bluuebunny/crossref_metadata_2025_split huggingface dataset:
TBIO-04. Comprehensive analysis of mutational signatures in pediatric cancers
Authors: Thatikonda Venu , Islam S M Ashiqul , Autry Robert J , Jones Barbara C , Gröbner Susanne , Warsow Gregor , Hutter Barbara , Huebschmann Daniel , Fröhling Stefan , Blattner-Johnson Mirjam , Jones David T W , Alexandrov Ludmil B , M, Pfister Stefan , Jäger Natalie 
Published: June 2022

Abstract
Analysis of mutational signatures can reveal the underlying molecular processes that have caused the somatic mutations found in genomes. We performed an extensive analysis encompassing mutational signatures of single base substitution and, for the first time, signatures of small insertions/deletions in ~800 whole-genome-sequenced tumor-normal pairs from 25 molecularly defined pediatric cancer types. More than half of this cohort consists of pediatric CNS-tumors (n=416), including high- and low-grade gliomas, ependymomas, and embryonal tumors. These were subsequently compared with COSMIC v.3 signatures to identify overlap with the latest set of known mutational signatures. We identified only a small number of mutational signatures active in pediatric cancers when compared to previously analyzed adult cancers. Amongst these, SBS1 and SBS5 were present in nearly all pediatric tumors analyzed, with a significant correlation of signature activity with age at diagnosis, as expected. Further, we found SBS21 activity in a fraction of high-grade gliomas, which is the result of defective DNA mismatch repair, SBS36 in fractions of ETMR and Group4-medulloblastoma, the result of defective base excision repair, and SBS44 in Group4-medulloblastomas, caused by defective DNA mismatch repair. For these signatures, no consistent genetic alteration was identified. We report a significantly smaller proportion of pediatric tumors which show homologous-recombination repair defect signature SBS3 compared to previously published analyses. Additionally, the previous mutational signature analysis of this cohort based on COSMIC v.2 reference signatures had identified a novel substitution signature (Signature.P1), active in the brain tumors ATRT and ependymoma. Our updated results suggest that Signature.P1 is not a pediatric specific mutational signature, but a treatment-associated signature identified in a small fraction of brain tumors that were annotated as treatment-naïve. This analysis provides a systematic overview of mutational signatures in pediatric cancers, which is relevant for understanding tumor biology and future research in defining biomarkers for treatment response.
TBIO-05. R-loops in pediatric brain tumors
Authors: Wang Shanzheng , Gopisetty Apurva , Jäger Natalie , Pfister Stefan , Kool Marcel 
Published: June 2022

Abstract
R-loops are structures containing DNA-RNA hybrids and displaced single-stranded DNA, which are widely distributed across genomic regions. The generation and removal of R-loops is dynamically regulated by several factors including helicases and topoisomerases. Previously, we have identified high levels of R-loops associated with genomic instability in Embryonal Tumors with Multilayered Rosettes (ETMR) (Lambo et al. 2019), which is associated with a sensitivity to drugs targeting topoisomerases and DNA repair. However, it is unknown whether there are other pediatric cancers with high levels of R-loops, and whether R-loops in these tumors are also associated with genomic instability and sensitivity to specific treatments. Here, we have used real R-loops sequencing data sets, including ETMR DRIP-seq data, and the bioinformatic tool QmRLFS-finder (Wongsurawat et al. 2012), which can predict R-loops forming sequences (RLFSs) based on DNA sequence composition. By performing bioinformatic analyses of DRIP-seq data sets and integrating these with RLFSs from human reference genome simulations, we aim to analyze how reliable the different methods are to measure and predict R-loops and what role they have in cancer genomes. In ETMR, R-loops signals from DRIP-seq data were enriched around transcriptional start sites (TSS), comparable to R-loops distribution and enrichment in other published cell models. However, the overlap with RLFSs was limited, indicating that more validations with real DRIP-seq data from more ETMRs and other pediatric cancers are needed to validate the different methods. Taken together, until now, we developed methods to (semi-)quantify R-loops by combining real sequencing data and computational simulation approaches to investigate R-loops distribution in cancer genomes and to investigate whether R-loops are associated with breakpoints or other genetic aberrations in pediatric cancer entities.
A pan‐cancer analysis identifies HDAC11 as an immunological and prognostic biomarker
Authors: Li Ran , Wu Xiaolu , Zhao Ping , Xue Kai , Li Junmin 
Published: June 2022

AbstractHistone deacetylase 11 (HDAC11) is aberrantly expressed in many types of cancer, and such abnormalities are associated with tumor immunity and heterogeneous clinical outcomes. Here, we explore the prognostic value and immunological function of HDAC11 across 33 cancer types. We observe HDAC11 is aberrantly expressed in 25 cancer types and positively or negatively associated with prognosis in different cancers. HDAC11 played a protective prognostic role in KIRP, KIRC, LGG, PCPG, READ, and UVM, which was contrary to the conventional opinion that HDAC11 was an oncogenic gene. Moreover, HDAC11 is negatively associated with tumor immune components, most immune checkpoint genes, and key cytokine expression. HDAC11 is correlated with tumor mutational burden in 11 cancer types and with microsatellite instability in 9 cancer types, suggesting HDAC11 may affect a patient's response to immune checkpoint inhibitor (ICI) therapy. In addition, HDAC11 is negatively correlated with the drug sensitivity of oxaliplatin, carmustine, ifosfamide, imexon, lomustine, and BN‐2629, indicating the potential synergy between HDAC11 inhibitors and these anti‐tumor drugs. In vitro assays indicate that HDAC11 inhibitor SIS17 combined with oxaliplatin shows a synergistic cytotoxic role in K562 cells while SIS17 has an antagonistic effect on the cytotoxic role of oxaliplatin in 769P cells. HDAC11 is also associated with hallmark pathways, including epithelial mesenchymal transition, IL‑6/JAK/STAT3, and allograft rejection pathways. Overall, we provide clues regarding the key role of HDAC11 in multiple cancers.
Retardation of Myopia by Multifocal Soft Contact Lens and Orthokeratology: A 1-Year Randomized Clinical Trial
Authors: Fang Jianxia , Huang Zhu , Long Yan , Zhu Miaomiao , Wu Qin , Chen Xiaojun , Xv Wei , Du Chixin 
Published: June 2022

Objectives:
This randomized, single-blind, clinical trial compared the effectiveness of multifocal soft contact lenses (MFSCLs), orthokeratology contact lenses (Ortho-kCLs), and single vision spectacles (SVSs) for myopia control.

Methods:
Sixty-six eligible Chinese subjects, aged 7 to 15 years old with cycloplegic refraction measurements between −1.00 and −8.00 diopters (D), astigmatism not more than 1.00 D, and no history of myopia control treatment, were randomly assigned to wear MFSCLs, Ortho-kCLs, or SVSs for 1 year. For all three groups, baseline measurements of cycloplegic refraction, axial length (AL), and corneal endothelial cell density (CECD) were made. At the 6- and 12-month follow-up visits, changes in cycloplegic refraction, AL, and CECD were measured in the MFSCL and SVS groups. For the Ortho-kCL group, only changes in the AL were measured at 6 and 12 months, and CECD was measured at the 12-month follow-up visit.

Results:
After 1 year of lens wear, myopia progression of the SVS group, −0.938±0.117 D, was greater than that of the MFSCLs group, −0.591±0.106 D (P=0.032). Thus, MFSCLs reduced the rate of myopia progression by 37.0% compared with the SVSs. The AL elongations after 1 year were 0.30±0.03 mm for MFSCLs (P=0.027 vs SVSs), 0.31±0.04 mm for Ortho-kCLs (P=0.049 vs SVSs), and 0.41±0.04 mm for SVSs. Compared with the SVS group, the reduction in AL elongation was 26.8% and 24.4% in the MFSCL and Ortho-kCL groups, respectively. There were no significant differences in CECD among the three groups (P>0.05).

Conclusions:
Compared with SVSs, wearing MFSCLs and Ortho-kCLs significantly delayed myopia progression. MFSCLs and Ortho-kCLs are safe and promising methods of myopia control (chictr.org number, ChiCTR2100048452).
The Coexistence of Upper and Lower Body Segmental Infantile Hemangiomas
Authors: Shayegan Leila H. , Frieden Ilona J. , Davies Olivia M. T. , Drolet Beth A. , Siegel Dawn H. , Chamlin Sarah L. , Maguiness Sheilagh M. , Powell Julie , Shawber Carrie , Garzon Maria C. 
Published: June 2022

Objectives:
PHACE and LUMBAR are distinct regional malformation sequences with a suspected shared pathogenesis. A dedicated case series illustrating an overlap between these entities has not been published. The purpose of this study was to characterize patients with both upper and lower body segmental infantile hemangiomas (sIHs) and congenital anomalies in an effort to further elucidate their etiology.

Methods:
We conducted a retrospective review of cases at 6 centers carrying a diagnosis of upper and lower body sIHs. A study instrument, including a map of cutaneous hemangiomas and congenital anomalies, was completed for each patient. A literature review for similar cases was conducted.

Results:
We identified 13 patients with both upper and lower body sIHs. 85% were female. Upper body sIH most commonly involved the periauricular region (62%), frontotemporal (54%), maxillary (54%), and mandibular (54%) segments. Lower body sIH were most frequently on the buttocks (77%), posterior thigh (62%), and anterior thigh (54%). Cerebrovascular (69%) and cardiac abnormalities (38%) were common. All 8 previously unreported cases demonstrated minimal, arrested growth (IH-MAG) of at least 1 sIH. We identified an additional 9 cases only partially meeting our criteria.

Conclusions:
In our cohort, certain reproducible embryological vascular patterns described in the literature seem to govern the distribution of sIH. The prevalence of periauricular involvement deserves additional exploration. Our characterization of patients only partially meeting criteria supports the concept that segmental patterns themselves carry risk for congenital anomalies and may merit additional evaluation.
Prediction of Future Health Care Utilization Through Note-extracted Psychosocial Factors
Authors: Dorr David A. , Quiñones Ana R. , King Taylor , Wei Melissa Y. , White Kellee , Bejan Cosmin A. 
Published: June 2022

Background:
Persons with multimorbidity (≥2 chronic conditions) face an increased risk of poor health outcomes, especially as they age. Psychosocial factors such as social isolation, chronic stress, housing insecurity, and financial insecurity have been shown to exacerbate these outcomes, but are not routinely assessed during the clinical encounter. Our objective was to extract these concepts from chart notes using natural language processing and predict their impact on health care utilization for patients with multimorbidity.

Methods:
A cohort study to predict the 1-year likelihood of hospitalizations and emergency department visits for patients 65+ with multimorbidity with and without psychosocial factors. Psychosocial factors were extracted from narrative notes; all other covariates were extracted from electronic health record data from a large academic medical center using validated algorithms and concept sets. Logistic regression was performed to predict the likelihood of hospitalization and emergency department visit in the next year.

Results:
In all, 76,479 patients were eligible; the majority were White (89%), 54% were female, with mean age 73. Those with psychosocial factors were older, had higher baseline utilization, and more chronic illnesses. The 4 psychosocial factors all independently predicted future utilization (odds ratio=1.27–2.77, C-statistic=0.63). Accounting for demographics, specific conditions, and previous utilization, 3 of 4 of the extracted factors remained predictive (odds ratio=1.13–1.86) for future utilization. Compared with models with no psychosocial factors, they had improved discrimination. Individual predictions were mixed, with social isolation predicting depression and morbidity; stress predicting atherosclerotic cardiovascular disease onset; and housing insecurity predicting substance use disorder morbidity.

Discussion:
Psychosocial factors are known to have adverse health impacts, but are rarely measured; using natural language processing, we extracted factors that identified a higher risk segment of older adults with multimorbidity. Combining these extraction techniques with other measures of social determinants may help catalyze population health efforts to address psychosocial factors to mitigate their health impacts.
Data-Driven Nurse Staffing in the Neonatal Intensive Care Unit
Authors: Feldman Keith , Rohan Annie J. 
Published: June 2022

Abstract
The challenge of nurse staffing is amplified in the acute care neonatal intensive care unit (NICU) setting, where a wide range of highly variable factors affect staffing. A comprehensive overview of infant factors (severity, intensity), nurse factors (education, experience, preferences, team dynamics), and unit factors (structure, layout, shift length, care model) influencing pre-shift NICU staffing is presented, along with how intra-shift variability of these and other factors must be accounted for to maintain effective and efficient assignments. There is opportunity to improve workload estimations and acuity measures for pre-shift staffing using technology and predictive analytics. Nurse staffing decisions affected by intra-shift factor variability can be enhanced using novel care models that decentralize decision-making. Improving NICU staffing requires a deliberate, systematic, data-driven approach, with commitment from nurses, resources from the management team, and an institutional culture prioritizing patient safety.
Angle κ Measurement and Its Correlation with Other Ocular Parameters in Normal Population by a New Imaging Modality
Authors: Gharieb Ibrahim Hani M. , Gharieb Hesham Mohamed , Othman Ihab Saad 
Published: June 2022

SIGNIFICANCE
This study obtained normative database for angle κ using Orbscan 3. The average angle κ values were 2.3 ± 1.34° in the whole sample, 2.23 ± 1.36° in myopic eyes, and 3.3 ±1.5° in hyperopic eyes. This is very important to optimize refractive surgery outcomes.

PURPOSE
The aim of this cross-sectional study was to obtain the value of mean angle κ in normal eyes of patients seeking laser vision correction, by the Orbscan 3.

METHODS
The study was conducted on healthy eyes of people seeking laser refractive surgery. A total of 1815 eyes of 908 candidates were included. These were examined as a part of pre-operative assessment. Orbscan 3 was used to measure angle κ and its XY intercepts, keratometry readings, central corneal thickness, thinnest location, white-to-white diameter, and corneal asphericity of front surface (Qf) and back surface (Qb).

RESULTS
The mean ± standard deviation angle κ in all eyes was 2.3 ± 1.34°. The values were 2.23 ± 1.36° in myopic eyes, 3.3 ±1.5° in hyperopic eyes, and 2.9 ±1.6° in emmetropic eyes. Positive correlation was found between angle κ and age, spherical equivalent, subjective sphere, and white-to-white diameter. On the other hand, axial length, average keratometry, central corneal thickness, pupil diameter, and asphericity Q front were negatively correlated with angle κ.

CONCLUSIONS
The mean ± standard deviation angle κ value measured by the Orbscan 3 was 2.3 ± 1.34°. This could be attributed to different software used, in addition to the relatively high axial length in the studied eyes.
International Perspectives on Joint Hypermobility
Authors: Nicholson Leslie L. , Simmonds Jane , Pacey Verity , De Wandele Inge , Rombaut Lies , Williams Cylie M. , Chan Cliffton 
Published: June 2022

Abstract
There is exponential clinical and research interest in joint hypermobility due to recognition of the complexity of identification, assessment, and its appropriate referral pathways, ultimately impacting management. This state-of-the-science review provides an international, multidisciplinary perspective on the presentation, etiology, and assessment of joint hypermobility, as it presents in those with and without a systemic condition. We synthesize the literature, propose standardizing the use of terminology and outcome measures, and suggest potential management directions. The major topics covered are (i) historical perspectives; (ii) current definitions of hypermobility, laxity, and instability; (iii) inheritance and acquisition of hypermobility; (iv) traditional and novel assessments; (v) strengths and limitations of current assessment tools; (vi) age, sex, and racial considerations; (vii) phenotypic presentations; (viii) generalized hypermobility spectrum disorder and hypermobility Ehlers-Danlos syndrome; and (ix) clinical implications and research directions. A thorough understanding of these topics will equip the reader seeking to manage individuals presenting with joint hypermobility, while mindful of its etiology. Management of generalized joint hypermobility in the context of a complex, multisystem condition will differ from that of acquired hypermobility commonly seen in performing artists, specific athletic populations, posttrauma, and so on. In addition, people with symptomatic hypermobility present predominantly with musculoskeletal symptoms and sometimes systemic symptoms including fatigue, orthostatic intolerance, and gastrointestinal or genitourinary issues. Some also display skeletal deformities, tissue and skin fragility, and structural vascular or cardiac differences, and these warrant further medical follow-up. This comprehensive review on the full spectrum of joint hypermobility will assist clinicians, coaches/sports trainers, educators, and/or researchers in this area.
Societal COVID-19 epidemic counter measures and activities associated with SARS-CoV-2 infection in an adult unvaccinated population – a case-control study in Denmark, June 2021
Authors: Munch Pernille Kold , Espenhain Laura , Hansen Christian Holm , Krause Tyra Grove , Ethelberg Steen 
Published: June 2022

AbstractMeasures to restrict physical inter-personal contact in the community have been widely implemented during the COVID-19 pandemic. We studied determinants for infection with SARS-CoV-2 with the aim of testing the efficiency of such measures.We conducted a national matched case-control study among unvaccinated persons aged 18-49 years. Cases were selected among those testing positive for SARS-CoV-2 by RT-PCR over a five-day period in June 2021. Controls were selected from the national population register and were individually matched on age, sex and municipality of residence and had not previously tested positive. Cases and controls were interviewed via telephone about contact with other persons and exposures in the community. We included 500 cases and 529 controls and determined odds ratios (ORs) and 95% confidence intervals (95%CIs) by conditional logistical regression with adjustment for household size and immigration status.We found having had contact with another individual with a known infection as the main determinant for SARS-CoV-2 infection. Reporting close contact with an infected person who either had or did not have symptoms resulted in ORs of 20 (95%CI:9.8-39) and 8.5 (95%CI 4.5-16) respectively. In contrast, community exposures were generally not associated with disease; several exposures were negatively associated. Exceptions were: attending fitness centers, OR=1.4 (95%CI:1.0-2.0) and consumption of alcohol in restaurants or cafés, OR=2.3 (95%CI:1.3–4.2).For reference, we provide a timeline of non-pharmaceutical interventions in place in Denmark from February 2020 to March 2022. Fitness centers and alcohol consumption were mildly associated with infection, in agreement with findings of our similar study conducted six month earlier (Epidemiology & Infection 2021;150:e9.). Transmission of disease through involvement in community activities appeared to occur only rarely, suggesting that community restrictions in place were efficient. Instead, transmission appeared to primarily take place in a confined space via contact to known persons.
The mIAA7 degron improves auxin-mediated degradation in C. elegans
Authors: Sepers Jorian J. , Verstappen Noud H. M. , Vo An A. , Ragle James Matthew , Ruijtenberg Suzan , Ward Jordan D. , Boxem Mike 
Published: June 2022

AbstractAuxin-inducible degradation (AID) is a powerful tool for the targeted degradation of proteins with spatiotemporal control. One limitation of the AID system is that not all proteins are degraded efficiently. Here, we demonstrate that an alternative degron sequence, termed mIAA7, improves the efficiency of degradation in C. elegans, as previously reported in human cells. We tested depletion of a series of proteins with various sub-cellular localizations in different tissue types and found that the use of the mIAA7 degron resulted in faster depletion kinetics for five out of six proteins tested. The exception was the nuclear protein HIS-72, which was depleted with similar efficiency as with the conventional AID* degron sequence. The mIAA7 degron also increased the leaky degradation for two of the tested proteins. To overcome this problem, we combined the mIAA7 degron with the C. elegans AID2 system (C.e.AID2), which resulted in complete protein depletion without detectable leaky degradation. Finally, we show that degradation of ERM-1, a highly stable protein that is challenging to deplete, could be improved further by using multiple mIAA7 degrons. Taken together, the mIAA7 degron further increases the power and applicability of the AID system. To facilitate the generation of mIAA7-tagged proteins using CRISPR/Cas9 genome engineering, we generated a toolkit of plasmids for the generation of dsDNA repair templates by PCR.
Longitudinal Electrocochleography as an Objective Measure of Serial Behavioral Audiometry in Electro-Acoustic Stimulation Patients
Authors: Tejani Viral D. , Kim Jeong-Seo , Etler Christine P. , Skidmore Jeffrey , Yuan Yi , He Shuman , Hansen Marlan R. , Gantz Bruce J. , Abbas Paul J. , Brown Carolyn J. 
Published: June 2022

ABSTRACTMinimally traumatic surgical techniques and advances in cochlear implant (CI) electrode array designs have allowed acoustic hearing present in a CI candidate prior to surgery to be preserved post-operatively. As a result, these patients benefit from combined electric-acoustic stimulation (EAS) post-operatively. However, 30-40% of EAS CI users experience a partial loss of hearing up to 30 dB after surgery. In the present study, electrocochleography (ECoG) was used to study cochlear microphonic (hair cell response) and auditory nerve neurophonic (neural response) in patients with preserved hearing and patients with loss of hearing. These measures were obtained longitudinally over the course of CI use. At each test session, ECoG amplitude growth functions for several low-frequency stimuli were obtained. The threshold, slope, and suprathreshold amplitude at a fixed stimulation level was obtained from each growth function at each time point. Subjects were categorized as having stable hearing or loss of hearing. Longitudinal linear mixed effects models were used study trends in ECoG thresholds, slopes, and amplitudes for these two categories of subjects. Results showed that CM and ANN thresholds and amplitudes were stable in CI users with preserved residual hearing. CM and ANN thresholds increased (worsened) while CM and ANN amplitudes decreased (worsened) for those with delayed hearing loss. The slope did not distinguish between subjects with stable hearing and subjects with delayed loss of hearing. These results provide a new application of post-operative ECoG as an objective tool to monitor residual hearing and understand the pathophysiology of delayed hearing loss.