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Background: The healing potential of a fracture is determined by mechanical and biological factors. Simulation-based workflows can help assess these factors to assist in predicting non-unions. The aim of this study was the introduction of two use cases for a novel patient-specific simulation workflow based on clinically available information. Methods: The used software is an extension of the "Ulm Bone Healing model" and was applied in two cases with non-union development after fracture fixation to show its principal feasibility. The clinical and radiographic information, starting from initial treatment, were used to feed the simulation process. Results: The simulation predicted non-union development and axial deviation in a mechanically driven non-union. In the case of a biological non-union, a slow, incomplete healing course was correctly identified. However, the time offset in callus bridging was discordant between the simulation and the distinctly slower healing response in the clinical case. Conclusions : The simulation workflow presented in the two clinical use cases allowed for the identification of fractures at risk for impending non-union immediately after the initial fixation based on available clinical and radiographic information. Further validation in a large non-union cohort is needed to increase the model's precision, especially in biologically challenging cases, and show its validity as a screening instrument.

Introduction: GBS may cause a devastating disease in newborns. In early onset disease of the newborn the bacteria are acquired from the colonized mother during delivery. We characterized type VII secretion system (T7SS), exporting small proteins of the WXG100 superfamily, in group B Streptococci (GBS) isolates from pregnant colonized women and newborns with early onset disease (EOD) to better understand T7SS contribution to virulence in these different clinical scenarios., Methods: GBS genomes [N=33, 17 EOD isolates (serotype III/ST17) and 16 colonizing isolates (12 serotype VI/ST1, one serotype VI/ST19, one serotype VI/ST6, and two serotype 3/ST19)] were analyzed for presence of T7SS genes and genes encoding WXG100 proteins. We also perform bioinformatic analysis. Galleria mellonella larvae were used to compare virulence between colonizing, EOD, and mutant EOD isolates. The EOD isolate number 118659 (III/ST17) was used for knocking out the essC gene encoding a membrane-bound ATPase, considered the driver of T7SS., Results: Most GBS T7SS loci encoded core component genes: essC, membrane-embedded proteins (essA; essB), modulators of T7SS activity (esaA; esaB; esaC) and effectors: [esxA (SAG1039); esxB (SAG1030)].Bioinformatic analysis indicated that based on sequence type (ST) the clinicalGBS isolates encode at least three distinct subtypes of T7SS machinery. In all ST1isolates we identified two copies of esxA gene (encoding putative WXG100proteins), when only 23.5% of the ST17 isolates harbored the esxA gene. Five ST17isolates encoded two copies of the essC gene. Orphaned WXG100 molecule(SAG0230), distinct from T7SS locus, were found in all tested strains, except inST17 strains where the locus was found in only 23.5% of the isolates. In ST6 andST19 isolates most of the structure T7SS genes were missing. EOD isolates demonstrated enhanced virulence in G. mellonella modelcompared to colonizing isolates. The 118659DessC strain was attenuated in itskilling ability, and the larvae were more effective in eradicating 118659DessC., Conclusions: We demonstrated that T7SS plays a role during infection. Knocking out the essC gene, considered the driver of T7SS, decreased the virulence of ST17 responsible for EOD, causing them to be less virulent comparable to the virulence observed in colonizing isolates., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Schindler, Rahav, Nissan, Valenci, Ravins, Hanski, Ment, Tekes-Manova and Maor.)

Background: Group B streptococcus (GBS) harbors many virulence factors but there is limited data regarding their importance in colonization in pregnancy and early-onset disease (EOD) in the newborn. We hypothesized that colonization and EOD are associated with different distribution and expression of virulence factors., Methods: We studied 36 GBS EOD and 234 GBS isolates collected during routine screening. Virulence genes (pilus-like structures- PI-1, PI-2a, PI-2b ; rib and hvgA ) presence and expression were identified by PCR and qRT-PCR. Whole genome sequencing (WGS) and comparative genomic analyses were used to compare coding sequences (CDSs) of colonizing and EOD isolates., Results: Serotype III (ST17) was significantly associated with EOD and serotype VI (ST1) with colonization. hvgA and rib genes were more prevalent among EOD isolates (58.3 and 77.8%, respectively; p < 0.01). The pilus loci PI-2b and PI-2a were more prevalent among EOD isolates (61.1%, p < 0.01), while the pilus loci PI-2a and PI-1 among colonizing isolates (89.7 and 93.1% vs. 55.6 and 69.4%, p < 0.01). qRT PCR analysis revealed that hvgA was barely expressed in colonizing isolates, even though the gene was detected. Expression of the rib gene and PI-2b was two-fold higher in EOD isolates compared to colonizing isolates. Transcription of PI-2a was three-fold higher in colonizing isolates compared to EOD isolates. ST17 isolates (associated with EOD) had a smaller genome size compared ST1 and the genome was more conserved relative to the reference strain and ST17 isolates. In a multivariate logistic regression analysis virulence factors independently associated with EOD were serotype 3, and PI-1 and PI-2a was protective., Conclusion: There was a significant difference in the distribution of hvg A , rib , and PI genes among EOD (serotype III/ST17) and colonizing (serotype VI/ST1) isolates suggesting an association between invasive disease and these virulence factors. Further study is needed to understand the contribution of these genes to GBS virulence., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Schindler, Rahav, Nissan, Treygerman, Prajgrod, Attia, Raz, Valenci, Tekes-Manova and Maor.)

Objective: Parturients with symptoms to COVID-19 have an increased risk for neonatal adverse outcomes and for any adverse outcome compared to the asymptomatic COVID-19 positive parturients and to the COVID-19-negative parturients. The purpose of this study was to determine the effect of COVID-19 on obstetric outcomes based on symptom status of parturients at or near term., Methods: Retrospective cohort study of parturients diagnosed with COVID-19 between 26 March and 30 September 2020. Maternal and neonatal outcomes were assessed by comparing three groups of parturients: COVID-19 negative, asymptomatic COVID-19, and symptomatic COVID-19., Results: A total of 2299 COVID-19-negative parturients and 172 patients with confirmed diagnosis of COVID-19 delivered during the study period. The median gestational age at the time of delivery was 39 (interquartile range 39-40) weeks. The most common symptom was cough (28/56, 50%). Gestational diabetes mellitus was significantly less common in COVID-19-negative than in COVID-19-positive patients. There was no significant increase in cesarean delivery in women who were COVID-19 positive and the incidence of preterm deliveries was not significantly different among the three groups. Of the 172 cases of COVID-19, only one parturient needed mechanical ventilation, and there were no maternal deaths in this group. There were no cases of severe neonatal asphyxia or neonatal death. Composite maternal adverse outcomes were not significantly different between the three groups. The aOR for composite neonatal adverse outcome and overall composite adverse outcome comparing COVID-19 positive to negative parturients was 2.1 (95% confidence interval [CI], 1.1-3.8; p  = .02) and 1.6 (95% CI, 1.1-2.3; p  = .02), respectively., Conclusions: An increased risk for neonatal adverse outcomes and for any adverse outcome was found in the symptomatic COVID-19 group compared to the asymptomatic COVID-19-positive parturients and to the COVID-19-negative parturients.

Background: There is limited data regarding the safety of vaginal delivery in women infected with COVID-19. Our goal was to assess the safety of vaginal delivery in women infected with COVID-19 and the risk of neonatal infection., Methods: This was a single medical center cohort study. Data were collected about the outcome of twenty-one women with laboratory-confirmed COVID-19 infection who delivered between March 23, 2020, and May 8, 2020., Results: Twenty-one gravidas were diagnosed with COVID-19 infection. None required admission to the intensive care unit (ICU) and there were no fatalities. Seventeen delivered vaginally and four by caesareans. Apgar scores of all neonates were 9 at 1 min and 10 at 5 min. One neonate was diagnosed with COVID-19 infection 24 h after birth., Conclusions: Vaginal delivery in women infected with COVID-19 is not associated with a significant risk of neonatal infection., Competing Interests: Declaration of competing interest The authors declare that they have no competing interest., (Copyright © 2020. Published by Elsevier B.V.)

Objectives: To study Group B Streptococcus (GBS) isolates associated with different clinical syndromes: asymptomatic carriage in pregnant women, intrauterine fetal death (IUFD), and early onset disease (EOD) in the newborn., Methods: GBS isolates were collected from asymptomatic pregnant women admitted for labor, IUFD cases, and neonates with EOD. Serotypes and antibiotic susceptibilities were determined. Multilocus sequence typing (MLST) was performed to assess genetic epidemiology., Results: GBS carriage rate was 26.1% (280/1074). The dominant serotype among asymptomatic pregnant women was VI [98/240 women (40.8%)], followed by serotypes III, V and IV in 42/240 (17.5%), 30/240 (12.5%) and 28/240 (11.7%) women, respectively. The dominant serotype in IUFD cases was serotype VI [10/13 (76.9%)]. In contrast the prevalent serotype among EOD cases was III [16/19 (84.2%)]. ST-1 was associated with IUFD [7/13 (53.8%)], ST-17 was associated with serotype III and EOD in the newborn 14/19 (73.7%)]. Erythromycin and clindamycin resistance reached 36.8%, 7.7% and 20.0%among EOD, vaginal carriage and IUFD, respectively., Conclusions: Serotypes VI and ST-1 were dominant among asymptomatic pregnant women and in IUFD cases while EOD was associated with serotype III and ST-17. Invasive mechanisms thus may differ between IUFD and EOD in the newborn and virulence may be related to capsule serotype. Resistance rates to erythromycin and clindamycin were high in EOD cases., Competing Interests: The authors have read the journal’s policy and the authors of this paper declare the following competing interests: YM and GR received consultant and lecture fees from Pfizer, MSD, Gilead and Astellas. There are no patents, products in development or marketed products associated with this research to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

We examined the dynamics of coronavirus 2019 (COVID-19) transmission within families. Our investigation demonstrated significantly lower rates of COVID-19 positivity in children compared with adults residing in the same household. Children of 5-17 years of age were 61% and children of 0-4 years of age were 47% less likely to have positive polymerase chain reaction results compared with adults residing in the same household.

Beta hemolytic particularly of group A Streptococcus meningitis, is a rare site of the group of invasive infections caused by this microorganism. It occurs frequently in healthy children, without predisposing factors. It represents 0.2-1 % of all meningitis. It is usually installed by dissemination from a nearby focus. The addition of clindamycin improves the treatment efficacy by inhibition of bacterial protein synthesis, including toxin production. The pathogenesis of the disease is not clear, the association with exotoxins was proposed. Co-infection with the influenza virus would favor invasive infections. We present this case of a previously healthy 6-year-old boy with a diagnosis of beta hemolytic Streptococcus meningitis group A, a rare location in children., Competing Interests: None, (Sociedad Argentina de Pediatría.)

Background: Introduction of pneumococcal conjugate vaccine (PCV) has nearly eliminated vaccine-type (VT) invasive pneumococcal disease (IPD) in children, yet the reported resulting reduction of adult IPD is variable. We present the indirect impact of sequential PCV7/PCV13 implementation in Israel on adult IPD., Methods: An ongoing nationwide active surveillance was initiated on July 2009 when PCV7 was implemented (with Catch-up). PCV7 was gradually replaced by PCV13 since November 2010. Comorbidity and outcome data were collected from medical files. Incidence rates were calculated for overall and vaccine-type IPD., Results: A total of 2579 IPD cases were diagnosed among a population of 5.0-5.5 million adults >18y (2009-2015). Incidence rates were 9.15/100,000 and 10.16/100,000 in the first and second study years, respectively. However, after PCV13 implementation, the rates decreased to 7.19 within four years, and remained stable in the two following years. Within 6years, PCV7-VT-IPD incidence decreased from 2.52 to 0.52 (79%) and PCV13-VT-IPD from 6.15 to 1.81 (71%). Concurrently, non-VT13 incidence increased from 2.99 to 5.25. Approximately 50% of all patients were adults ≥65y, in whom the decrease in PCV13-VT-IPD incidence was smaller and slower (65% vs. >80% decrease in adults <50y)., Conclusions: Despite continued reduction in PCV13-VT-IPD, overall IPD was stable during the last two years due to serotype replacement. Yet, the significant decrease in adult IPD, six years post-PCV7/13 implementation emphasizes the importance of indirect protection in achieving overall population impact and should be considered when discussing the potential additional benefits of direct adult PCV vaccination., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Hematopoietic development occurs in complex microenvironments and is influenced by key signaling events. Yet how these pathways communicate with master hematopoietic transcription factors to coordinate differentiation remains incompletely understood. The transcription factor RUNX1 plays essential roles in definitive hematopoietic stem cell (HSC) ontogeny, HSC maintenance, megakaryocyte (Mk) maturation, and lymphocyte differentiation. It is also the most frequent target of genetic alterations in human leukemia. Here, we report that RUNX1 is phosphorylated by Src family kinases (SFKs) and that this occurs on multiple tyrosine residues located within its negative regulatory DNA-binding and autoinhibitory domains. Retroviral transduction, chemical inhibitor, and genetic studies demonstrate a negative regulatory role of tyrosine phosphorylation on RUNX1 activity in Mk and CD8 T-cell differentiation. We also demonstrate that the nonreceptor tyrosine phosphatase Shp2 binds directly to RUNX1 and contributes to its dephosphorylation. Last, we show that RUNX1 tyrosine phosphorylation correlates with reduced GATA1 and enhanced SWI/SNF interactions. These findings link SFK and Shp2 signaling pathways to the regulation of RUNX1 activity in hematopoiesis via control of RUNX1 multiprotein complex assembly.

Laryngeal extranodal non-Hodgkin lymphoma is uncommon, accounting for less than 1% of all laryngeal neoplasms; the B-cell phenotype is predominant. Lymphomas outside the nasal cavity are rare and highly aggressive. We present a case of primary natural killer T-cell (NK/T-cell) lymphoma of the larynx that arose in a 45-year-old man. Because only a limited amount of data is available on laryngeal NK/T-cell lymphoma, the mainstay of treatment remains unclear, although some data suggest that radiotherapy alone is the best option. Our patient was treated with chemotherapy and radiotherapy, and he remained in remission 2 years later.

The transcription factor GATA-1 is required for terminal erythroid maturation and functions as an activator or repressor depending on gene context. Yet its in vivo site selectivity and ability to distinguish between activated versus repressed genes remain incompletely understood. In this study, we performed GATA-1 ChIP-seq in erythroid cells and compared it to GATA-1-induced gene expression changes. Bound and differentially expressed genes contain a greater number of GATA-binding motifs, a higher frequency of palindromic GATA sites, and closer occupancy to the transcriptional start site versus nondifferentially expressed genes. Moreover, we show that the transcription factor Zbtb7a occupies GATA-1-bound regions of some direct GATA-1 target genes, that the presence of SCL/TAL1 helps distinguish transcriptional activation versus repression, and that polycomb repressive complex 2 (PRC2) is involved in epigenetic silencing of a subset of GATA-1-repressed genes. These data provide insights into GATA-1-mediated gene regulation in vivo.

Angiomyomatous hamartomas have been found almost exclusively in the inguinal and femoral lymph nodes; few reports of these lesions in the head and neck region have been published. We present a case of angiomyomatous hamartoma in the submandibular area, a site that has not been previously reported in the literature. The mass was initially diagnosed as an enlarged lymph node. When it did not regress following broad-spectrum antibiotic treatment, the patient, a 51-year-old woman, underwent an excisional biopsy. Histopathology identified the mass as an angiomyomatous hamartoma. At follow-up 3 years and 9 months postoperatively, the patient exhibited no evidence of recurrence on physical examination and computed tomography. Even though angiomyomatous hamartoma of the head and neck is rare, we suggest that otolaryngologists include it in the differential diagnosis of head and neck masses.