Although suicide is a leading cause of death among children, the optimal approach for using health care data sets to detect suicide-related emergencies among children is not known.This study aimed to assess the performance of suicide-related International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes and suicide-related chief complaint in detecting self-injurious thoughts and behaviors (SITB) among children compared with clinician chart review. The study also aimed to examine variations in performance by child sociodemographics and type of self-injury, as well as develop machine learning models trained on codified health record data (features) and clinician chart review (gold standard) and test model detection performance.A gold standard classification of suicide-related emergencies was determined through clinician manual review of clinical notes from 600 emergency department visits between 2015 and 2019 by children aged 10 to 17 years. Visits classified with nonfatal suicide attempt or intentional self-harm using the Centers for Disease Control and Prevention surveillance case definition list of ICD-10-CM codes and suicide-related chief complaint were compared with the gold standard classification. Machine learning classifiers  were then trained and tested using codified health record data  and the gold standard classification. The accuracy, sensitivity, and specificity of each detection approach and relative importance of features were examined.SITB accounted for 47.3% (284/600) of the visits. Suicide-related diagnostic codes missed nearly one-third  and suicide-related chief complaints missed more than half  of the children presenting to emergency departments with SITB. Sensitivity was significantly lower for male children than for female children  and for preteens compared with adolescents . Specificity was significantly lower for detecting preparatory acts  and attempts  than for detecting ideation . Machine learning–based models significantly improved the sensitivity of detection compared with suicide-related codes and chief complaint alone. Models considering all 84 features performed similarly to models considering only mental health–related ICD-10-CM codes and chief complaints (34 features) and models considering non–ICD-10-CM code indicators and mental health–related chief complaints (53 features).The capacity to detect children with SITB may be strengthened by applying a machine learning–based approach to codified health record data. To improve integration between clinical research informatics and child mental health care, future research is needed to evaluate the potential benefits of implementing detection approaches at the point of care and identifying precise targets for suicide prevention interventions in children. In the United States, suicide is the second leading cause of death among children aged 10 to 14 years, and 1 in 13 children attempts suicide before adulthood . EmergenMedical records provide an expanding repository of clinical and phenotypic data to enable low-cost population-based studies on a large scale  and infoNevertheless, little is known about whether the detection of suicide-related emergency department visits using medical record data can be improved through the development and application of phenotype algorithms. Children experience heterogenous manifestations of suicidal thoughts and behaviors across the developmental continuum, and the codified health data elements that differentiate children with SITB from those without are not well characterized. Most surveillance applications exclude children or combine children with adults -26. TradTo address the aforementioned gaps, the study objectives were to (1) compare the detection performance of suicide-related ICD-10-CM codes and chief complaint with that of clinician manual chart review, (2) examine variations in the detection performance by child sociodemographics and type of SITB , and (3) sequentially train and test a series of phenotype algorithms (machine learning classifiers) to detect SITB using codified health record data of varying complexity.This was a cross-sectional observational study of emergency department visits by children aged 10 to 17 years. The primary outcome was the classification of the presence or absence of SITB at the emergency department visit. The classification performance of codified medical record data (structured data elements) was compared with that of expert classification by clinician manual chart review of medical records. Algorithmic detection considering three sets of structured data elements was compared with detection considering suicide-related ICD-10-CM codes and suicide-related chief complaint alone (comparator) and chart review (gold standard): (1) mental health–related codes and mental health–related chief complaints, (2) suicide-related codes and non–ICD-10-CM code data elements , and (3) all structured data elements.The study followed the STROBE  statement guidelines.The study was approved by the University of California Los Angeles institutional review board (20-001512).The data source was a large university hospital health system comprising 4 hospitals  across 2 sites . For each child meeting the inclusion criteria, all emergency department medical records were delivered to the study team by the Clinical and Translational Science Institute from the Integrated Clinical and Research Data Repository, a large-scale clinical data warehouse that supports data analyses and extractions for research. The academic medical center site is a primary teaching hospital in Los Angeles, California. This site includes a colocated affiliated children’s hospital and an independently accredited psychiatric hospital with 3 inpatient child psychiatric units serving children with mental illnesses and developmental disabilities. The academic medical center is staffed 24/7 with child and adolescent psychiatrists and general psychiatrists. The community hospital is affiliated with a 25-bed general inpatient pediatric ward. At the community hospital site, children with acute psychiatric complaints are seen by emergency department physicians and licensed clinical social workers.P=.02).The flowchart of study inclusion is presented in Sociodemographics included child age, natal sex, race, and ethnicity. These variables were self- or parent-reported at the point of care. Socioeconomic disadvantage was assessed using the Area Deprivation Index (ADI) . The Fedsuicidal or suicide attempt by nursing triage upon the child’s arrival at the emergency department. Laboratory tests were restricted to those ordered and collected during the emergency department visit and included those related to overdose , urine drug screen results, and serum alcohol. All psychotropic medications (n=97) received during the visit were consolidated using the Anatomical Therapeutic Chemical classification system into 8 categories . Additional clinical characteristics were encounter year, site, emergency department disposition, provider sex, as well as the child’s number of prior 90-, 180-, and 365-day emergency department visits and general medical and psychiatric hospitalizations. A full list of sociodemographic and clinical characteristics and definitions are included in Clinical characteristics included diagnostic or billing codes, chief complaint, orders , site , and prior care use. All mental health–related diagnostic or billing codes (ICD-10-CM) from the emergency department visit were categorized using the CAMHD-CS . The preAll clinical notes from each emergency department visit were extracted and provided to the study team verbatim. The notes included physician history and physical examinations, progress notes, social work notes, and nursing notes.Classification by the manual review of records was adapted from the Columbia Classification Algorithm of Suicide Assessment (C-CASA) . The C-CConsistent with operationalized guidelines for C-CASA, if >1 category was present, the abstractor coded the visit as consistent with the most severe category: suicide death, nonfatal attempt, preparatory behavior, suicidal ideation, self-injurious behavior intent unknown, not enough information, and self-injurious behavior without suicidal intent . To captClassifications were compared and differed in only 0.3% (2/600) of the cases for presence or absence of SITB. Classifications differed in 2.5% (15/600) of the cases for type of SITB. In the second stage, a second board-certified child psychiatrist (BZ) and child psychiatric nurse practitioner (KC), also blinded, separately reviewed all discordant cases. Of the discordant cases for which concordance was not reached , consensus discussion yielded a final classification.Contingency matrixes were constructed comparing classification with suicide-related ICD-10-CM code and suicide-related chief complaint (comparator) and manual chart review (gold standard). The sensitivity, specificity, and accuracy were calculated, with 95% CIs computed using Clopper-Pearson CIs. Variations in performance by demographics were examined by subsetting the sample by demographic characteristics . Variations in detection performance for type of SITB  were examined by comparing classification using structured data elements with classification of type upon manual chart review.Fit metrics were measured via 10-fold cross-validation. For each fold, a machine learning model was trained with structured data elements (features) and the manual chart review (gold standard) for each child in a training set. Next, this model was used to classify the presence or absence of SITB (predicted outcome) of each child in a test set, and this predicted outcome was compared with the manual chart review (gold standard) to yield fit metrics. CIs for fit metrics were calculated by examining the variations in fit metrics across the test sets.Three sets of structured data elements were compared, representing varying levels of complexity of codified health record data: (1) mental health–related ICD-10-CM codes and mental health–related chief complaints (34 features); (2) suicide-related ICD-10-CM codes and all child sociodemographics and clinical characteristics, excluding mental health–related ICD-10-CM codes (53 features); and (3) all structured data elements (84 features). The first set was chosen to evaluate classification performance using mental health–related ICD-10-CM codes and chief complaints to detect cases. The second set was used to determine the relative importance of considering other, non–ICD-10-CM–based structured data elements . Variables in the first and second sets are mutually exclusive, except for suicide-related ICD-10-CM codes and chief complaints, which are included in both sets. The third set was used to comprehensively evaluate the structured data elements that might support the detection of cases and to test the optimization of detection using a broad set of codified data.Two classifier types were compared: least absolute shrinkage and selection operator (LASSO)–penalized logistic regression (hereinafter referred to as LASSO) and random forest. LASSO was selected to perform variable selection and yield a parsimonious model involving only a subset of variables relevant to the classification task . Random scikit-learn (version 1.2.2) toolboxes sklearn.linear_model.lasso, sklearn.ensemble.RandomForestClassifier, and sklearn.metrics. Hyperparameters were set to default and were as follows: LASSO-penalized logistic regression  and random forest . The random forest was run with out-of-bag samples to estimate generalization error. A set seed was used to ensure replicability. The code is available from the authors upon request.Feature engineering was conducted using R statistical software , and the models were implemented using Python  with As the study population was a stratified random subsample of the total population, we compared rule-based classification fit metrics, both with and without the adjustment for sampling probability. The adjustment was performed by considering the subsample as a stratified 2-phase sample and applying inverse probability weighting. Further detail on this method is described by Katki et al .Child sociodemographics and clinical characteristics are presented in The detection performance of suicide-related ICD-10-CM codes and chief complaints compared with that of manual chart review is presented in Detection performance by type of SITB is presented in Fit metrics by classifier type and considered features are presented in The feature importances of models containing all structured data elements are presented in χ21=20.2, P<.001 and random forest: χ21=21.6, P<.001). However, the detection sensitivity of the models considering all structured data elements (84 features) was not significantly different from the sensitivity of the models considering a smaller number of features (25 features and 53 features): both models considering mental health–related diagnostic codes and chief complaints  and the models considering structured data elements other than diagnostic codes  did not significantly differ in sensitivity from the models considering all data elements. Fit metrics and per-fold feature importances are reported in There were significant differences in model performances by number and types of considered features. The sensitivity of detection of the machine learning models that considered all structured data elements was significantly higher than the sensitivity of detection using only suicide-related ICD-10-CM code and suicide-related chief complaint . Thus, the results suggest that machine learning–based models may strengthen the sensitivity of detection of childhood-onset SITB, even when considering a focused set of potential indicators.In this sample, nearly one-third  of the children presenting for suicide-related emergency care were missed by suicide-related ICD-10-CM codes, and more than half  of the children were missed by suicide-related chief complaints alone. Although accurate and timely detection of suicide-related emergency visits among children aligns with suicide prevention efforts by supporting tracking and rapid response to epidemiologic shifts at a population scale , the resThis study's findings add to previously described concerns regarding the validity of suicide risk prediction models relying solely on ICD-10-CM codes to screen for the outcome of interest and discover potential antecedents . The sigMore severe behaviors (preparatory acts and suicide attempt) were most accurately detected by requiring both suicide-related codes and chief complaints to be affirmed, whereas suicidal ideation was most accurately detected if only 1 of these (code or complaint) was required to consider the case affirmed. This is perhaps because the receipt of 2 suicide-related codified data elements may be a proxy for severity, with children with more severe behaviors receiving both data elements. The accuracy of the detection of nonsuicidal self-injurious behavior was poor compared with other SITB types, which suggests that separate phenotype definitions for types of SITB  may produce more accurate classification than combining all SITB into a single category.The optimal choice of detection approach may also depend on the specific use case; for instance, the results of this study suggest that suicide-related codes and chief complaints are sufficient when high specificity is important, such as flagging previous suicide-related emergencies in a patient chart. The finding that suicide-related codes and chief complaints have good specificity parallels a recent systematic assessment of self-harm coding under the ICD-10-CM in adults, which suggested that 90% of the events coded as self-harm had documentation of self-harm intent in the clinical notes . In the In addition, the findings suggest that although machine learning–based approaches to detection are potentially advantageous in improving sensitivity, it may not be necessary to have access to a highly comprehensive set of data elements to meaningfully improve the sensitivity of detection. Smaller sets of mental health-related data elements, both ICD-10-CM–code based and non–ICD-10-CM–code based, performed similarly to more comprehensive data elements in the detection task. This finding aligns with work involving the phenotyping of suicidal thoughts and behaviors using discharge summaries from intensive care unit admissions in the Medical Information Mart for Intensive Care III (MIMIC-III) database and demonstrating promise of using elastic net penalized regression to detect SITB with as few as 11 features .This study has several limitations. The sample is limited to a single health system in urban Los Angeles and may not generalize to less-resourced settings. The sample was also restricted to oversample case positives and individuals without missingness. Despite adjustment for selective stratification, the study sample size remained insufficient to develop and test separate machine learning–based models by sociodemographic characteristic to explore potential bias with a machine learning–based approach. The triage screening question, “Does this patient have a primary psychiatric complaint or suspicion of psychiatric illness?” was used to determine the study sample, but triage screening questions related to suicide  were subsequently not selected for inclusion from the classification models because questions were asked using flow sheet cascades with a high degree of nonrandom missingness of individual items. Although commonly regarded as a gold standard for classification, the manual chart review is a silver standard for truth because it ultimately depends on information documented in clinical notes that contain the biases and idiosyncrasies of the clinical documenter and may imperfectly reflect the reality of the clinical scenario. Chief complaints were documented through an electronic health record speed button and thus may not generalize to less-structured text descriptions of the presenting problem.Taken together, this study adds to existing efforts made toward developing clinical phenotypes of pediatric health conditions. Going forward, future research is needed to refine the detection of SITB across different health systems and populations, elucidate the potential advantage of including point-of-care universal suicide screening tools into phenotype detection algorithms, and determine whether including indicators of suicide-related behavior from clinical text improves detection. To achieve better integration between clinical research informatics and child mental health care, further work is needed to test the implementation of detection approaches at the point of care and assess the potential benefits of the precise identification of targets for suicide prevention interventions in children.


The aim of this data paper is to describe a collection of 33 genomic, transcriptomic and epigenomic sequencing datasets of the B-cell acute lymphoblastic leukemia (ALL) cell line REH. REH is one of the most frequently used cell lines for functional studies of pediatric ALL, and these data provide a multi-faceted characterization of its molecular features. The datasets described herein, generated with short- and long-read sequencing technologies, can both provide insights into the complex aberrant karyotype of REH, and be used as reference datasets for sequencing data quality assessment or for methods development.This paper describes 33 datasets corresponding to 867 gigabases of raw sequencing data generated from the REH cell line. These datasets include five different approaches for whole genome sequencing (WGS) on four sequencing platforms, two RNA sequencing (RNA-seq) techniques on two different sequencing platforms, DNA methylation sequencing, and single-cell ATAC-sequencing. Human cell lines are commonly used by researchers as accessible models of disease , 2. The A subset of the datasets in this project were used for downstream analysis with the purpose of cataloging the structural variants and fusion genes of the REH cell line . For thiHere, we present the raw sequencing reads as well as assemblies and mapped BAM files in order to make the data available to the research community.The project consists of 33 sequencing datasets generated from the ALL cell line REH, which was obtained from DSMZ (ACC 22) and cultured according to the supplier’s specifications  , 14. TheThe genomic data consists of short- and long-read sequencing datasets, including de-novo assemblies, providing a combination of generous coverage and contiguity that allows for the in-depth analysis of the genomic variation present in this cell line. Included are FASTQ files from the short-read WGS sequencing of two lanes prepared with the Illumina TruSeq DNA PCR-Free kit and sequenced on the HiSeq X sequencer with PE150 read-length, as well as a BAM file of the reads mapped to human reference genome GRCh38.Long-read WGS datasets include FASTQ files generated from a CLR library and a HiFi library sequenced on the PacBio Sequel II, as well as six ONT libraries prepared with three different kits using DNA selected to varying sizes and sequenced on the PromethION 24. BAM files mapping reads generated from both PacBio libraries and the ONT ultralong library to GRCh38 are included, as are three de-novo assemblies generated from these reads using hifiasm and flye.Additionally, there are FASTQ files from one WGS library prepared with BGI’s MGIEasy stLFR kit and sequenced on the MGISEQ-2000RS, as well as from two linked-read WGS libraries prepared using the 10x Genomics Gemcode kit and sequenced on the Illumina HiSeq 2500.Single-cell ATAC-seq enables the selective sequencing of chromatin-accessible genomic regions, allowing for the determination of chromatin accessibility profiles on a cellular level. A library was prepared using the Chromium Single Cell ATAC Reagent Kit from 10X Genomics and sequenced on an SP flowcell on an Illumina NovaSeq 6000 instrument. FASTQ data, plus a BAM file mapping this data to GRCh38, are included among the datasets.Methylome analysis of the REH cell line can be performed using the epigenomic data sets, which identify 5-mC or 5-hmC modifications to DNA. Two such libraries were prepared with 10 ng and 100 ng input DNA using the NEBNext enzymatic methyl-seq kit (EM-seq). The libraries were sequenced on an Illumina NovaSeq 6000 on an S4 flowcell.The datasets include both short-read and long-read transcriptomic data, allowing insight into gene expression and aberrations such as fusion genes, as well as detailed transcript splicing information. The RNA-seq datasets include FASTQ files from the short-read sequencing of two lanes prepared with the Illumina TruSeq Stranded Total RNA kit and sequenced PE-100 on a NovaSeq 6000 instrument, as well as a BAM file of these reads mapped to GRCh38. The long-read RNA-seq data consists of two IsoSeq libraries, with a varying bead ratio used to generate one library with standard-length transcripts and one library with full-length transcripts. An additional dataset containing resulting FLNC reads and a BAM file mapping them to GRCh38 is included for each of the IsoSeq libraries.The 10x Genomics Gemcode linked-read sequencing technology is discontinued.The MGISEQ WGS data was sequenced to low (~ 10x) sequencing depth.The REH cells used to generate the datasets herein were obtained from a single source. Given that cell lines may undergo alterations during proliferation, leading to genetic heterogeneity within the cell population, these data may not serve as a universal reference for all REH cultures.


The anteroposterior (ap) radiograph of the pelvis is decisive in the diagnosis of different pathologies of the hip joint. Technical advantages have reduced the radiation dose of pelvic CT to levels comparable to radiographs. The purpose of this study was to validate if standard radiographic parameters  can accurately be determined on radiograph-like projections reconstructed from the CT dataset pre- and postoperatively.A consecutive series of patient with symptomatic dysplasia of the hip and a full radiologic workup (radiographs and CT scan pre- and postoperatively) who underwent periacetabular osteotomy were included. Standard radiographic parameters were compared between radiographs and radiograph-like projections by two authors pre- and postoperatively.A total of 16 hips (32 radiographs/32 radiograph-like projections) were included in the study. No significant difference was found between the radiographs and radiograph-like images for all parameter for both examiners. ICC between radiograph and radiograph-like projections for all investigated parameters showed good to excellent reliability (0.78–0.99) pre- and postoperatively.Radiograph-like projections show comparable results to radiographs with regard to the important investigated parameters . Thus, ultra-low-dose CT scans may reduce the need for conventional radiographs in pre- and postoperative analyses of 3-dimensional hip pathologies in the future, as the advantages increasingly outweigh the disadvantages. Radiographs are the standard modality for imaging in orthopedic surgery and are commonly acquired before and after surgical procedures. The anteroposterior (ap) radiograph of the pelvis is decisive in the diagnosis of different pathologies of the hip joint. Various quantitative and semi-quantitative parameters define common pathologies such as developmental dysplasia of the hip (DDH) and increased acetabular coverage in pincer type femoroacetabular impingement (FAI) which are both associated with early development of osteoarthritis –4. ImporAcetabular coverage and roof orientation can also be quantified by computed tomography (CT) , 10, 11.An unrelated but until recently important disadvantage of CT imaging was the greater radiation exposure in this typically young patient population carrying an increased lifetime risk for malignancy .However, technical updates with tin prefiltration markedly reduced the radiation dose of pelvic CT scans to levels comparable to conventional X-rays without sacrificing image quality with respect to the bone contrast .A logical next step is to exploit technical possibilities in data processing and 3D reconstruction of the obtained CT datasets to generate radiograph-like projections, which could relevantly reduce and/or omit the need for conventional radiographs in the assessment of 3-dimensional hip pathologies in young patients.While the above-mentioned pelvic parameters can be readily assessed on a radiograph-like projection they have not yet been validated.Therefore, the purpose of this study was to validate if standard radiographic parameters  can reliably be determined on virtual radiograph-like projections based on CT data of the pelvis and whether they provide comparable results to the parameters obtained from standard ap pelvis radiographs pre- and postoperatively after PAO.This study was approved by our ethical review board (KEK ZH: BASEC Nr. 2018-01921) and all participants gave written informed consent.A consecutive series of patients with symptomatic developmental dysplasia of the hip and a full radiologic workup (pre- and postoperative radiographs and CT scans) who underwent a periacetabular osteotomy (PAO) from July 2017 to October 2019 were identified. Ethical approval was obtained at the local ethics committee. All the patients gave their informed consent .The pelvic radiograph was obtained supine with internal leg rotation of 15° and a film-focus distance of 120 cm. The center of the X-ray beam was directed to the midpoint of the symphysis and a line connecting the anterosuperior iliac spines . CT wereThe radiographic parameters were independently measured by a board-certified orthopedic surgeon  and a board-certified musculoskeletal radiologist  on the preoperative radiograph and the preoperative radiograph-like projection as well as on the postoperative radiograph and the postoperative radiograph-like projection. The institutional picture archiving and measurement system  was used for all measurements.The angles were measured as defined in Table p values < 0.05. The ICC (Intraclass Correlation Coefficient) for the different parameters were calculated using SPSS 27.0  between the two examiners (Orthopedic surgeon and MSK radiologist) as well as between the two image entities (radiograph and radiograph-like projection). Values of < 0.5 indicate poor reliability, 0.5–0.75 moderate reliability, 0.75–0.9 indicate good reliability and values > 0.9 indicate excellent reliability.Statistical analysis to determine the difference between the measured parameters on the radiograph and the radiograph-like projection for each examiner was performed using the Wilcoxon test. Differences were considered to be statistically significant for A total of 16 hips (15 patients) were included with an average age of 26 years range 15–35 years) at the time of surgery. A total of 32 radiographs (16 preoperative/16 postoperative after PAO) and 32 radiograph-like projections based on CT examinations (16 preoperative/16 postoperative after PAO) were analyzed  can reliably be determined on virtual radiograph-like projections based on CT data and if they provide comparable results to the parameters obtained from standard ap pelvis radiographs and if these measurements cannot only be reliably determined on CT scans of native pelvises but also postoperatively after PAO.With this study, we could confirm our hypotheses. There was no significant difference between the measurements for LCEA, MCEA, acetabular arc, Extrusion index, AI between the radiographs and the radiograph-like images pre- and postoperatively for both examiners Table .The intraclass correlation coefficient showed good to excellent reliability (ICC 0.84–0.99) when comparing the results of the measured parameters between radiograph and radiograph-like projections for both examiners pre- and postoperatively. A good to excellent ICC was seen between the two examiners as well for all parameters (ICC 0.76–0.96) pre- and postoperatively, except the extrusion index (poor to moderate reliability). These results are comparable to the literature where radiographic studies have shown that the extrusion index has a greater variability and less reliability than the other measurements , 18, 19.Assessment of the crossover sign and posterior wall sign showed minimal variation between radiographs and radiograph-like projections (0–13%) and a slightly greater variation between the two examiners (0–19%). The overall comparability is very good. The differences were seen in two patients with a small cranial cross over sign.In view of these results, in our opinion, it is justifiable to perform only a CT scan for preoperative planning of a periacetabular osteotomy and postoperative follow-up. Admittedly, in everyday clinical life, a conventional radiograph has often been obtained in most patients prior to our consultation. To change this standard will of course take some time and require increased awareness of the technical possibilities and dose reduction potential of tin prefiltration in ultra-low-dose CT. In an in-house study, we have shown that tin-filtered ultra-low-dose pelvic CT produce excellent images depicting anatomy and osseous pathologies comparable to standard CT, while substantially reducing the median effective dose to 0.38 mSv per patient . Albeit,The driving force to change the standard of procedure is the overall dose reduction that can be achieved in this typically young patient collective while maintaining the quality and accuracy of the assessment of the mentioned parameters combined with greater precision in the assessment of osseous consolidation. Thus, the number of necessary examinations can be reduced by omitting our routine conventional radiographs . This does not only reduce the radiation dose but also the administrative effort, the time required for the patient and the infrastructure, as well as the costs. Further downsides of the conventional radiographs are the projection-based and examiner-dependent technique. The radiograph is prone to rotational as well as centering errors potentially leading to a repetition of the examination.The use of CT as a standard procedure allows three-dimensional deformity analysis, 3D planning, but also 3D quantification of the achieved surgical result. With the CT dataset, not only a pelvic ap can be reconstructed. Additional reconstruction options include cross-table radiographs and false-profile images  which caIn summary, we believe that by reconstructing radiograph-like projections from tin-filtered ultra-low dose CT scans, we can maintain the diagnostic quality in cases of DDH and FAI due to acetabular overcoverage and acetabular retroversion while substantially reducing radiation exposure to a median effective dose of 0.38 mSv, which is not only 84% lower compared to standard CT scans as noted by Stern et al. but alsoThere are limitations to this study. The number of participants was low, although we do not believe a greater number will change the clear findings and the achieved accuracy which was good to excellent. We have focused on parameters obtained from the pelvic ap radiograph as they are most clinically relevant.Radiograph-like projections show comparable results to radiographs with regard to the important investigated parameters. Thus, ultra-low dose CT scans may reduce the need for conventional radiographs in pre- and postoperative analyses of 3-dimensional hip pathologies in the future as the advantages increasingly outweigh the disadvantages.


It is acknowledged that a classical definition of the geoid-to-quasigeoid separation as a function of the simple planar Bouguer gravity anomaly is compatible with Helmert’s definition of orthometric heights. According to Helmert, the mean actual gravity along the plumbline between the geoid and the topographic surface in the definition of orthometric height is computed approximately from the measured surface gravity by applying the Poincaré-Prey gravity reduction. This study provides theoretical proof and numerical evidence that this assumption is valid. We demonstrate that differences between the normal and (Helmert) orthometric corrections are equivalent to the geoid-to-quasigeoid separation differences computed for individual levelling segments. According to our theoretical estimates, maximum differences between these 2 quantities should be less than ±1 mm. By analogy, differences between the Molodensky normal and Helmert orthometric heights at levelling benchmarks should be equivalent to the geoid-to-quasigeoid separation computed from the Bouguer gravity data. Both theoretical findings are inspected numerically by using levelling and gravity data along selected closed levelling loops of the vertical control network in Hong Kong. Results show that values of the geoid-to-quasigeoid separation at levelling benchmarks differ less than ±0.1 mm from differences between the normal and orthometric corrections. Relatively large differences (slightly exceeding 2 mm) between values of the geoid-to-quasigeoid separation and differences between the normal and (Helmert) orthometric heights at levelling benchmarks are explained by errors in levelling measurements rather than by inconsistencies in computed values of the geoid-to-quasigeoid separation and (Helmert) orthometric correction.  Orthometric and normal heights are the two most commonly used types of heights for a practical realization of geodetic vertical controls by physically establishing levelling benchmarks. Both types of heights are determined from precise levelling and gravity measurements . Since the realization of levelling networks and their maintenance is extremely costly, geoid and quasigeoid models have been used in many countries around the world for a realization of geodetic vertical datums (either solely or together with a levelling network). Detailed geoid/quasigeoid models are also indispensable for the conversion of geodetic (geometric) heights measured by the Global Navigation Satellite Systems (GNSS) techniques (such as GPS) for officially adopted orthometric/normal heights. In essence, concepts of defining orthometric and normal heights  depend on a treatment of the topographic density. Whereas the topographic density is taken into consideration in the definition of orthometric heights, Molodensky ,2 compleDespite the fact that Molodensky’s argument was widely accepted by the geodetic community, the requirement of taking into consideration the topographic density in the definition of physical heights has also not been completely dismissed. The most obvious way of addressing a lack of knowledge about the actual topographic density distribution is to adopt a constant density value, preferably an average topographic density for a particular region where a levelling network is established. Following this principle, Helmert ,5 defineUntil now, Helmert’s definition of orthometric heights was almost exclusively used in countries where this type of height is adopted, despite numerous studies addressing a possible improvement of the accuracy by reducing errors due to disregarding a topographic density distribution, terrain relief, and density heterogeneities below the geoid surface. The Molodensky normal and Helmert orthometric heights are, thus, the most commonly used types of heights for a practical realization of geodetic vertical datums around the world. The difference between these two types of heights  is defined by means of applying the Poincaré-Prey gravity gradient to approximate the actual gravity gradient in the computation of the mean gravity value along the plumbline within the topography. This formulation yields the expression for computing the geoid-to-quasigeoid separation from the simple (incomplete) planar Bouguer gravity anomaly and the height of the computation point e.g.,  and EquaAs stated above, the computation of the geoid-to-quasigeoid separation from the Bouguer gravity data should provide results that agree with differences between the Helmert orthometric and Molodensky normal heights, because the same assumptions were adopted in both definitions. This study investigates this aspect by providing theoretical proof that both definitions are fully compatible, except for small errors due to adopted approximations that are completely negligible. Theoretical findings are then numerically inspected by using levelling and gravity data. The study is organized into five sections. Theoretical definitions are briefly reviewed in This section briefly summarizes definitions of heights, the geoid-to-quasigeoid separation, and the normal and orthometric corrections. Rigorous  and approximate expressions for the geoid-to-quasigeoid separation difference and its relationship with the normal and orthometric correction difference for a levelling segment are derived. The orthometric height y (3)HN-OHeights of levelling benchmarks in some countries and territories (such as Hong Kong) have been determined only from levelling measurements, involving neither the actual nor normal gravity information. In this case, heights Heights rrection ,52,53. Ti and i + 1 is defined by  and (6), the normal and orthometric correction difference  of an individual levelling segment between two benchmarks i and i + 1). Equation (7) defines the normal and orthometric correction difference rigorously as a function of heights The geoid-to-quasigeoid separation i and i + 1) can be defined in the following form: By analogy with Equation (8), the geoid-to-quasigeoid separation difference i and i + 1) is obtained by applying the orthometric correction The orthometric height difference The application of the normal correction By combining Equations (9)–(11), the following relation is found: As seen in Equation (12), the difference between the normal and orthometric height differences Substitution from Equation (7) to Equation (12) yieldsBy combining Equations (9) and (13), the following expression is obtained:i and i + 1) in terms of the normal and orthometric correction difference Equation (14) defines the geoid-to-quasigeoid separation difference As stated in e, e.g., , it is wInserting from Equations (1) and (2) to Equation (8), the geoid-to-quasigeoid separation 3 m and the geocentric gravitational constant GM = 3.986 × 1014 m3 s−2 . For maximum elevations of −2 (Equation (16)). In Hong Kong, these errors are obviously much smaller. As seen in Equation (15), the geoid-to-quasigeoid separation is defined rigorously as a function of the difference between the mean actual and normal gravity values. The mean normal gravity The error Note that a standard error propagation was not applied to derive the expression in Equation (17), because only the mean normal gravity Substitution from Equation (16) to Equation (17) yieldsFor maximum values of the geoid-to-quasigeoid separation Approximations adopted in Helmert’s definition of orthometric heights are applied to the difference between the mean actual and normal gravity values Note that in Equation 20), the normal height lodensky ,2,3. 0, the noThe mean actual gravity gradient in Equation (19) is further approximated the Poincaré-Prey gravity gradient so that−3 [T in geodetic and geophysical applications. It is worth noting that the actual topographic density could vary substantially with respect to the average topographic density of 2670 kg m−3. In the Hong Kong territories, for instance, the igneous and sedimentary rocks of lower densities represent most of the geological setting. Nevertheless, the density value of 2670 kg m−3 is, until now, exclusively used to define the (Helmert) orthometric heights in countries around the world where this type of height is adopted officially for a realization of the geodetic vertical control. Consequently, this density value is used to compute the geoid-to-quasigeoid separation. The actual mean gravity in Equation (21) is first described as a function of the surface gravity 0 kg m−3  is typicCombining Equations (20) and (21), the following expression is found: Assuming thatEquation (22) further simplifies toNote that approximations applied in Equations (22)–(24) do not affect the accuracy. Inserting from Equation (24) to Equation (19), the geoid-to-quasigeoid separation is then obtained in the following form: From a definition of the free-air gravity anomaly The simple planar Bouguer gravity anomaly Substitution from Equation (28) to Equation (27) yields  defines the geoid-to-quasigeoid separation i and i + 1) was rigorously formulated. To find the corresponding approximate definition of the geoid-to-quasigeoid separation difference, the rigorous definition of the geoid-to-quasigeoid separation was first used to derive the rigorous definition of the geoid-to-quasigeoid separation difference. From Equation (15), we can writeIn Equation (14), the relation between the geoid-to-quasigeoid separation difference and the normal and orthometric correction difference (for a levelling segment between two benchmarks Combining expressions defining the geoid-to-quasigeoid separation difference in Equations (14) and (30), the following relation is obtainedSubstitution from Equations (30) and (14) yieldsTo estimate approximation errors caused by using heights Substitution from Equations (34) and (35) back to Equation (33) then yieldsThe error Finally, the approximate definition of the geoid-to-quasigeoid separation in Equation (29) is used to introduce the approximate definition of the geoid-to-quasigeoid separation difference Again, normal heights in Equation (37) can be disregarded. Instead, heights Consequently,Rigorous and approximate relations between the normal and orthometric correction difference and the geoid-to-quasigeoid separation difference were derived and presented above. The rigorous definition in Equation (30) was described by means of the difference between the actual mean and normal gravity values. The corresponding approximate relation in Equation (39) is described as a function of the simple planar Bouguer gravity anomaly values. If the Poincaré-Prey gravity gradient closely approximates the actual vertical gravity gradient inside the topography, both definitions should provide results that differ less than ±1 mm. In other words, the relation The accuracy of the geoid-to-quasigeoid separation differences was assessed at a vertical geodetic control in Hong Kong, practically realized by the Vertical Control Network 2022 (VCN2022). Since gravity values along levelling lines were not measured directly, detailed terrestrial and marine gravity measurements were used to interpolate gravity values along levelling lines . InterpoTo keep the presentation simple but still instructive, we conducted the numerical analysis only along four closed levelling loops of the VCN2022 levelling network which were characterized by the largest topographic elevation changes in Hong Kong. The location of the selected VCN2022 levelling sections is illustrated in Since gravity data from mainland China are not publicly available,  applied  mm (cf. ). Finalli and i + 1 of a levelling segment, the orthometric correction Nsiah Ababio and Tenzer  used therding to  using thBy analogy with Equation (40), the normal correction Adopting Helmert’s definition of orthometric heights, the mean gravity in Equation (40) was computed fromSubstitution from Equation (43) to Equation (42) yields−3. To check the correctness of both results, the orthometric and normal corrections were also computed according to Equations (5) and (6), finding that both results are equal. Equations (21) and (44) are equivalent. The last term on the right-hand side of Equation (44) is computed for the topographic density value of 2670 kg mi and i + 1 were computed according to Equations (10) and (11) by applying the orthometric The orthometric height differences Values of the orthometric corrections pared by  were useThe orthometric and normal corrections and their cumulative values along four selected closed levelling loops are plotted in Both corrections reach maximum (absolute) values at levelling sections characterized by the largest elevation changes. Cumulative values of the orthometric correction closely mimic a topographic relief, while this trend in cumulative values of the normal correction is less pronounced  agree. Finally, we compared values of the geoid-to-quasigeoid separation In Hemert’s definition of orthometric heights, the Poincaré-Prey gravity gradient was adopted to approximate the actual gravity gradient. The mean gravity within the topography was then approximated by the surface gravity continuing downward to a midpoint by using the normal gravity gradient and by applying the Poisson equation to take the topography into consideration. To convert the Molodensky normal heights to the Helmert orthometric heights and vice versa, the geoid-to-quasigeoid separation was defined as a function of the simple planar Bouguer gravity anomaly As demonstrated in the numerical examples, this assumption is correct. Both computed differences are almost the same with differences reaching less than ±0.1 mm. It is worth noting that  inspecteThese findings ascertain that the computation of the geoid-to-quasigeoid separation from the Bouguer gravity data is fully compatible with Helmert’s definition of orthometric heights. The expression for computing the geoid-to-quasigeoid separation from the simple planar Bouguer gravity anomaly provides the result that is equal to the geoid-to-quasigeoid separation differences.Finally, we demonstrated that the geoid-to-quasigeoid separation differs from differences between the Molodensky normal and Helmert orthometric heights obtained after the levelling network readjustment , particularly along the L12/HK closed levelling loop. According to our results, the differences between the geoid-to-quasigeoid separation and differences between the Molodensky normal and Helmert orthometric heights there exceed even 2 mm. This inconsistency is explained mainly by the propagation of errors in measured levelling height differences. This was confirmed by the analysis of the adjusted levelled height differences. The results of this analysis revealed that levelled height differences along the L12/HK closed levelling loop located in the Lantau Island are systematically affected by errors of levelling measurements conducted along the bridge, which connect the island with the rest of the territories. Elsewhere, these differences are much smaller. We have demonstrated that the geoid-to-quasigeoid separation defined as a function of the simple planar Bouguer gravity anomaly is fully compatible with Helmert’s definition of orthometric heights. Since both definitions involve the same assumptions regarding the approximation of the actual gravity gradient by the Poincaré-Prey gravity reduction, the computation of the geoid-to-quasigeoid separation in terms of the simple planar Bouguer gravity anomaly in Equation (29) introduces errors that should not exceed more than ±1 mm . Obviously, the mean gravity values computed by means of applying the Poincaré-Prey gravity reduction might still be quite inaccurate. Nevertheless, the approximately-computed geoid-to-quasigeoid separation (from the Bouguer gravity data) is consistent with the Helmert’s definition of orthometric heights that has been, until now, exclusively used for a practical realization of geodetic vertical controls in countries where orthometric heights are officially adopted.


Automated distinct bone segmentation from CT scans is widely used in planning and navigation workflows. U-Net variants are known to provide excellent results in supervised semantic segmentation. However, in distinct bone segmentation from upper-body CTs a large field of view and a computationally taxing 3D architecture are required. This leads to low-resolution results lacking detail or localisation errors due to missing spatial context when using high-resolution inputs.We propose to solve this problem by using end-to-end trainable segmentation networks that combine several 3D U-Nets working at different resolutions. Our approach, which extends and generalizes HookNet and MRN, captures spatial information at a lower resolution and skips the encoded information to the target network, which operates on smaller high-resolution inputs. We evaluated our proposed architecture against single-resolution networks and performed an ablation study on information concatenation and the number of context networks.Our proposed best network achieves a median DSC of 0.86 taken over all 125 segmented bone classes and reduces the confusion among similar-looking bones in different locations. These results outperform our previously published 3D U-Net baseline results on the task and distinct bone segmentation results reported by other groups.The presented multi-resolution 3D U-Nets address current shortcomings in bone segmentation from upper-body CT scans by allowing for capturing a larger field of view while avoiding the cubic growth of the input pixels and intermediate computations that quickly outgrow the computational capacities in 3D. The approach thus improves the accuracy and efficiency of distinct bone segmentation from upper-body CT. Segmentation of bones is used in bone disease diagnosis, in image-based assessment of fracture risks , bone-deBone tissue segmentation from CT has been shown to work well using slice-wise 2D CNN-based segmentation algorithms –6. The tSimultaneous segmentation of distinct bones of multiple groups is still relatively little studied. A cascade of a bone tissue segmentation and a distinct bone segmentation network have been used by  to segmeThe region of interest in upper-body or full-body CT scans is typically larger than the possible input sizes of 3D convolutional neural networks (CNNs). As a result, the input needs to be sampled as patches, restricting the input field of view to the patch size. This problem exacerbates with the development of CT scanners that produce ever more highly resolved images. While a higher resolution allows for capturing more fine-grained details, it covers smaller body areas within a fixed-size input patch.In order to extend the field of view, larger input patches can be sampled. Using bigger patches, i.e. more input pixels does not increase the number of trainable parameters in a fully connected network, but it does increase the number of necessary intermediate computations. Doubling the patch size in all three dimensions leads to at least eight times more forward- and backward computations, which are taxing for the generally scarce GPU memory. Countermeasures fall into two categories. (A) keeping the resolution and input pixel size high, but reducing the computational load elsewhere. Those measures include reducing the batch size (not to be confused with the patch size), using a simpler model, or reducing the output size. All of those means potentially hamper training and inference. (B) Keeping a large field of view by using a small patch size of down-sampled inputs. This approach allows for a wider field of view for a constant input size while losing detail information.To decide upon the better of the two approaches presented above, the requirements for the task at hand need to be considered. A suitable network for our task of complete distinct bone segmentation from upper-body CT scans see  should pThe merits of high-resolution inputs—accurate details—and low-resolution inputs—a larger field of view—can be combined in many ways. Cascaded U-Nets consist of two or more individual U-Nets that are trained consecutively. A first model is trained on down-sampled input. Its one-hot encoded segmentation results are then upsampled, potentially cropped and used as additional input channels for the following model at higher resolution . These aEnd-to-end trained multi-resolution architectures have been proposed in histopathology whole-slide segmentation. For example, MRN  combinesThe purpose of our work is to address common segmentation errors that originate from a lack of global context while using 3D U-Nets for distinct bone segmentation. We propose to use a multi-resolution approach and present SneakyNet, an expansion and generalization of the MRN and HookNet architectures. We compare the segmentation accuracy, complexity, and run-time of baseline 3D U-Nets with the SneakyNet. We ablate the model components and find that the use of our generalized architecture improves the results over the HookNet and MRN variants. We will use our bone segmentation in conjunction with 3D rendering of anatomical images in augmented- and virtual reality applications, where segmentations can be used on top or in conjunction with existing transfer functions , 19.To assess the performance of SneakyNet on upper-body distinct bone segmentation, we train it on our in-house upper-body CT dataset. We make ablation studies on the combination of context and target information and on the optimal number of context networks.The CT images have been acquired post-mortem from body donours aged 44–103 years, 7 female and 9 male. The acquisition of the scans and the manual target segmentations have been done by specialists of the anatomical department of the University of Basel. All CT scans were taken with the body donours lying on their backs, and arms placed in front of the body. The arms are bent to various degrees, and the hands overlap in some instances.Prior to using them for training and for inference, we resampled all scans to 2 mm isotropic resolution, see also Table In general, SneakyNet consists of one target network and one or more context networks. The target network operates on high-resolution data and eventually produces the desired segmentation maps. The context networks operate on lower resolution inputs spanning a larger field of view. Information is propagated from the context networks to the target network using crop-skip connections presented in section “Crop-skip connections”. We present a detailed visual overview of the architecture with one context network in Fig. M denotes the number of levels of the U-Net. We use the basic architecture of In our previous work , we haveSx, Sy, Sz) at full resolution. For each of the context networks, we use that input plus its surrounding area, which together span a field of view of Sx, Sy, Sz). We perform the down-sampling using Sx, Sy, Sz), but at different resolutions and fields of view.For the target network, we use inputs of size . To indicate the performance over all classes, we give the median and the 16 and 84 quantiles (Our experiments show how automated distinct bone segmentation can be improved using a multi-resolution approach. We evaluate our results on multiple target resolutions with different numbers of context networks and field of view sizes and perform an ablation study to determine the most beneficial way to combine context and target network information.We evaluated some of the most common errors when using a baseline segmentation method. We found that the missing context information leads to similar-looking bones in different body regions being mistaken for one another. In the confusion matrix presented in Fig. We performed an ablation study to see how different strategies of combining the context and target information within the network perform. In Table The combination of skip connections at every level and a context loss function in our proposed architecture increases the accuracy further, as compared to the HookNet  and the In Table We provide a comparison to other results published on distinct bone segmentation in Table This work presents improvements in distinct bone segmentation from upper-body CT. The proposed multi-resolution networks use additional inputs at a lower resolution but with a larger field of view to provide the necessary context information to assign the proper bone classes. We compared three different ways of combining the context and target information and evaluated the results using zero to three context networks. Using context networks improves the segmentation results on all target patch sizes.


Editorial on the Research TopicCase reports in pediatric hematology and hematological malignancies 2022Case reports on pediatric hematology and hematologic malignancies are featured in this issue. Oncohematology and pediatric hematology are poorly characterized in the scientific literature, particularly in case reports. This type of information, based on professional experience with clinical cases, is very relevant for clinical practice because it enables the professional who attends to this group of patients to adequately clarify and manage these cases, bringing the appropriate resolution to many cases and improving the quality of life of these patients.Thalji et al. included a 4-year-old male boy who had a blueberry muffin rash on his face and neck but had no additional systemic involvement. A biopsy revealed that the patient had congenital cutaneous LCH. This early detection shields patients from needless and potentially harmful systemic treatment .The case described by Wang et al. reported a 13-year-old male child with recurrent epistaxis for 6 months, anemia for 1 month, and a chest CT scan compatible with hemorrhagic foci was given in the second case report. He was diagnosed with acquired von Willebrand syndrome, had no family history, and tests revealed that he had antinuclear and anti-Sm antibodies, indicating a link to Systemic Lupus Erythematosus .The case reported by Jenei et al., is a 5-year-old male child diagnosed with interdigitating dendritic cell sarcoma during treatment for B-cell precursor acute lymphoblastic leukemia, according to another clinical case described in this issue. Multiple lymph nodes in the cervical chain were discovered in this patient, who was detected with positron emission tomography CT, treated with chemotherapy, and then had bone infiltration 4 years later. With this condition, an allogeneic hematopoietic stem cell transplant was conducted successfully .The third case, described by Zhou et al. described a 6-year-old girl who had a clinical manifestation of leukemia cutis with a 10-month history of presentation with cutaneous plaques and abscesses as furuncles. The initial clinical indications of Chronic Neutrophil Leukemia BCR-ABL Negative Myeloproliferative Neoplasm were these cutaneous appearances. Successful allogeneic hematopoietic stem cell transplantation was also used to treat the patient. This discovery was pertinent to dermatologists .Hannemann et al. highlighted a major but rare complications of allogeneic hematopoietic cell transplantation (HCT): an invasive fungal infection with fusariosis as a lethal infections despite neutrophil engraftment and uninterrupted treatment with voriconazole. Unfortunately, this 16-year old patient with severe aplastic anemia developed splenic rupture and endocarditis. He also developed embolic cerebral infarctions with unilateral hemiparesis, and despite cardiac surgery, he did not regain consciousness because of diffuse cerebral ischemia and died on day +92 post HCT. Disseminated infection with fusarium solani is a rare complications post allogeneic HCT with poor outcomes .A report of Krstic et al. described the first case of T-cell acute lymphoblastic leukemia (T-ALL) with CCDC88C:JAK2 fusion, with normal karyotype, detected by whole genome sequencing. The patient fortunately, responded to nelarabine and intensive chemotherapy and so proceeded to allogeneic HCT. The patient is now in remission 8 months post HCT. High throughput sequencing technologies have shown enormous potential in the genetic characterization of hematological malignancies, particularly in pediatric ALL, and are paving the way to personalized treatment strategies. Pediatric patients with ALL and genomic features consistent with JAK/STAT pathway activation are currently recruited in ongoing clinical trials for targeted treatment with Ruxolitinib in addition to chemotherapy. However, this report serves as an example of the power of WGS in the diagnostic setting of acute leukemia, as it enables timely recognition of potential therapeutic targets in high-risk pediatric ALL .The case presented by Ipe et al., reported a 12-year old patient with B-ALL who relapsed 15 months after diagnosis while receiving maintenance chemotherapy. For his relapsed disease, he underwent CAR-T cell therapy to avoid allogeneic HCT and risk of DNA damage with radiation due to lately discovered germline heterozygous checkpoint kinase 2 (CHEK2) mutation. This mutation was discovered when the patient presented with papillary thyroid carcinoma 7 months after initial diagnosis and before relapse of his B-ALL. The patients remains in remission 3 years after CAR-T cell therapy. CHEK2 is a tumor suppressor gene that plays a critical role in the cell cycle and response to DNA damage induced by replication stress. Whether the CHEK2 gene is a true cancer predisposition syndrome gene remains a topic of debate especially in relation to acute leukemia. More research in delineating the true role of pathogenic CHEK2 gene mutations in hematologic malignancies as a potential cancer predisposition gene is needed .The case presented by Leonardi et al., a patient with a long and really challenging clinical history is reported. Kabuki syndrome (KS) is a rare multisystemic disease due to mutations in the KMT2D or KDM6A genes, which act as epigenetic modulators of different processes, including immune response. The syndrome is characterized by anomalies in multiple organ systems, and it is associated with autoimmune and inflammatory disorders, and an underlying immunological phenotype characterized by immunodeficiency and immune dysregulation. This case emphasizes the importance of suspecting immune dysregulation in KS .In the report of Naviglio et al., a case of treatment with venetoclax and azacitidine in a patient with AML in Shwachman-Diamond syndrome is reported. BCL-2 inhibitor venetoclax has revolutionized the treatment of AML in elderly adults, especially for treatment-naive elderly patients who are ineligible for intensive chemotherapy and there is limited evidence on the use of venetoclax in pediatric patients with SDS-related MDS or AML. This represents an experience suggestisting the potential role of the combination venetoclax/azacitidine for patients with SDS and AML, whose safety and efficacy need to be evaluated in a clinical experimental model .In the report of Akiely et al. the first pediatric case of myeloid/lymphoid neoplasm with PDGFRA rearrangement presenting with synchronous myeloproliferative disease and B-LBL. The patient was started on imatinib with concomitant therapy for B-LBL per the Children Oncology Group (COG) standard therapy for localized B-LBL and demonstrated a favorable outcome in the 2.5-year follow-up period .In the report of Guerra et al. describe a rare case of patients with pediatric myelofibrosis, showing different clinical and pathological features when compared to the WHO 2016 Primary Myelofibrosis classification. They aslo retrospectively collected and analyzed 14 consecutive pediatric myelofibrosis, classified into three subgroups: adult-like myelofibrosis, pediatric immune myelofibrosis, idiopathic myelofibrosis. Pediatric Immune Myelofibrosis was the predominant subgroup in our cohort (7/14). Pediatric Immune Myelofibrosis is characterized by peculiar bone marrow features  and a milder course compared to the other patients Pediatric Immune Myelofibrosis is a novel and distinct pathological entity .In this report Eguchi et al. describe 10-month-old infant with an extremely rare combination of Juvenile Myelomonocytic Leukemia and Ornithine Transcarbamylase Deficiency Safely. One noteworthy aspect of the present case is the proven involvement of congenital UCD in the pathogenesis of hyperammonemia associated with cancer treatment. The treatment of the patient was complicated by occurrence of severe hyperammonia. Authors underline that hyperammonemia should be considered a differential diagnosis when unexplained and non-specific symptoms occur during the treatment of hematologic malignancies .In the report Saettini et al. two patients with identical germline CBL mutation and clinical and immune-hematological overlapping features with autoimmune lymphoproliferative syndrome (ALPS) and B-cell expansion with NF-κB and T-cell anergy (BENTA) syndrome are described. CBL syndrome is a Noonan-like RASopathy with heterogeneous clinical phenotype and predisposition to juvenile myelomonocytic leukemia (JMML). Although the phenotype of children affected by CBL syndrome has been increasingly delineated over time, the immunological features of CBL syndrome have not been extensively described .In the report of We really hope that reading this issue, which contains these rare clinical situations in pediatrics, hematology, and oncohematology, would be beneficial to professional knowledge and clinical care for this population.


Nature Communications 10.1038/s41467-023-35876-8, published online 17 January 2023Correction to: The original version of this Article contained an error in the Abstract, which incorrectly read ‘However, no experimental evaluation has been conducted to reveal the effect of radiation emitted by UV-nail polish dryers on mammalian cells.’ The correct version replaces this sentence with ‘However, the effect of radiation emitted by UV-nail polish dryers on the physiology and mutagenesis of mammalian cells remains unclear.’. This has been corrected in both the PDF and HTML versions of the Article.


Objectives: Our study aims to evaluate developments in vaccine uptake and digital proximity tracing app use in a localized context of the SARS-CoV-2 pandemic.Methods: We report findings from two population-based longitudinal cohorts in Switzerland from January to December 2021. Failure time analyses and Cox proportional hazards regression models were conducted to assess vaccine uptake and digital proximity tracing app (SwissCovid) uninstalling outcomes.Results: We observed a dichotomy of individuals who did not use the SwissCovid app and did not get vaccinated, and who used the SwissCovid app and got vaccinated during the study period. Increased vaccine uptake was observed with SwissCovid app use  compared to SwissCovid app non-use. Decreased SwissCovid uninstallation risk was observed for participants who got vaccinated  compared to participants who did not get vaccinated.Conclusion: In evolving epidemic contexts, these findings underscore the need for communication strategies as well as flexible digital proximity tracing app adjustments that accommodate different preventive measures and their anticipated interactions. Digital proximity tracing apps have played an important role in assisting public health measures to mitigate spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in absence of vaccines , 2. SuchAs SARS-CoV-2 vaccines became widely available in 2021, digital proximity tracing apps shifted from a recommended measure in the absence of vaccines to a complementary measure, working alongside vaccination efforts to further minimize the spread of the virus , 5. SuchBarriers and facilitators for digital proximity tracing app use, taking preventive measures and vaccine uptake have been discussed extensively in recent papers. Some studies have attributed long-term digital proximity tracing app non-use to a lack of perceived benefits and privacy concerns , 9. FurtHowever, there is little evidence on the possible effect of SARS-CoV-2 vaccine availability on individual-level decisions to continuously use digital proximity tracing apps. Investigating the interplay between these may offer further insights on the use of novel public health technologies and their possible interactions with other preventive measures. Furthermore, it can provide context on adherence to public health guidance based on different individual-level and public risk-benefit profiles.vaccine uptake) and the use of Switzerland’s digital proximity tracing app, SwissCovid. We do so by exploring hypotheses based on individual trade-off theories from economics applied to public health . In. In23]. We assessed self-reported outcome and exposure measures from the CI-DFU and CSM. The questions in the surveys assessed in our study from both data sources were aligned in terms of content and possible answer choices. As such, the assessments of the outcome and exposure measures of the CI-DFU and CSM were identical. The primary outcomes assessed in two substudies are (1) vaccine uptake and (2) SwissCovid app uninstalling. Participants were assessed until the time to event of interest or right-censoring, depending on which occurred first. The exposures are whether (a) participants actively used the SwissCovid app or (b) got vaccinated during the study period.Participants were stratified based on when they officially became eligible for SARS-CoV-2 vaccines and allocated to three baseline groups accordingly: (a) ages 65+, (b) ages 50–64 and (c) ages 18–49. Within these groups, we included participants who reported having a severe chronic condition  or who worked as healthcare professionals and received their first vaccine dose before it was made available to their age groups. All other participants who were vaccinated at or before the baseline were excluded from the study. A flow chart outlining the inclusion steps for the final participant samples is available in In this study, we described participant characteristics and outcomes of interest using counts and percentages, as well as median and interquartile range (IQR). We conducted failure-time analyses for the primary outcomes of interest using Kaplan-Meier curves and log-rank tests. Specifically, we assessed vaccine uptake and SwissCovid app uninstalling outcomes, with the outcomes interchanging as the exposures in two separate substudies. First, we assessed the time to vaccine uptake with the SwissCovid app use as the exposure. All participants were included in this substudy and were separated into app user or app non-user groups based on their reported use of the SwissCovid app over time. Second, we assessed the time to SwissCovid app uninstalling with vaccine uptake as the exposure. Only participants using the SwissCovid app at baseline were included in this substudy and were separated into vaccinated and non-vaccinated participants based on their reported uptake of the vaccine over time. For both outcomes, time of observation started at the date of the inclusion in the study and ended at time of vaccine uptake/app uninstalling or end of follow-up, depending on which occurred first. We assessed precise dates for the vaccine uptake outcome and time-varying app uninstalling from monthly self-reports. In the case of missing data in survey follow-up during the assessment period, we applied the last observation carried forward (LOCF) method to reduce attrition bias . For senWe further performed multivariable Cox regressions to assess associations between vaccine uptake and app uninstalling with additional variables of interest, stratified by age group and chronic condition to account for varying baseline risks. Specifically, these outcomes were assessed against whether participants reported the following in the past assessment month: (a) frequently or always adhered to preventive measures , (b) entered quarantine, (c) got tested for SARS-CoV-2 and (d) received an exposure notification from the SwissCovid app. A detailed description of the choice of the time-varying variables of interest and confounders is in p-values of less than 0.05 were considered statistically significant. Analyses were conducted between January and May 2022.All statistical analyses were done in R (version 4.0.0) using ggplot2 (version 3.3.3) for plots and the survival package for survival analyses. Two-sided A total of 4,514 participants from the CI-DFU and 1,969 participants from the CSM were included in the analysis  and most participants resided in the German speaking regions of Switzerland .Median IQR age in the CI-DFU was 62 (IQR 49–70) years and 51 (IQR 37–61) years in the CSM. For both studies, approximately half of the participants were female . Most participants  reported adhering frequently or always to at least one preventive measure against SARS-CoV-2 spread at baseline. Furthermore, 15% (n = 693) of the CI-DFU participants and 7.7% (n = 152) of the CSM participants reported having at least one severe chronic condition at baseline.For both studies, around half of the participants were self-reported SwissCovid app users at baseline  but was violated for the CSM cohort (p = 0.0021). We therefore conducted sensitivity analyses to model the aHRs over the follow-up period through point-process Poisson regressions, which show that the aHRs for vaccine uptake in both cohorts increased over time  but was violated for the CSM cohort (p = 0.0077). We therefore conducted sensitivity analyses to model the aHRs over the follow-up period through point-process Poisson regressions, which show that the aHRs for SwissCovid app uninstalling in both cohorts decreased over time  and delta (widely known as B.1.617.2) variants , 41, andContrary to our trade-off hypothesis, we did not find a significant trend of reduced app use after getting vaccinated. However, high counts of app uninstalling were observed, with approximately 7% (pooled study population) of self-reported SwissCovid app users at baseline uninstalling the app following vaccine uptake during the study period. Observed app uninstalling might be due to a lack of perceived benefits from the app or due to experienced difficulties in using the app , 44. AppOur failure time analyses depicted a dichotomy of participants who did not use the SwissCovid app and did not get vaccinated (16% of pooled study population) versus participants who used the app and got vaccinated (40% of pooled study population) during the study period. The persistent divergence of these two groups over the study period suggests a continued low acceptance of public health measures in reducing viral transmission, such as from the observed negative discourse on the implementation of COVID-19 vaccine certificate in June 2021 –49. On tOur study presents some limitations. First, in both the CI-DFU and CSM there may have been self-selection during enrollment that may have led to study participants with higher digital or health literacy, and higher socioeconomic status than the general population. Here, self-selection could have also been in the form of people taking part in the surveys as an additional measure to contribute to the public pandemic response. Second, both panel surveys were based on self-reports and possibly subject to common measurement biases due to socially desirable responding, which may have led to an overestimation of our study’s outcomes of interest. Third, although substantial efforts were presented by the CI-DFU to streamline data collection across various geographical regions in Switzerland, local heterogeneity in the implementation of the questionnaires was not avoidable at times, which may have contributed to disparate results. Fourth, the proportional hazards assumption was violated in the multivariable analyses with the CSM cohorts. However, sensitivity analyses with point-process Poisson regressions suggested the aHR for vaccine uptake increased over time and the aHR for SwissCovid app uninstalling decreased over time, which both confirm the results obtained with the CI-DFU cohort. Fifth, reporting of SwissCovid app uninstalling outcomes may not be suggestive of an active choice to not use the app as a preventive measure anymore but, e.g., participants buying a new phone and not reinstalling the app. Similarly, not reporting SwissCovid app uninstalling outcomes does not necessarily mean that the app was in use. Lastly, our approach to analyze the data with the last observation carried forward (LOCF) method for our exposures of interest may have introduced bias in estimating our study’s effects of interest, even though only a small amount of data in both study cohorts was affected by conditional study participation .To our knowledge, this study is the first to draw on two nationwide panel studies to assess trends in the use of the digital proximity tracing app in Switzerland, SwissCovid, during the SARS-CoV-2 pandemic in a period when vaccines became widely available. We observed a dichotomy of individuals who did not use the app during the study period and did not get vaccinated, and who used the app during the study period and got vaccinated during the alpha and delta variants of concern. We found a higher probability for vaccine uptake in individuals with app use and adherence to other preventive measures. Furthermore, we found a decreased risk of app uninstalling among individuals with vaccine uptake. Our findings highlight the importance of relevant decision makers to consider possible interactions between different preventive measures in future epidemic contexts. These can inform the development of focused communication campaigns and flexible digital tracing app development that accommodate various preventive measures and their anticipated interactions.