Characteristics of pediatric recurrent acute mastoiditis: A case-control study.

BACKGROUND: Data on pediatric recurrent acute mastoiditis are lacking, despite its morbidity and clinical significance. Our aim was to describe the incidence, characteristics, and associated factors of recurrent mastoiditis in hospitalized children. METHODS: Using a case-control design, analyzing electronic data of hospitalized children with acute mastoiditis between June 2011 and December 2018, children with recurrent mastoiditis were compared to children with a single episode at the time of hospitalization. Recurrent episodes of mastoiditis were compared to the first episodes. Recurrent acute mastoiditis was defined as recurring mastoiditis ≥4-weeks after a completely resolved event. RESULTS: Of 347 children hospitalized with acute mastoiditis, 22 (6.3%) had recurrent mastoiditis; the median interval between episodes was 3 months (range: 1-36). The mean ± SD age was 2.3 ± 2.25 years. A comparison of first episodes in recurring cases to single episodes by univariate and multivariate analysis, showed no differences in the pre-admission management or in the isolated pathogens; however, a history of atopic dermatitis and percutaneous abscess drainage were more frequent in first episodes of recurring cases (27.3% vs. 1.2%, p < 0.001, and 27.3% vs. 10.0%, p = 0.026, respectively). The second episode of acute mastoiditis was characterized by a milder clinical course and shorter durations from symptoms to hospitalization, intravenous antibiotic therapy, and length of hospital stay. Linear regression showed that an increased interval from symptoms to hospitalization significantly increased length of hospital stay (regression coefficient of 0.215 [95% CI: 0.114-0.317], p < 0.001). CONCLUSIONS: Recurrent episodes of mastoiditis were clinically milder, with shorter length of hospital stay compared to first episodes, possibly because of early admission.

Drivers of within-host genetic diversity in acute infections of viruses.

Genetic diversity is the fuel of evolution and facilitates adaptation to novel environments. However, our understanding of what drives differences in the genetic diversity during the early stages of viral infection is somewhat limited. Here, we use ultra-deep sequencing to interrogate 43 clinical samples taken from early infections of the human-infecting viruses HIV, RSV and CMV. Hundreds to thousands of virus templates were sequenced per sample, allowing us to reveal dramatic differences in within-host genetic diversity among virus populations. We found that increased diversity was mostly driven by presence of multiple divergent genotypes in HIV and CMV samples, which we suggest reflect multiple transmitted/founder viruses. Conversely, we detected an abundance of low frequency hyper-edited genomes in RSV samples, presumably reflecting defective virus genomes (DVGs). We suggest that RSV is characterized by higher levels of cellular co-infection, which allow for complementation and hence elevated levels of DVGs.

Hyperlactatemia in children following brain tumor resection: prevalence, associated factors, and clinical significance.

PURPOSE: Hyperlactatemia is associated with worse outcome among critically ill patients. The prevalence of hyperlactatemia in children following craniotomy for intracranial tumor resection is unknown. This study was designed to assess the prevalence, associated factors, and significance of postoperative hyperlactatemia in this context. METHODS: A retrospective study was conducted at an intensive care unit of a tertiary, pediatric medical center. Children younger than 18 years admitted following craniotomy for brain tumor resection between October 2004 and November 2019 were included. RESULTS: Overall, 222 elective craniotomies performed in 178 patients were analyzed. The mean age ± SD was 8.5 ± 5.5 years. All but two patients survived to discharge. All were hemodynamically stable. Early hyperlactatemia, defined as at least one blood lactate level ≥ 2.0 mmol/L during the first 24 h into admission, presented following 74% of the craniotomies; lactate normalized within a mean ± SD of 11 ± 6.1 h. The fluid balance per body weight at 12 h and 24 h into the intensive care unit admission was similar in children with and without hyperlactatemia [7.0 ± 17.6 vs 3.5 ± 16.4 ml/kg, p = 0.23 and 4.0 ± 27.2 vs 4.6 ± 29.4 ml/kg, p = 0.96; respectively]. Hyperlactatemia was associated with higher maximal blood glucose, older age, and a pathological diagnosis of glioma. Intensive care unit length of stay was similar following craniotomies with and without hyperlactatemia (p = 0.57). CONCLUSIONS: Hyperlactatemia was common in children following craniotomy for brain tumor resection. It was not associated with hemodynamic impairment or with a longer length of stay.

Correction: Within-patient mutation frequencies reveal fitness costs of CpG dinucleotides and drastic amino acid changes in HIV.

[This corrects the article DOI: 10.1371/journal.pgen.1007420.].

Within-patient mutation frequencies reveal fitness costs of CpG dinucleotides and drastic amino acid changes in HIV.

HIV has a high mutation rate, which contributes to its ability to evolve quickly. However, we know little about the fitness costs of individual HIV mutations in vivo, their distribution and the different factors shaping the viral fitness landscape. We calculated the mean frequency of transition mutations at 870 sites of the pol gene in 160 patients, allowing us to determine the cost of these mutations. As expected, we found high costs for non-synonymous and nonsense mutations as compared to synonymous mutations. In addition, we found that non-synonymous mutations that lead to drastic amino acid changes are twice as costly as those that do not and mutations that create new CpG dinucleotides are also twice as costly as those that do not. We also found that G→A and C→T mutations are more costly than A→G mutations. We anticipate that our new in vivo frequency-based approach will provide insights into the fitness landscape and evolvability of not only HIV, but a variety of microbes.

Site-Specific Evolutionary Rate Shifts in HIV-1 and SIV.

Site-specific evolutionary rate shifts are defined as protein sites, where the rate of substitution has changed dramatically across the phylogeny. With respect to a given clade, sites may either undergo a rate acceleration or a rate deceleration, reflecting a site that was conserved and became variable, or vice-versa, respectively. Sites displaying such a dramatic evolutionary change may point to a loss or gain of function at the protein site, reflecting adaptation, or they may indicate epistatic interactions among sites. Here, we analyzed full genomes of HIV and SIV-1 and identified 271 rate-shifting sites along the HIV-1/SIV phylogeny. The majority of rate shifts occurred at long branches, often corresponding to cross-species transmission branches. We noted that in most proteins, the number of rate accelerations and decelerations was equal, and we suggest that this reflects epistatic interactions among sites. However, several accessory proteins were enriched for either accelerations or decelerations, and we suggest that this may be a signature of adaptation to new hosts. Interestingly, the non-pandemic HIV-1 group O clade exhibited a substantially higher number of rate-shift events than the pandemic group M clade. We propose that this may be a reflection of the height of the species barrier between gorillas and humans versus chimpanzees and humans. Our results provide a genome-wide view of the constraints operating on proteins of HIV-1 and SIV.

Competition between social cheater viruses is driven by mechanistically different cheating strategies.

Cheater viruses, also known as defective interfering viruses, cannot replicate on their own yet replicate faster than the wild type upon coinfection. While there is growing interest in using cheaters as antiviral therapeutics, the mechanisms underlying cheating have been rarely explored. During experimental evolution of MS2 phage, we observed the parallel emergence of two independent cheater mutants. The first, a point deletion mutant, lacked polymerase activity but was advantageous in viral packaging. The second synonymous mutant cheater displayed a completely different cheating mechanism, involving an altered RNA structure. Continued evolution revealed the demise of the deletion cheater and rise of the synonymous cheater. A mathematical model inferred that while a single cheater is expected to reach an equilibrium with the wild type, cheater demise arises from antagonistic interactions between coinfecting cheaters. These findings highlight layers of parasitism: viruses parasitizing cells, cheaters parasitizing intact viruses, and cheaters may parasitize other cheaters.

Inferring population genetics parameters of evolving viruses using time-series data.

With the advent of deep sequencing techniques, it is now possible to track the evolution of viruses with ever-increasing detail. Here, we present Flexible Inference from Time-Series (FITS)-a computational tool that allows inference of one of three parameters: the fitness of a specific mutation, the mutation rate or the population size from genomic time-series sequencing data. FITS was designed first and foremost for analysis of either short-term Evolve & Resequence (E&R) experiments or rapidly recombining populations of viruses. We thoroughly explore the performance of FITS on simulated data and highlight its ability to infer the fitness/mutation rate/population size. We further show that FITS can infer meaningful information even when the input parameters are inexact. In particular, FITS is able to successfully categorize a mutation as advantageous or deleterious. We next apply FITS to empirical data from an E&R experiment on poliovirus where parameters were determined experimentally and demonstrate high accuracy in inference.