infect and their prevalence seems to increase. Despite an increased prevalence the carcinogenicity of the individual HPV genotypes is not enhanced.p < 0.0001). This significant reduction in HPV16 and HPV18 prevalence among unvaccinated women can be an explained by herd protection effects conferred by the implemented HPV vaccination program, as also reported from other populations  to 8% in 2017/2018. Prevalence of HPV16/18 among non-vaccinated women in our present study was significantly lower compared to non-vaccinated women from the baseline study  . HoweveOur study has several strengths. It used a nation-wide sampling frame to recruit participants with diverse socio-economic backgrounds from the resident population in Germany. Applying a well-established test kit and self-sampling method, we were able to obtain HPV prevalence that is unlikely to be confounded by health-care seeking behaviour. We could use detailed data on factors like pre-existing co-morbidities, socio-economic status, sexual behaviour and former vaccination to perform our analyses. Even though the self-sampling material used in the baseline study was different to the one used in the present study , both studies had a similar study design and we were therefore able to compare HPV genotype-specific prevalence data in 2017/18 with those in 2010–12 and to demonstrate the extent of the impact of the German HPV vaccination strategy on population level including indirect effects such as herd immunity.However, our study also has limitations. The present study had a low response rate of only 15.6% in spite of two recruitment waves and the use of incentives. Non-responders were more often of non-German citizenship and of lower education background than participants. Considering the intense cost- and time-consuming effort in reaching the sample size minimum, this study design seems to be not efficient enough for estimating population-based prevalence data of HPV in Germany. Moreover, the target population of our study is generally considered to be one of the harder to reach populations at least in Germany. Additionally, we may have a common response bias regarding our questions targeting sexual behaviour . Like other population-based cross-sectional studies, we may additionally have a healthy population bias, which leads to a potentially higher number of women who are interested in healthy behaviour and prevention of HPV-infections. Furthermore, HPV infection at only one time point might not be the relevant outcome to estimate vaccine effectiveness and future studies in Germany should focus on persistent infections or even more informative endpoints than genotype-specific prevalent infection.In summary, the prevalence of vaccine-covered HPV genotypes among the 20–25 year-old participants in Germany was low and decreased compared with HPV prevalence estimated shortly after the introduction of the HPV vaccination program. In comparison to unvaccinated women, HPV prevalence of almost all vaccine-covered genotypes was strongly reduced in vaccinated participants. Interestingly, a significant decrease of HPV16 and HPV18 was even observed in unvaccinated participants, compared to baseline study results, indicating indirect protection of unvaccinated women through herd immunity effects. Estimated VE against HPV16/18 and HPV6/11/16/18 was rather low in our study, assuming that the study design in combination with the endpoint selection of (mainly transient) HPV DNA positivity is not an effective and appropriate study design for defining HPV VE. This study presents additional data showing that since the introduction of HPV vaccination in Germany, HPV prevalence of the most relevant HPV types HPV16 and HPV18 further decreased in the German female population compared to prevalence data from the baseline study.In many participants, vaccination was not received as recommended before sexual debut. Therefore, there is an urgent need to raise awareness to physicians and the public that a large group of girls is not vaccinated, and even if they are, they are not vaccinated according to STIKO recommendations, and that these girls are not receiving the full potential of vaccine protection against HPV infections and associated cervical dysplasia. To ensure that girls are vaccinated before sexual debut and that the series of vaccinations is completed before their 15th birthday, HPV vaccination should be given starting at age 9 years when girls and boys are still being managed in pediatric care.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 Charité—Universitätsmedizin Berlin Ethics Committee (Reg. No. EA1/094/17). The patients/participants provided their written informed consent to participate in this study.MW-P, TH, OW, and AK designed the study. AL, AT, VS, and AM conducted the study, prepared the data base, and performed statistical analyses. AK and ST performed laboratory analyses. MS developed the sampling strategy. MW-P, OW, and TH supervised the study conduct and data analysis. AL, AT, and VS developed the first manuscript draft. AL, VS, AT, MW-P, AM, ST, MS, AK, OW, and TH contributed to the interpretation of the data and provided important intellectual content to the manuscript. All authors contributed to the article and approved the submitted version.


The outcome of a tibial plateau fracture (TPF) depends on the fracture reduction achieved and the extent of soft-tissue lesions, including lesions in the ligaments, cartilage, and menisci. Sub-optimal treatment can result in poor knee function and osteoarthritis. Preoperative planning is primarily based on conventional X-ray and computed tomography (CT), which are unsuitable for diagnosing soft-tissue lesions. Magnetic resonance imaging (MRI) is not routinely performed. To date, no literature exists that clearly states the indications for preoperative MRI. This systematic review aimed to determine the frequency of soft-tissue lesions in TPFs, the association between fracture type and soft-tissue lesions, and the types of cases for which MRI is indicated.A systematic review of the literature was based on articles located in PubMed/MEDLINE and the Cochrane Central Register of Controlled Trials (CENTRAL), supplemented by searching the included articles’ reference lists and the ePublication lists of leading orthopedic and trauma journals.A total of 1138 studies were retrieved. Of these, 18 met the eligibility criteria and included a total of 877 patients. The proportion of total soft-tissue lesions was 93.0%. The proportions of soft-tissue lesions were as follows: medial collateral ligament 20.7%, lateral collateral ligament 22.9%, anterior cruciate ligament 36.8%, posterior cruciate ligament 14.8%, lateral meniscus 48.9%, and medial meniscus 24.5%. A weak association was found between increasing frequency of LCL and ACL lesions and an increase in fracture type according to Schatzker's classification. No standard algorithm for MRI scans of TPFs was found.At least one ligament or meniscal lesion is present in 93.0% of TPF cases. More studies with higher levels of evidence are needed to find out in which particular cases MRI adds value. However, MRI is recommended, at least in young patients and cases of high-energy trauma. Tibial plateau fractures (TPFs) are rare, representing 1.0% of all fractures, and are associated with an increased risk of post-traumatic osteoarthritis (OA) . In addiThe initial diagnostic modalities for a suspected TPF are usually X-ray and computed tomography (CT). Because clinical examination of the ligamentous structures is not always possible in the acute condition due to swelling and patient pain , attemptFracturoscopy is another strategy that has been suggested as an intraoperative diagnostic tool with the possibility of detecting and treating internal knee damage during treatment. However, no greater benefit in diagnosis or therapy has been shown compared to traditional treatment .The literature is inconsistent regarding the added benefits of preoperative MRI for planning TPF treatment. To better understand this issue, we performed a systematic review that aimed to determine the frequency of soft-tissue lesions in TPF, the association between fracture type and soft-tissue lesions, and the cases for which MRI is indicated.A systematic review was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines (PROSPERO: CRD42021244398).Clinical Orthopaedics and Related Research, Archives of Orthopaedic and Trauma Surgery, Journal of Bone and Joint Surgery (American and British versions), Injury, and The Knee. All the studies that evaluated outcomes were selected, and the full text was obtained. Biomechanical, in vitro and in vivo studies, review articles, articles about surgical techniques, case reports, letters to the editor, editorials, and conference abstracts were excluded.We searched PubMed/MEDLINE and the Cochrane Central Register of Controlled Trials (CENTRAL) using the Boolean operators OR/AND: ). The search was supplemented by searching the reference lists of the included articles and the ePublication lists of leading orthopedic and trauma journals, including Two authors (GT and AK) independently reviewed the titles and abstracts of each article identified in the literature search. The full text of each article was obtained and evaluated for eligibility when the eligibility was unclear from the title and abstract. Any disagreements were resolved through a consensus discussion between the two independent reviewers. A third reviewer (MK) was consulted if consensus could not be achieved.The full text of the selected articles was screened for the following inclusion criteria: (1) a prospective or retrospective study design on MRI prior to TPF surgery; (2) a comparative or correlative study on MRI and conventional X-ray and/or CT for TPF.Articles were excluded based on the following criteria: (1) an incomplete comparison or correlation of conventional X-ray or CT and MRI; (2) no reported classification of proximal tibial fracture; (3) no tissue lesions described; and (4) studies written in a language other than English. No restrictions were imposed on demographic characteristics, surgical technique, choice of classification, or choice of osteosynthesis material.The initial search produced 1139 articles. After reviewing the abstracts, 22 articles were eligible for initial screening according to the inclusion and exclusion criteria. All 22 articles presented an assessment of TPF with conventional X-ray, CT, and MRI, and were therefore included in the preliminary analysis. Four articles were excluded: two were excluded for not reporting whether every patient had a conventional X-ray or CT scan, one was excluded for only reporting the fracture classification without evaluating tissue lesions, and one was excluded for not reporting the results. Therefore, 18 studies were included in this systematic review , 14–26 (The Centre for Evidence-Based Medicine (OCEBM)’s modification for orthopedic literature  was usedThe patient demographic details, including age, sex, mode of trauma, and the radiological investigation used, were extracted to provide an overview of the population. The type of classification, total lesions, lesions to collateral and cruciate ligaments, lesions to menisci, and lesions by classification were obtained. Information regarding recommendations for additional MRI diagnostics was gathered. The data were synthesized in narrative and tabular formats.The data analyses were performed using R statistical software  with the R function “metaprop” from the R package “meta”  and IBM SPSS Statistics version 26 program .In the cases of normally distributed data, an analysis using the Freeman–Tukey double arcsine transformation was performed. In the cases of skewed distribution, an approach based on the logit transformation using generalized linear mixed models was performed, according to the recommendation of Schwarzer et al. .The proportions and 95% confidence intervals (CIs) were calculated for 7 dichotomous variables: total soft-tissue lesions and medial collateral ligament (MCL), lateral collateral ligament (LCL), anterior cruciate ligament (ACL), posterior cruciate ligament (PCL), and medial and lateral meniscus lesions.I2 statistic was used to evaluate heterogeneity, with I2 > 50% indicating significant heterogeneity, as was Cochran’s Q p value, with a p value < 0.05 indicating significant heterogeneity. A random-effects model was used throughout. Egger’s and Begg’s tests were performed for each variable to test for small-study effect. A p value < 0.05 denoted statistical significance.The rrb, with a p value < 0.05 indicating statistical significance). The value was calculated according to Cohen [rrb ≥ 0.1 to < 0.3 corresponds to a weak effect, rrb ≥ 0.3 to < 0.5 corresponds to a moderate effect, and rrb ≥ 0.5 corresponds to a strong effect).A subgroup analysis to measure the association between the different types according to Schatzker’s classification  and the to Cohen   years, suffered 878 TPFs. Of these, 322 patients were female, and 463 were male, while two studies did not provide information on sex –87 years. Nine stThe chosen radiological modalities were conventional X-ray and MRI in four studies , 17, 26,Due to skewed distribution, the meta-analysis of single proportions was conducted using the logit transformation . The folI2 statistic (85.3%) and Cochran’s Q test (p < 0.0001), which showed heterogeneity. The total soft-tissue lesions had an overall proportion of 93.0% (95% CI 71.20–98.59), independent of the fracture type. This was a statistically significant result. Egger’s test and Begg’s test showed no small-study effects   and Cochran’s Q test (p < 0.0001), which showed heterogeneity. The overall proportion was 20.7% (95% CI 13.51–30.42), independent of the fracture type, which was statistically significant. Egger’s test and Begg’s test showed no small-study effects   and Cochran’s Q test (p < 0.0001), which showed heterogeneity. The overall proportion of 22.9% (95% CI 14.01–35.2) was independent of the fracture type and statistically significant. Egger’s test and Begg’s test showed no small-study effects   and Cochran’s Q test (p < 0.0001), which showed heterogeneity. The overall proportion of 36.8% (95% CI 24.87–50.61) was independent of the fracture type, which was a statistically significant result. Egger’s test and Begg’s test showed no small-study effects   and Cochran’s Q test (p < 0.0001), which showed heterogeneity. The overall proportion of 14.8% (95% CI 8.3–25.1) was independent of fracture type. This was a statistically significant result. Egger’s test and Begg’s test showed no small-study effects   and popliteus tendon were referred to in two studies , 17. HowI2 statistic (83.9%) and Cochran’s Q test (p < 0.0001), which showed heterogeneity. The overall proportion of 48.9% (95% CI 38.28–59.62) was independent of fracture type, which was statistically significant. Egger’s test and Begg’s test showed no small-study effects   Fig. .Fig. 7LaI2 statistic (75%) and Cochran’s Q test (p < 0.0001), which showed heterogeneity. An overall proportion of 24.5% (95% CI 17.67–33.0) was independent of fracture type. This was a statistically significant result. Egger’s test and Begg’s test showed no small-study effects   or an ACL lesion . For both, there was a weak association according to Cohen’s test [A rank bi-serial correlation identified a significant relationship between the type of fracture according to Schatzker’s classification and an LCL lesion , PCL lesion , medial meniscus lesion , or lateral meniscus lesion .A rank bi-serial correlation identified no significant relationship between the type of fracture according to Schatzker’s classification and an MCL lesion (Table The recommendations for and against preoperative MRI diagnostics are shown in Table Table This review shows that at least one ligament or meniscal lesion is present in 93% of TPF cases. A weak association exists between an increasing frequency of LCL and ACL lesions and an increased type of fracture according to Schatzker’s classification . The queUsing conventional X-ray and CT as the primary diagnostic methods in TPF is standard. However, soft tissues cannot be assessed using these diagnostic tools. MRI is suitable for this purpose, as it provides accurate non-invasive assessment of knee pathology . SeveralVarious studies have investigated articular depressions and tibial plateau widening in TPFs to find an association with soft-tissue lesions. According to Kolb et al. , who perIdentification of soft-tissue injuries is crucial for postoperative outcomes , 40. A rThe reviewed studies showed wide variation in the incidence rate of individual soft-tissue lesions, but most lacked precise information on grading and which lesions required surgical treatment. Mustonen et al.  documentConservative or surgical treatment of ACL lesions in the acute stage, regardless of grade, remains under discussion. However, clinical assessment of ligament stability alone may be insufficient, due to swelling and fractures, especially in nonoperative minimally displaced TPFs , but MRIInjuries to the PLC are reported to be present in 16.0–28.0% of knee injuries and are frequently underdiagnosed –43. TheyThe literature reviewed reports a frequency of 48.9% for lateral meniscus lesions and 24.5% for medial meniscus lesions Table , which tIn the presence of a longitudinal, radial, or root tear, surgery is indicated. Initial treatment leads to positive long-term outcomes –51. PossOne can argue that the quality of MRI is limited by acute soft-tissue swelling or an external fixator due to a metal artifact. Nevertheless, MRI examinations in patients with non-ferromagnetic external fixators for traumatic knee dislocations can be safely performed under certain conditions and provide diagnostic-quality images , 57–59. The potential to overestimate soft-tissue injuries in MRI is high and requires extensive experience. Therefore, radiologists and surgeons should be familiar with how specific injury patterns influence management to achieve optimal outcomes .The most commonly used systems for classifying TPFs were the Schatzker  and AO cAs presented in Table Accurate preoperative identification of all injured structures by MRI is useful. The current review shows that the literature does not allow a clear recommendation. However, from clinical practice experience and the available literature, the authors believe MRI is indicated in patients with high-energy trauma, fracture morphology with a dislocation mechanism, posterolateral fractures, and fractures with tibial plateau widening. However, this recommendation should be supported with further studies.This review has some limitations. The review only considered studies using conventional X-ray, CT, and MRI. This review could not assess a correlation between soft-tissue lesions and fracture type, but reports the sum of soft-tissue injuries. The presence of high heterogeneity regarding patients’ mode of trauma, the classification used, and diversity in the design of the individual studies means that the data comparisons were of poor quality. Most studies have a level of evidence of type IV. Future studies should be more uniform in the assessment of the internal structures of the knee, trauma mechanisms and severity, and treated soft-tissue lesions.This review shows that at least one ligament or meniscal lesion is present in 93% of TPF cases. A weak association exists between an increasing frequency of LCL and ACL lesions and an increase in fracture type according to Schatzker’s classification. The indications for preoperative MRI are still a matter of discussion, and a standardized algorithm for MRI in TPF cases is still lacking. Nevertheless, preoperative MRI for the evaluation of soft-tissue injuries is an important diagnostic tool. More studies with higher levels of evidence are needed to find out in which particular cases MRI adds value.


We present an unusual clinical case of a 39-year-old woman admitted to the Department of Cardiology due to stenocardial pain accompanied by hypertensive crisis. The patient presented with severe chest pain and high blood pressure, along with a history of type 2 diabetes, hyperlipidemia, smoking, and hypertension. Initial tests showed elevated troponin T, glucose, CRP, and D-dimer levels, and electrocardiography and transthoracic echocardiography showed abnormalities suggesting acute myocardial infarction, but angiography did not reveal any significant coronary artery blockages. Further tests and imaging led to a diagnosis of takotsubo syndrome (TTS) and suspicion of pheochromocytoma, which was confirmed later biopsy. The presented case is very rare because the coexistence of TTS and pheochromocytoma is not common due to the rarity of the tumor. It is very important to make a quick and accurate diagnosis, because improperly treated cases can lead to death. We would like to share an intriguing and unusual clinical case of a 39-year-old woman who presented to our Department of Cardiology with stenocardial pain and accompanying hypertensive crisis. The patient’s symptoms were suggestive of acute myocardial infarction (AMI) and therefore, the initial diagnosis was made accordingly. However, as the case progressed, the final diagnosis turned out to be quite unexpected.On admission, the patient complained of severe chest pain accompanied by symptoms associated with an increase in blood pressure (BP) to 210/110 mmHg. There was a stressful situation before admission to the hospital. In the history: type 2 diabetes, hyperlipidemia, nicotinism, arterial hypertension with accompanying spikes for 6 months and weight loss – 20 kg within 6 months. The patient was permanently on temisartan 40 mg and bisoprolol 2.5 mg.Physical examination revealed a systolic murmur over the 3/6 apex and tenderness in the right hypochondrium. Laboratory tests showed an increase in the troponin T 0.6–1.1 ng/ml), glucose (300 mg%), CRP (27.5 mg/L) levels and D-dimers (910 ng/ml). Electrocardiography (ECG) showed ST segment depression in leads II and V4 (Fig. .1 ng/ml,The case shows unusual presentation of phaeochromocytoma with baseline diagnostic process including AMI and TTS. Association between pheochromocytoma and TTS seems to be obvious, however, coexistence of these two diseases is rare because of rare frequency of the tumor ,3. It isThere are no conflicts of interest.


The development of morality is vital for fostering prosocial behavior and enhancing both individual and societal well-being. Clarifying what contextual and individual factors play a role in moral processes during childhood can contribute to our understanding of the development of morality. Given the previous acknowledgment of importance, yet lack of existing empirical findings, the study focused on the significance of callous-unemotional traits  and emotion regulation  for moral emotions and cognitions during middle childhood. The concrete aim was to examine direct and indirect effects of callous-unemotional trait dimensions  onto immoral emotional attribution  and admissibility of immoral actions  via emotion regulation skills.A cross-sectional study was conducted with 194 children attending Grades 1 to 4, and their primary caregivers. The children completed the Inventory of Callous-Unemotional Traits and caregivers completed the Emotion Regulation Checklist. The children were also presented with a set of moral dilemma vignettes, and asked about the emotions of protagonists who acted immoral, and the admissibility of their actions.Path-model analysis revealed (1) negative direct effects of emotion regulation skills onto immoral emotional attribution and admissibility of immoral actions, (2) positive direct effects of the dimensions callousness and uncaring onto immoral emotional attribution and admissibility of immoral actions, and (3) negative direct effects of dimensions callousness and uncaring onto emotion regulation skills. Indirect effects, indicating that emotion regulation skills mediate the association between the callous-unemotional trait dimensions and morality, were also found.The findings address a knowledge gap and indicate that emotion regulation skills, callousness, and uncaring play an important role in morality in middle childhood and should be included in frameworks of moral decision-making and development. Morality comprises the concept of distinguishing right from wrong, guiding individuals’ actions and interactions within society . In middThe aim of the current study is to examine the association between callous-unemotional traits, emotion regulation skills, and morality in middle childhood. We postulate a theoretically- and empirically-driven integrative mediational path model between the constructs. We first examine hypothesized direct associations between (1) callous-unemotional trait dimensions  and emotion regulation skills, (2) emotion regulation skills and cognitive and emotional morality, and (3) callous-unemotional trait dimensions and cognitive and emotional morality. We then examine hypothesized indirect effects in a mediational path model.Moral psychology has a long tradition and distinguishes various constructs of morality . Discussions about the concept of morality and the moral development of children span across diverse theoretical perspectives and models. These perspectives and models encompass distinct foundations  and employ varied operationalizations of morality , 15. In Emotional attribution is a component of moral motivation, i.e., an emotional moral construct , and encThe perceived admissibility of immoral actions is part of moral cognition, i.e., a cognitive moral construct , 21. AdmPerceptions and information processing play an important role in moral conflict situations . When coEmotion regulation is a core aspect of emotional competence , consistcallousness, i.e., a lack of remorse and concern about others, uncaring, i.e., not caring about others or own performance, and unemotionality, i.e., not expressing emotions  the callous-unemotional trait dimensions callousness, uncaring, and unemotionality are negatively associated emotion regulation skills ; [H2] emotion regulation skills are negatively associated with immoral emotional attribution and admissibility of immoral actions ; [H3] the callous-unemotional trait dimensions callousness, uncaring, and unemotionality are positively associated with immoral emotional attribution and admissibility of immoral actions ; [H4] emotion regulation skills mediate the association between the callous-unemotional trait dimensions and immoral emotional attribution and admissibility of immoral actions .We focus on middle childhood, as it constitutes an interesting developmental stage for morality. In early childhood, children learn moral rules through authorities, e.g., parents or preschool teachers, whereby their orientation is still very rigid and rule-following . In middIn addition, important methodological considerations flow into the current study. Oser  highlighThe data stems from a larger project with the aim of examining the social-emotional development of morality in middle childhood. The current study is a cross-sectional questionnaire study, and we only report on the instruments and data relevant to the current research question. Approval was obtained from the institutional review board and the regional school authority board. Aiming to recruit participants in middle childhood, i.e., ages ranging from six to eleven years , 78, stuMage = 8.53, SDage = 1.40; 58.8% male) and their primary caregivers . Primary caregivers were asked to indicate their familial relation to the child , and whether they filled out the questionnaire alone or together with someone else . Of the primary caregivers 75.8% were biological parents  and 10.3% were other primary caregivers; 13.9% of primary caregivers did not respond. 146 children visited regular primary schools and 48 special education schools; a total of 52 children had a special educational need in emotional-social development status. In Germany a school-oriented diagnostic procedure is undertaken by specialized educators to assign special educational needs. A special educational need in emotional-social development, represents a specific educational need due to emotional and behavioral difficulties. 2.1% of the children and 12.4% of the caregivers were not born in Germany. Caregivers were asked to report the highest level of education completed by both the mother and father. Concerning mothers and fathers respectively, 2.6% and 3.6% did not complete secondary school; 4.6% and 8.8% completed Grade 9; 29.4% and 27.8% completed Grade 10; 12.9% and 11.3% completed Grade 12/13; 26.3% and 22.2% obtained a university degree; 4.6% and 5.2% indicated other; 19.6% and 21.1% left the question unanswered.The sample consisted of 194 six- to eleven-year-olds (N = 194) yielded a power of 92.76%, when an effect size f² = 0.05, α err prob. = 0.05, and a number of seven predictors were included.Initially, we set out to recruit 300 children. However, as a result of limited resources at schools (due to the covid-19 pandemic and integration of migrant children), we stopped data collection after five months. To determine if the current study was sufficiently powered, a sensitivity analysis using G*Power  was condCallous-Unemotional Traits. The German-version of the Inventory of Callous-Unemotional Traits [α = .85, Ω = .85), which form the sub-scales callousness , uncaring ” ; 8 items, α = 0.77, Ω = 0.77), and unemotionality . The participating children were asked to respond to the items on a scale ranging from (1) not at all true to (4) definitely true. Items that required reverse scoring were recoded. Hence, high values per dimension indicate higher levels of callousness, uncaring, and unemotionality.l Traits , 80 was l Traits , 35, 62.Emotional Regulation Skills. The Emotion Regulation Checklist is an other-report instrument used to assess emotion regulation skills [α = 0.81, Ω = 0.76), was translated into German. In addition, an exploratory factor analysis was conducted, which yielded a single-factor structure (Bartlett’s test: χ2(28) = 377.68, p < .001; KMO = 0.83; R2 = 0.44) with high factor loadings ranging from 0.51 to 0.79. Caregivers were asked to respond to the items on a scale ranging from (1) rarely or never to (4) almost always. Items that required reverse scoring were recoded. High values indicate higher levels of emotion regulation skills.n skills , encompan skills , 83. Then skills ; Italiann skills ; Persiann skills ; Preschon skills ). UtilizImmoral Emotional Attribution and Admissibility of Immoral Actions. The Moral Attitudes in Adolescence questionnaire [ionnaire  was usedionnaire . The queionnaire , 90. Theionnaire , namely:ionnaire . The morionnaire . The stoα = 0.86, Ω = 0.86). Not feeling bad after an immoral decision may reflect a lack of guilt or shame. Furthermore, the participants are asked how admissible the immoral action was . The participants are asked to respond on a scale ranging (1) not okay at all to (5) very okay. This question is indicative of participants’ admissibility of immoral actions, with high values reflecting high permissibility of immoral actions . As there are eight stories, the immoral emotional attribution and admissibility of immoral actions variables constitute eight items each.The following is an example of a moral conflict story presented to girls: “Lisa enters the schoolyard and sees that a girl is hitting Sandra because she sat on the bench that the girl normally sits on. Lisa thinks about what she can do. She knows that if she intervenes and tells the girl to stop, she will be late for class. But, if she goes into the school building, the girl will continue beating Sandra.”. After reading the story, the participants are asked how they think the protagonist would feel if opting for the immoral choice . The participants are asked to respond on a scale ranging from (1) very bad to (5) very good. This question is indicative of participants’ immoral emotional attribution, with high values reflecting feeling good after an immoral decision  [RMSEA), Comparative Fit Index (CFI), Normed Fit Index (NFI), Tucker-Lewis Index (TLI), χ²- and p-value were examined. An adequate model fit is indicated with the following values: χ²/df < 5, χ² not significant, CFI, NFI and TLI near 1 (> 0.90), and RMSEA and SRMR near 0 (< 0.08) [The data was analyzed with SPSS 27 and AMOS 27. Descriptive and preliminary analysis were conducted first. The callous-unemotional trait dimensions, emotion regulation skills, and immoral emotional attribution and admissibility of immoral actions, are the key variables in the path model. Gender, age and SEN are the control variables. The path model included the dimensions of callous-unemotional traits as independent variables, emotion regulation skills as the mediator variable, and immoral emotional attribution and admissibility of immoral actions as the dependent variables. To control for gender, age and special educational needs, these were added as additional independent variables with direct paths onto all key variables in the path model. Direct effects between the variables were estimated. Indirect mediation effects were determined using a bootstrap method with confidence estimates; a confidence interval at the 95% level with a bootstrap of 1000 samples was used for the estimation . Bootstr(< 0.08) , 97.Table The three callous-unemotional trait dimensions were positively correlated with each other, and with immoral emotional attribution and admissibility of immoral actions, as well as being negatively correlated with emotion regulation skills. Emotion regulation skills were negatively correlated with immoral emotional attribution and admissibility of immoral actions. Age correlated with the three dimensions of callous-unemotional traits and emotion regulation skills, but not with immoral emotion attribution and admissibility of immoral actions. Gender correlated only with the dimension of callousness and emotion regulation skills. Special educational needs in emotional-social development significantly correlated with the dimensions of callousness and unemotionality and with emotion regulation skills. Cronbach’s alpha and McDonald’s omega were calculated,  and indicated sufficient or good reliability for all , 99.χ²(df = 1) = 3.55; p = .06; CFI = 1.00; NFI = 1.00; TLI = 0.86; RMSEA = 0.12, SRMR = 0.02). Figure The tested path model revealed an adequate model fit , as well as the mediation by emotion regulation skills between callous-unemotional traits and morality (H4). Hypotheses concerning the callous-unemotional trait dimensions were only partially supported, as callousness and uncaring had direct effects onto emotion regulation skills (H1) and morality (H3), but not the unemotionality dimension.Considering the first hypothesis (H1), we found that the dimensions callousness and uncaring were negatively associated with emotion regulation skills. Hence, children with higher levels of callousness and uncaring, also report lower levels of emotion regulation skills. Similarly, correlations between callous-unemotional traits and emotion regulation have been found in other studies , 101. YeConsidering the second hypothesis (H2), we found that emotion regulation skills were negatively associated with immoral emotional attribution and admissibility of immoral actions. Thus, the higher the emotion regulation skills were, the less likely children are to associate positive feelings with immoral decisions, i.e., they are more likely to link immoral decisions with feeling bad. Furthermore, the higher the emotion regulation skills were, the less likely children are to view immoral acts as permissible, i.e., they are more likely to consider the actions unacceptable. These findings are consistent with previous research and provide preliminary indications that emotion regulation skills may be conducive for children’s morality –33. PossRegarding the third hypothesis (H3), we found that the dimensions callousness and uncaring were positively associated with immoral emotional attribution and admissibility of immoral actions, whilst unemotionality was not. The results align with the general connection observed between callous-unemotional traits and morality –48, 106.In line with our fourth hypothesis (H4), indirect effects demonstrate that emotion regulation skills mediate the association between callous-unemotional traits  and immoral emotional attribution and admissibility of immoral actions. The current findings indicate that children with high levels of callous-unemotional traits , possess lower emotion regulation skills, which in turn impacts immoral emotional attribution and admissibility of immoral actions. Reduced emotion regulation skills, thus detail one mechanism by which children with callous-unemotional traits respond to moral conflicts and transgression. This finding aligns with related studies, which revealed that emotion regulation difficulties mediate the association between overarching callous-unemotional traits and antisocial behaviors in young adults , and emoThrough the inclusion of control variables, we found gender generally did not have an effect on the variables, whilst age had a direct effect on callous-unemotional traits, as previously shown in the literature . We furtRMSEA value was quite high and the TLI somewhat low; this could be due to the complexity of the model. The callous-unemotional trait dimension of unemotionality neither had a direct effect on emotion regulation skills, nor on immoral emotional attribution and admissibility of immoral actions, despite significant correlations (see Table A methodological limitation of the current study is that the German version of the Emotion Regulation Checklist  has not Morality is a complex, multifaceted construct, with multiple existing theories  and nume


To compare a fixed-volume contrast medium (CM) protocol with a combined total body weight (TBW) and body composition-tailored protocol in chest CT.t-test and Pearson’s r.Patients referred for routine contrast enhanced chest CT were prospectively categorised as normal, muscular or overweight. Patients were accordingly randomised into two groups; Group 1 received a fixed CM protocol. Group 2 received CM volume according to a body composition-tailored protocol. Objective image quality comparisons between protocols and body compositions were performed. Differences between groups and correlation were analysed using vs 396 HU; p = 0.004) and overweight categories , while normal category patients showed increased attenuation . In Group 1, strongest correlation was found between attenuation and TBW in muscular  and waist circumference in overweight patients . In Group 2, no significant correlations were found for the same body size parameters. In Group 1, 13% of the overweight patients was below 250 HU (p = 0.053).A total of 179 patients were included: 87 in Group 1 ; and 92 in Group 2 . Compared to Group 2, Group 1 showed lower vascular attenuation in muscular (mean 346 Hounsfield unit (HU) A combined TBW and body composition-tailored CM protocol in chest CT resulted in more homogenous enhancement and fewer outliers compared to a fixed-volume protocol.This is, to our knowledge, the first study to investigate the impact of various body compositions on contrast medium enhancement in chest CT. In chest CT, contrast medium (CM) is required to assess, delineate, and differentiate between a wide range of thoracic disorders. Factors affecting CM enhancement include injection parameters; CM volume, injection rate and delay; and patient-related factors such as cardiac output and body size. A fixed-volume protocol may be effective for average-sized patients. However, patient populations are not homogenous. Therefore, this approach may lead to CM over- or underdosage resulting in non-uniform enhancement. One way of solving this is to relate CM volume linearly to TBW. This may reduce interpatient variability, but does not adapt CM volume to patient body composition. Because of the increased vascularisation in muscle tissue compared to fatty tissue, the blood volume does not increase linearly to TBW. Clinically, this discrepancy in blood volume may affect CM enhancement, resulting in insufficient enhancement in younger and muscular patient, while patients with higher fat mass, may receive unnecessarily high CM volumes. Therefore, several strategies to personalise CM volume have been suggested in the literature, none are, however, reported as superior.CM volume in chest CT is most commonly fixed or adjusted to patient total body weight (TBW). One such strategy is the use of modified weight-based look-up tables. This patient-tailored approach is an easy applicable method to estimate a personalised CM volume in a clinical context, facilitating adaption of CM volume to body size or allometric parameters. However, this may introduce inaccuracy compared to methods utilising more individualised size predictors such as lean body weight or body surface area.Due to practical considerations, simplified CM volume adaptions can be utilised in daily clinical practice. However, there is a lack of recognised guidelines and consensus related to CM administration in chest CT. Given the increasing prevalence of overweight and obesity in all segments of the population, it is important to identify the relationship between pharmacokinetic parameters such as CM distribution and body size. This identification may allow development of CM protocols suitable for patients of any size.The performance of various body weight adapted CM protocols have been explored for coronary arteries in CT angiography, and for abdominal CT.In this study, CM volumes are stratified across a range of body parameters to explore and provide knowledge related to CM administration for routine chest CT. The aim was to compare the performance of a fixed-volume CM protocol with a combined weight and body composition-tailored CM protocol in chest CT.This prospective study was approved by the Regional Committee for Medical and Health Research. All patients participated upon written and oral consent.2), contraindications to contrast-enhanced CT, and age <18 years. Age, gender, TBW, height, body mass index (BMI), waist circumference, CM volume, and injection rate were recorded (n = 89) from Group 2 have been included in a study estimating the variation in CM dose using various lean body mass methods, but all results are new for this study.179 eligible patients undergoing chest CT examination between August 2019 and September 2021 at Oslo University Hospital were included . Exclusirecorded . Some sun = 62); (b), muscular (n = 56); and (c), overweight (n = 61)  trained in subjective assessment for this study.Based on predefined factors and subjective assessment, the patients were divided into three body composition categories: (a), normal ((n = 61) . The wairef , pitch 2.5, and rotation time 0.25 s. Image reconstruction was performed with individually adapted field of view, 2.0 mm slice thickness, and increment of 1.5 mm. Image reconstruction used was Admire iterative reconstruction strength 2, br40 kernel (“std. soft”).Scans were performed using state-of-the-art CT scanner , with a 192 × 0.6 mm slice collimation, tube voltage 120 kV, reference tube current 130 mAs−1 , prewarmed to standardised 37◦C (99◦F) and injected with a power injector. The maximum pressure threshold was set to 325 psi for all injections.A 16–20-gauge intravenous injection catheter was inserted in either left or right antecubital vein for CM administration. The CM concentration was 350 mgI mln = 87) received a fixed CM volume of 90 ml, injected with a flow rate of 5 ml s−1. Group 2 (n = 92) received a body composition-tailored CM volume using a look-up table based on the patient weight and body composition  in the pulmonary artery, ascending aorta and descending aorta, left atrium, right and left pulmonary artery, and the paravertebral muscle. ROIs were placed in the same anatomical levels between patients with approximate areas of 1.0 cm2  or as la:Secondary, the paravertebral muscle measurements were used to calculate contrast-to-noise ratio (CNR) and signal-to-noise ratio (SNR). CNR and SNR were defined using the following equationst-test, while variations in attenuation between body composition categories were compared for both groups using one-way ANOVA followed by post hoc Tuckey test to compare differences between each body composition category. Pearson’s χ2 or Fisher’s exact test was used as appropriate to calculate differences between categorical variables. Correlation of data was assessed using Pearson’s correlation coefficient. Data analysis was performed with STATA v. 16.0 . Statistical significance was accepted at the 0.05 level.Continuous data were presented as the mean ± SD. Absolute numbers and percentages were used for categorical variables. Differences between groups were analysed using Student’s The demographic characteristics of the study population are summarised in p = 0.043). vs the muscular  and overweight  body composition categories.The comparisons of CM parameters between the two groups are shown in p = 0.047), but not between the other categories. In Group 2, the overall mean attenuation values were 374 ± 81 HU, 396 ± 63 HU, and 367 ± 57 HU for the normal, muscular and overweight categories, respectively. There were no significant differences between the categories.In Group 1, the overall mean vascular attenuation values for each body composition category  were 385 ± 76 HU, 346 ± 59 HU, and 342 ± 71 HU, respectively . A signip = 0.004 and p = 0.12, respectively), while the normal category patients showed increased attenuation (p = 0.61) (p = <0.001)  . A signi <0.001) .p = 0.053). In Group 2, one patient in the normal body composition category measured below the preferred attenuation level. No significant difference in attenuation was found between patients <30 years old when compared to patients >30 years for Group 1 and Group 2 .Mean diagnostic attenuation of ≥250 HU was reached for all body categories for overall mean intravascular attenuation, and separately for all included vascular structures, regardless of CM protocol . Howevervol and noise. A statistical difference in mean image noise (HU) between the two groups was observed for the muscular category for overall CM structures (p = <0.001) and pulmonary trunc (p = 0.01). No significant differences in CNR was found between the two groups , gender , BMI , and waist circumference . In the overweight category, moderate but significant negative correlation was also noted between CM attenuation and TBW , and waist circumference . In the normal category, there were no significant results, but negative correlation was noted between attenuation and TBW .In Group 1, moderate but significant negative correlations were found in the muscular category between CM attenuation and TBW , indicating increased vascular enhancement with age. In the normal body category, moderate but significant positive correlations were noted between attenuation and BMI , and waist circumference . A low positive correlation was also found in the muscular group for the same demographic factors, whereas weak negative correlations were noted for the overweight group, none being significant.In Group 2, there were no significant correlations between CM attenuation and TBW. In the muscular category moderate but significant positive correlation was found between attenuation and age  were significantly different, with a higher CM volume and flow rate utilised in Group 2. For the muscular category, this increase of mean 16 ml and 0.8 ml s Given the global rise in overweight and obesity, approaches that stratify CM doses across a range of body compositions are favored. Ratnakanthan et al investigated the variation in pulmonary artery enhancement between an individual adapted CM protocol using TBW and a fixed strategy in pulmonary CT angiography. A more homogenous enhancement was shown when individually tailored CM volume was used, especially in obese patients. These findings are in line with our results; fixed CM protocol caused significantly lower mean vascular attenuation in the overweight body composition category than in the normal composition category. However, as expected, the slope of the fitted regression line was similar for normal and overweight composition patients due to the relatively smaller blood volume per TBW in overweight patients. In other words, the same decrease in CM enhancement occurred with increased TBW in both overweight and normal composition patients. When adjusting CM volume to TBW and body composition, the association between CM enhancement and TBW was still negative for overweight patients in Group 2, however, to a lesser extent than for overweight patients in Group 1. This may indicate a more limited dispersing effect from not metabolically active body fat in the early CM phase. Notably, the CM volume was lowest per kg TBW for this body composition category. As a result, the highest number of patients below the diagnostic acceptance value of ≥250 HU was found in this body composition category using fixed-volume. Although the difference was not significant between the two groups of overweight patients, the lower attenuation levels may be clinically relevant. In addition, the steeper negative regression slope using fixed CM volume in muscular patients may indicate a higher diluting effect in this category.There is a lack of studies investigating the impact of patient-related factors on CM enhancement in chest CT. However, several authors have investigated the use of TBW with more personalised strategies within pulmonary, cardiac and abdominal CT.In Group 1, there was a negative correlation between thoracic vascular attenuation and both TBW and waist circumference for all body categories. This indicates that an increase of body size leads to decrease in enhancement levels. In comparison, no significant correlation was found in Group 2 for the same body composition parameters for muscular and overweight categories indicating a more consistent enhancement level across various body size parameters, thus reduced under- and overdosage of CM. In the current study, a significant difference in vascular enhancement was observed in ascending aorta, descending aorta, and left atrium between the two strategies  for muscular body composition patients. This indicates a more pronounced diluting effect in the systemic circulation, compared to the pulmonary circulation. As a longer delay may be preferential for parenchymal and venous enhancement, the prolonged effect of diluting the CM in the blood for various body compositions, especially in muscular patients, may be more prominent. Our results indicate that individualisation to TBW and body composition may be of greater importance in delayed phases than earlier phases of chest CT. However, higher volumes may be considered for younger and/or muscular patients.As routine chest CT is utilised for a wide range of clinical conditions, the preferred scan delay and scan timing is highly dependent on the clinical indications and diagnostic target organs.In this study, the CNR and SNR were not significantly different between the two groups supporting the use of a body composition-tailored protocol. These findings are consistent with previous published studies.Although mainly objective measures was utilised in the current study for body composition assessment, this modified look-up table also facilitates a coarser division of body composition by using only TBW together with observable muscle and body fat mass. Consequently, this approach can maintain clinical efficiency, reduce interpatient variability, and be easy applicable in bedridden patients. Third, the age limit introduce some uncertainties with regard to age-related muscle loss. Although aging affects a wide range of physiological processes, the most observable are reported being body composition changes including loss of muscle mass and increased body fat. Moreover, no significant difference in enhancement was found in the muscular category for patients under or over 30 years old. Also, the study does not include subjective image quality assessment. Although these analyses are important, other studies have consistently reported corresponding results between objective CM enhancement and subjective image quality assessment. Lastly, the sample size could be considered relatively small.This study has several limitations. First, the scan protocols did not take into account variations in cardiac output, which may introduce some variability. Second, the inclusion of patients for the muscular body composition categories partly included subjective assessment. Although a bioelectric impedance analyser, calculating fat-free mass may have been more accurate, a limited number of trained radiographers performed the assessment.In conclusion, a fixed-volume CM protocol in chest CT showed large variations between different body compositions indicating suboptimal use of CM. In comparison, a combined TBW and body composition-tailored CM protocol resulted in more homogenous enhancement for all body composition categories with fewer outliers.


GNPTAB gene. MLII patients exhibit clinical phenotypes in the prenatal or neonatal stage, such as marked dysmorphic features, cardiac involvement, respiratory symptoms, dysostosis multiplex, severe growth abnormalities, and mental and motor developmental abnormalities. The median age at diagnosis for MLII is 0.7 years, the median survival is 5.0 years, and the median age at death is 1.8 years. No cure for MLII exists.Mucolipidosis type II (MLII), or I-cell disease, is a rare lysosomal storage disease (LSD) caused by variants in the GNPTAB gene identified the compound heterozygous mutations c.673C > T in exon 7 and c.1090C > T in exon 9, which were novel double heterozygous mutations first reported in China. For the first time, we describe our experience in the use of HSCT for MLII. Our patient underwent HSCT with cells from a 9/10 human leukocyte antigen (HLA)-matched unrelated donor at 12 months of age. Myeloid neutrophil and platelet engraftment occurred on Days 10 and 11, respectively.Sanger sequencing of the The patient's limb muscle tension was significantly reduced, and his gross and fine motor skills were improved four months after transplantation. DST results showed that the patient's fine motor skills and mental development were improved compared with before HSCT.MLII is a very severe lysosomal storage disease, to date, only 3 cases have been reported on the use of HSCT to treat MLII. Our data show that HSCT is a potential way to prolong the life of patients and improve their quality of life. Due to the lack of comparable data and time, the exact benefit remains unclear in MLII patients. Longer-term follow-up and in-depth prospective studies are indispensable. GNPTAB gene on chromosome 12q23.2 and generally results in death before the age of 10 years  phosphotransferase (EC 2.7.8.17) localized in the Golgi apparatus, which is essential for normal processing and packaging of soluble lysosomal enzymes by initiating the first step of tagging lysosomal enzymes with mannose-6-phosphate (M6P)  gene family (Mucolipidosis type II (MLII), or I-cell disease, is a lysosomal storage disease (LSD) caused by variants in the te M6P) . There ate (M6P) , 6. MLIVP . Therease EC 2..8.17 loce family .β-glucuronidase are transported to lysosomes in an M6P-dependent pathway, biochemical criteria including an at least tenfold increase in plasma lysosomal enzyme levels (arylsulfatase A and β-glucuronidase activities) could be used as a reference index for the diagnosis of ML , it has been performed for over 30 years in the treatment of various lysosomal storage disorders. Evidence on the efficacy of HSCT in MLII is still scarce. The combined international experience in the use of HSCT for MLII are only 23 patients, and only 3 cases have been reported in detail –13. HemaThis report summarizes the case of a 16-month-old ML patient with novel double heterozygous mutations in the GNPTAB gene who underwent HSCT at 12 months of age in China.α-hydroxyprogesterone and thyroid-stimulating hormone (TSH), were all normal. This patient first visited our hospital when he was 6 months old, presenting with unstable head erection, an inability to support the weight of his lower limbs, and decreased muscle tension and reflexes of the limbs. At the age of 8 months, his parents found that his motor development was significantly behind that of children of the same sex and age, and he was still unable to raise his head, turn over or sit  and was delivered by cesarean section because of little amniotic fluid. The newborn presented with a birth weight of 2,800 g (50th percentile), a body length of 48 cm (50th percentile) and an occipitofrontal circumference (OFC) of 32 cm (25th percentile). The postnatal physical examination confirmed thoracic deformity, a large inguinal hernia, a prominent forehead, puffy eyelids, epicanthus, a flat nasal bridge, anteverted nostrils, gingival hyperplasia, macroglossia and contractures of all large joints . Neonatar or sit . In addiβ-glucuronidase, in this patient's serum identified a more than tenfold increase  criterion, and were novel double heterozygous mutations first reported in China  2.5 mg/kg/d , fludarabine 30 mg/m2/day , cyclophosphamide 50 mg/kg/day , Busulfex 4.0 mg/kg/d . For graft-vs.-host disease (GVHD) prophylaxis, tacrolimus, and methylprednisolone were administered.Considering the young age at diagnosis in this patient and the parents' strong desire, HSCT was the only choice to be made after parents were well informed of the limitations and potential risks. Written informed consent was obtained from both parents. This patient underwent HSCT at 12 months of age. He received unrelated umbilical cord blood from Zhejiang Cord Blood Bank, which was 9/10 human leukocyte antigen (HLA) matched. The donor had the same blood type as the recipient (O Rh pos). The nucleated and CD34 cell doses of the infused CB were 1.697 × 10GNPTAB (NM_024312) c.637C > T  and c.1090C > T  variants were detected in the patient. The c.637C > T  variant was detected in heterozygous state in the father, was a novel nonsense variant (Sanger sequencing was found two heterozygous variants (c.673C > T in exon 7 and c.1090C > T in exon 9) in this patient. Heterozygous  variant . The oth variant . The bioThe pretransplantation myeloablative conditioning regimen was well tolerated by the patient. Because of the young age, this patient still developed acute GvHD of the skin (grade III), which was steroid sensitive and resolved. Myeloid neutrophil and platelet engraftment occurred on Days 10 and 11, respectively. The engraftment remained stable with complete donor chimerism.β-glucuronidase was slightly changed from before  showed the development of ages around 3 months old. At the age of 8 months, the patient's gross motor development was significantly delayed, and he could not turn over, crawl, or sit alone. At the same time, fine motor development and mental retardation were manifested as the inability to change small objects alone, no obvious response to names, and unable to laugh. The patient's overall development progressed continuously after HSCT . At the m before .GNPTAB gene, which encodes the α/β-precursor of GlcNAc-1-phosphotransferase. The clinical manifestations of patients with MLII alpha/beta are similar to those observed in some LSDs, such as MPS, which could show physical characteristics, such as coarse facial features, short stature, skeletal deformity, hepatosplenomegaly, and a reduced life expectancy . Kudo, Brem  at chronological ages of 6 and 15 months. The DST results showed that the patient's fine motor skills and mental development were improved compared with before HSCT. The functional M6P-containing lysosomal enzymes which was produced by hematopoietic donor cells, are transported to the lysosomes for degradation of macromolecule. Thus, metabolic “cross-correction” is achieved. In MLII patient, numerous enzymes which are associated with M6P signal are disrupted. This results in inappropriate secretion and insufficient delivery of multiple enzymes to the lysosome. Due to the inappropriate plasma secretion of several enzymes in MLII patients, the evaluation of lysosomal enzyme activity may remain significantly elevated months to years after successful HSCT . This ma