Background: Paenibacillus thiaminolyticus was identified as an important contributor to postinfectious hydrocephalus (PIH) among Ugandan infants as a sequela from prior neonatal sepsis (NS). To better determine the significance of this organism’s role in NS and PIH, we complete separate studies of Ugandan with hydrocephalus, with and without prior evidence of infection (case-control), as well as neonates with sepsis (observational cohort), and maternal-newborn pairs (case-control, with and without maternal fever). Methods: From 2016-2019, 400 infants with hydrocephalus were recruited. 16S rDNA sequencing was used to characterize the bacterial content of infant cerebrospinal fluid (CSF). One hundred maternal-newborn pairs and 800 neonates with sepsis were recruited. Two quantitative polymerase chain reactions (qPCR) targeting either the Paenibacillus genus or Paenibacillus thiaminolyticus species of all 2578 specimens were performed. In addition, cranial ultrasound and computed tomography images were collected.Findings: Paenibacillus was the most enriched bacterial genera in PIH CSF (44%), with 16S demonstrating 94% accuracy when validated by qPCR. No Paenibacillus was detected in vaginal, maternal blood, placental or cord blood specimens. Paenibacillus was detected in 5% of septic neonates, and of these 19% developed PIH. Imaging demonstrated progression from Paenibacillus meningitis to PIH over months. PIH patients with Paenibacillus infections were geographically clustered. Interpretation: Paenibacillus causes neonatal sepsis and meningitis in Uganda, and is the dominant cause of subsequent PIH. There was no evidence of transplacental transmission, and geographical evidence was consistent with an environmental source of neonatal infection. Further work is needed to identify routes of infection and optimize treatment of neonatal Paenibacillus infection to lessen the burden of morbidity and mortality.Funding: The National Institutes of Health (NIH) Director’s Pioneer Award 5DP1HD086071 and NIHDirector’s Transformative Award 1R01AI145057 to SJS, and Boston Children’s Hospital Officeof Faculty Development Career Development Award to SUM.Declaration of Interest: None to declare. Ethical Approval: Ethics oversight was provided by the CURE Children's Hospital of Uganda (CCHU) Institutional Review Board, Mbarara University of Science and Technology Research Ethics Committee, Ugandan National Council on Science and Technology, and Pennsylvania State University Institutional Review Board.
Chiari I malformation is a common entity in pediatric neurosurgery. Prior studies have shown that surgical treatment at children’s hospitals (CH) is associated with higher costs compared to non-children’s hospitals (NCH) for other diagnoses. Therefore, we hypothesized that costs would be increased for the treatment of Chiari I malformation at a CH. Data were extracted from the Agency for Healthcare Research and Quality’s (AHRQ) Healthcare Cost and Utilization Project (HCUP) Kids' Inpatient Database (KID). Patients who underwent surgery for Chiari I malformation were identified using International Classification of Diseases, 9th Edition, Clinical Modification (ICD-9-CM) diagnosis and procedure codes. Univariate statistical tests, multivariable linear regression models, and propensity score matching were utilized to determine differences in hospital length of stay (LOS) and costs between patients treated at CH versus NCH. Treatment at a CH was associated with significantly higher costs compared to treatment at an NCH while hospital LOS and mortality were similar. In the multivariable linear regression model, the adjusted average cost for surgical treatment of Chiari I malformation was $13,716, and treatment at a CH was associated with an additional $6,343 (p<0.0001). Similar results were seen after propensity score matching: costs for treatment at a CH were $6,047 higher than they were for treatment at an NCH (p<0.0001). In our analysis, a significant increase in cost was seen with treatment at a CH while controlling for patient demographics and hospital characteristics, as well as imbalanced covariates between the cohorts. Further investigation is warranted to determine the drivers of increased cost outside of the patient and hospital characteristics we analyzed in our study.
Abstract Background Streptococcus pneumoniae (Spn) is typically an asymptomatic colonizer of the nasopharynx but it also causes pneumonia and disseminated disease affecting various host anatomical sites. Transition from colonization to invasive disease is not well understood. Studies have shown that such a transition can occur as result of influenza A virus coinfection. Methods We investigated the pneumococcal (serotype 19F, strain EF3030) and host transcriptomes with and without influenza A virus (A/California/07 2009 pH1N1) infection at this transition. This was done using primary, differentiated Human Bronchial Epithelial Cells (nHBEC) in a transwell monolayer model at an Air-Liquid Interface (ALI), with multispecies deep RNA-seq. Results Distinct pneumococcal gene expression profiles were observed in the presence and absence of influenza. Influenza coinfection allowed for significantly greater pneumococcal growth and triggered the differential expression of bacterial genes corresponding to multiple metabolic pathways; in totality suggesting a fundamentally altered bacterial metabolic state and greater nutrient availability when coinfecting with influenza. Surprisingly, nHBEC transcriptomes were only modestly perturbed by infection with EF3030 alone in comparison to that resulting from Influenza A infection or coinfection, which had drastic alterations in thousands of genes. Influenza infected host transcriptomes suggest significant loss of ciliary function in host nHBEC cells. Conclusions Influenza A virus infection of nHBEC promotes pneumococcal infection. One reason for this is an altered metabolic state by the bacterium, presumably due to host components made available as result of viral infection. Influenza infection had a far greater impact on the host response than did bacterial infection alone, and this included down regulation of genes involved in expressing cilia. We conclude that influenza infection promotes a pneumococcal metabolic shift allowing for transition from colonization to disseminated disease. Author summary Secondary Streptococcus pneumoniae bacterial infections typically occur after influenza A virus respiratory infection. Such coinfections often lead to invasive pneumococcal disease. The mechanisms involved in this process are not well understood. Here, using an ex vivo human lung bronchial epithelial cell model, we investigated the biological processes of the host and pneumococcus occurring at this niche, during coinfection with multi-species transcriptomics techniques, and in vivo mouse model experimentation. We observed stark differences in global pneumococcal metabolism in different infection states, as well as viral induced epithelial cell changes in ciliary function, potentially aiding pneumococcal dissemination. Overall, this study identified broad and targeted biological processes involved in this host-pathogen interaction.
Paenibacillus thiaminolyticus is a cause of postinfectious hydrocephalus among Ugandan infants. To determine whether Paenibacillus spp is a pathogen in neonatal sepsis, meningitis, and postinfectious hydrocephalus, we aimed to complete three separate studies of Ugandan infants. The first study was on peripartum prevalence of Paenibacillus in mother-newborn pairs. The second study assessed Paenibacillus in blood and cerebrospinal fluid (CSF) from neonates with sepsis. The third study assessed Paenibacillus in CSF from infants with hydrocephalus.In this observational study, we recruited mother-newborn pairs with and without maternal fever (mother-newborn cohort), neonates (aged ≤28 days) with sepsis (sepsis cohort), and infants (aged ≤90 days) with hydrocephalus with and without a history of neonatal sepsis and meningitis (hydrocephalus cohort) from three hospitals in Uganda between Jan 13, 2016 and Oct 2, 2019. We collected maternal blood, vaginal swabs, and placental samples and the cord from the mother-newborn pairs, and blood and CSF from neonates and infants. Bacterial content of infant CSF was characterised by 16S rDNA sequencing. We analysed all samples using quantitative PCR (qPCR) targeting either the Paenibacillus genus or Paenibacillus thiaminolyticus spp. We collected cranial ultrasound and computed tomography images in the subset of participants represented in more than one cohort.No Paenibacillus spp were detected in vaginal, maternal blood, placental, or cord blood specimens from the mother-newborn cohort by qPCR. Paenibacillus spp was detected in 6% (37 of 631 neonates) in the sepsis cohort and, of these, 14% (5 of 37 neonates) developed postinfectious hydrocephalus. Paenibacillus was the most enriched bacterial genera in postinfectious hydrocephalus CSF (91 [44%] of 209 patients) from the hydrocephalus cohort, with 16S showing 94% accuracy when validated by qPCR. Imaging showed progression from Paenibacillus spp-related meningitis to postinfectious hydrocephalus over 1-3 months. Patients with postinfectious hydrocephalus with Paenibacillus spp infections were geographically clustered.Paenibacillus spp causes neonatal sepsis and meningitis in Uganda and is the dominant cause of subsequent postinfectious hydrocephalus. There was no evidence of transplacental transmission, and geographical evidence was consistent with an environmental source of neonatal infection. Further work is needed to identify routes of infection and optimise treatment of neonatal Paenibacillus spp infection to lessen the burden of morbidity and mortality.National Institutes of Health and Boston Children's Hospital Office of Faculty Development.
Object The purpose of this study was to determine a reliable estimate of the size, demographic, and practice characteristics of the current pediatric neurosurgical workforce. The authors also sought to differentiate pediatric from nonpediatric neurosurgical practitioners and compare the demographic and practice characteristics of these 2 groups. The term “pediatric practitioner” will be used in this study to describe a practitioner whose practice is > 75% pediatric patients in accordance with the American Board of Pediatric Neurological Surgery (ABPNS) requirements for board certification in pediatric neurosurgery. Those practitioners with < 75% pediatric patients in their practice will be designated as “nonpediatric practitioners.” Methods The authors aggregated multiple databases of professional neurosurgical societies in an effort to identify pediatric neurosurgical practitioners. A 30-question survey was then administered to all identified practitioners, and responses were collected for 6 months. Primary analysis of pediatric versus nonpediatric practitioners was performed. Subgroup analyses of the characteristics of the pediatric practitioners were also performed to identify the effects of practitioner age, sex, and practice setting on survey responses. Results A total of 342 practitioners received the survey, and 267 responded (78.1% response rate); 158 pediatric practitioners and 92 nonpediatric practitioners were identified. Seventeen respondents were excluded from analysis. Pediatric practitioners were more likely to be women, ABPNS certified, have completed a pediatric fellowship, do fewer operative cases per year, have a more frequent call schedule, practice in a freestanding children's hospital, be in academic practice, and in need of recruiting additional faculty. Pediatric practitioners spent fewer hours per week in patient care, and were less likely to have a productivity-based salary or salary incentive based on relative value unit–production. Among pediatric practitioners, American Board of Neurological Surgery and ABPNS certification rates differed significantly among age groups, with older age groups being more likely to be certified by the American Board of Neurological Surgery and ABPNS. The rate of pediatric fellowship completion was significantly higher in the younger age groups. Anticipating retirement by age 65 was significantly more likely in the younger age groups, and hours spent per week spent in teaching and administrative duties were lower in the younger age groups. There were 27 female and 131 male pediatric practitioners. The women were more likely to have completed a pediatric fellowship and performed fewer operative cases per year than the men. Nonacademic pediatric practitioners were more likely to have a relative value unit–based salary incentive, be reimbursed for call coverage, and spend more hours per week in patient care than academic pediatric practitioners. Academic pediatric practitioners spent more hours per week in clinical research. Conclusions The authors estimate that there are fewer than 200 pediatric neurosurgeons currently practicing in the United States. Current practice patterns unique to pediatrics may have important implications in recruiting and retaining the next generation of pediatric neurosurgeons.
Rare mutations in the gene encoding for tau (MAPT, microtubule-associated protein tau) cause frontotemporal dementia-spectrum (FTD-s) disorders, including FTD, progressive supranuclear palsy (PSP) and corticobasal syndrome, and a common extended haplotype spanning across the MAPT locus is associated with increased risk of PSP and Parkinson's disease.We identified a rare tau variant (p.A152T) in a patient with a clinical diagnosis of PSP and assessed its frequency in multiple independent series of patients with neurodegenerative conditions and controls, in a total of 15 369 subjects.Tau p.A152T significantly increases the risk for both FTD-s (n 5 2139, OR 5 3.0, CI: 1.6 -5.6, P 5 0.0005) and Alzheimer's disease (AD) (n 5 3345, OR 5 2.3, CI: 1.3 -4.2, P 5 0.004) compared with 9047 controls.Functionally, p.A152T (i) decreases the binding of tau to microtubules and therefore promotes microtubule assembly less efficiently; and (ii) reduces the tendency to form abnormal fibers.However, there is a pronounced increase in the formation of tau oligomers.Importantly, these findings suggest that other regions of the tau protein may be crucial in regulating normal function, as the p.A152 residue is distal to the domains considered responsible for microtubule interactions or aggregation.These data provide both the first genetic evidence and functional studies supporting the role of MAPT p.A152T as a rare risk factor for both FTD-s and AD and the concept that rare variants can increase the risk for relatively common, complex neurodegenerative diseases, but since no clear significance threshold for rare genetic variation has been established, some caution is warranted until the findings are further replicated.
