BACKGROUND: Sinonasal malignancies are a rare and heterogeneous group of tumors for which there is a paucity of robust data with which to guide management decisions. The authors used the National Cancer Data Base to better understand the presenting characteristics of these tumors and to compare outcomes by treatment modality. METHODS: The National Cancer Data Base was queried for sinonasal malignancies diagnosed between 2004 and 2012. Overall survival was assessed using multivariate analyses and propensity score matching. RESULTS: A total of 11,160 patients were identified for the initial analysis. The majority were male, aged 40 to 69 years, with tumors of the nasal cavity or maxillary sinus. Squamous cell histology was most common. The majority of patients presented with advanced tumor stage but without locoregional lymph node or distant metastases. Treatment modalities were compared for squamous cell carcinomas. In multivariate analysis, compared with surgery alone, patients who received adjuvant radiotherapy (hazard ratio [HR], 0.658 [P<.001]), adjuvant chemoradiotherapy (HR, 0.696 [P=.002]), or neoadjuvant therapy (HR, 0.656 [P = .007]) had improved overall survival. Patients who received radiotherapy alone (HR, 1.294 [P=.001]) or chemotherapy alone (HR, 1.834 [P<.001]) had worse outcomes. These findings were validated in propensity score matching. It is important to note that neoadjuvant chemoradiotherapy was associated with achieving a negative surgical margin (odds ratio, 2.641 [P=.045]). CONCLUSIONS: Surgery is the mainstay of therapy for patients with sinonasal malignancies, but multimodality therapy is associated with improved overall survival.

A key energy-saving adaptation to chronic hypoxia that enables cardiomyocytes to withstand severe ischemic insults is hibernation, i.e., a reversible arrest of contractile function. Whereas hibernating cardiomyocytes represent the critical reserve of dysfunctional cells that can be potentially rescued, a lack of a suitable animal model has hampered insights on this medically important condition. We developed a transgenic mouse system for conditional induction of long-term hibernation and a system to rescue hibernating cardiomyocytes at will. Via myocardium-specific induction (and, in turn, deinduction) of a VEGF-sequestering soluble receptor, we show that VEGF is indispensable for adjusting the coronary vasculature to match increased oxygen consumption and exploit this finding to generate a hypoperfused heart. Importantly, ensuing ischemia is tunable to a level at which large cohorts of cardiomyocytes are driven to enter a hibernation mode, without cardiac cell death. Relieving the VEGF blockade even months later resulted in rapid revascularization and full recovery of contractile function. Furthermore, we show that left ventricular remodeling associated with hibernation is also fully reversible. The unique opportunity to uncouple hibernation from other ischemic heart phenotypes (e.g., infarction) was used to determine the genetic program of hibernation; uncovering hypoxia-inducible factor target genes associated with metabolic adjustments and induced expression of several cardioprotective genes. Autophagy, specifically self-digestion of mitochondria, was identified as a key prosurvival mechanism in hibernating cardiomyocytes. This system may lend itself for examining the potential utility of treatments to rescue dysfunctional cardiomyocytes and reverse maladaptive remodeling.hypoxia ͉ ischemia ͉ remodeling ͉ VEGF ͉ heart

Nud1p, a protein homologous to the mammalian centrosome and midbody component Centriolin, is a component of the budding yeast spindle pole body (SPB), with roles in anchorage of microtubules and regulation of the mitotic exit network during vegetative growth. Here we analyze the function of Nud1p during yeast meiosis. We find that a nud1-2 temperature-sensitive mutant has two meiosis-related defects that reflect genetically distinct functions of Nud1p. First, the mutation affects spore formation due to its late function during spore maturation. Second, and most important, the mutant loses its ability to distinguish between the ages of the four spindle pole bodies, which normally determine which SPB would be preferentially included in the mature spores. This affects the regulation of genome inheritance in starved meiotic cells and leads to the formation of random dyads instead of non-sister dyads under these conditions. Both functions of Nud1p are connected to the ability of Spc72p to bind to the outer plaque and half-bridge (via Kar1p) of the SPB.

Rationale Necrotizing pneumonia is characterized by destruction and liquefaction of the lung tissue and loss of the normal pulmonary parenchymal architecture. During the course of resolution areas of hyperlucency are formed, sometimes with the development of giant lung cysts that can be a field with fluid resembling lung abscess. There is no consensus on the management of these abnormalities. Objective To assess the prevalence of giant lung cysts as a complication of necrotizing pneumonia and to report our experience with conservative treatment that achieved complete resolution. Methods Medical chart reviews of all children aged 0 to 18 years hospitalized with necrotizing pneumonia in a single tertiary center from 2015 to 2017, demographic data, and clinical course during and after hospitalization as well as serial chest imaging were collected. Results During the study period, 761 children were diagnosed with community‐acquired pneumonia, 16 of 761 (2.3%) had necrotizing pneumonia and 6 of 16 (37.5%) with necrotizing pneumonia complicated by a giant lung cyst or lung abscess. All were closely observed and showed complete clinical and radiographic resolution with antibiotic treatment. Conclusions Treatment of giant lung cyst formation following necrotizing pneumonia by a conservative approach with prolonged antibiotics results in complete recovery with no need for invasive procedures.

Molecular imaging is an emerging technology that enables the noninvasive visualization, characterization, and quantification of molecular events within living subjects. Positron emission tomography (PET) is a clinically available molecular imaging tool with significant potential to study pathogenesis of infections in humans.

Streptococcus pneumoniae rapidly kills Staphylococcus aureus by producing membrane-permeable hydrogen peroxide (H2O2). The mechanism by which S. pneumoniae-produced H2O2 mediates S. aureus killing was investigated. An in vitro model that mimicked S. pneumoniae-S. aureus contact during colonization of the nasopharynx demonstrated that S. aureus killing required outcompeting densities of S. pneumoniae. Compared to the wild-type strain, isogenic S. pneumoniae ΔlctO and S. pneumoniae ΔspxB, both deficient in production of H2O2, required increased density to kill S. aureus. While residual H2O2 activity produced by single mutants was sufficient to eradicate S. aureus, an S. pneumoniae ΔspxB ΔlctO double mutant was unable to kill S. aureus. A collection of 20 diverse methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) strains showed linear sensitivity (R2 = 0.95) for S. pneumoniae killing, but the same strains had different susceptibilities when challenged with pure H2O2 (5 mM). There was no association between the S. aureus clonal complex and sensitivity to either S. pneumoniae or H2O2. To kill S. aureus, S. pneumoniae produced ∼180 μM H2O2 within 4 h of incubation, while the killing-defective S. pneumoniae ΔspxB and S. pneumoniae ΔspxB ΔlctO mutants produced undetectable levels. Remarkably, a sublethal dose (1 mM) of pure H2O2 incubated with S. pneumoniae ΔspxB eradicated diverse S. aureus strains, suggesting that S. pneumoniae bacteria may facilitate conversion of H2O2 to a hydroxyl radical (·OH). Accordingly, S. aureus killing was completely blocked by incubation with scavengers of ·OH radicals, dimethyl sulfoxide (Me2SO), thiourea, or sodium salicylate. The ·OH was detected in S. pneumoniae cells by spin trapping and electron paramagnetic resonance. Therefore, S. pneumoniae produces H2O2, which is rapidly converted to a more potent oxidant, hydroxyl radicals, to rapidly intoxicate S. aureus strains. IMPORTANCE Streptococcus pneumoniae strains produce hydrogen peroxide (H2O2) to kill bacteria in the upper airways, including pathogenic Staphylococcus aureus strains. The targets of S. pneumoniae-produced H2O2 have not been discovered, in part because of a lack of knowledge about the underlying molecular mechanism. We demonstrated that an increased density of S. pneumoniae kills S. aureus by means of H2O2 produced by two enzymes, SpxB and LctO. We discovered that SpxB/LctO-produced H2O2 is converted into a hydroxyl radical (·OH) that rapidly intoxicates and kills S. aureus. We successfully inhibited the toxicity of ·OH with three different scavengers and detected ·OH in the supernatant. The target(s) of the hydroxyl radicals represents a new alternative for the development of antimicrobials against S. aureus infections.

Background Multisystem Inflammatory Syndrome in Children (MIS-C) is a severe clinical phenotype of SARS-CoV-2 infection that remains poorly understood. Methods Hospitalized children &lt;18 years of age with suspected COVID-19 (N=53) were recruited into a prospective cohort study; 32 had confirmed COVID-19, with 16 meeting the U.S. Centers for Disease Control criteria for MIS-C. Differences in nasopharyngeal viral RNA levels, SARS-CoV-2 seropositivity, and cytokine/chemokine profiles were examined, including after adjustments for age and sex. Results The median ages for those with and without MIS-C were 8.7 years (IQR 5.5-13.9) and 2.2 years (IQR 1.1-10.5), respectively, (p=0.18) and nasopharyngeal levels of SARS-CoV-2 RNA did not differ significantly between the two groups (median 63,848.25 copies/mL versus 307.1 copies/mL, p= 0.66); 75% of those with MIS-C were antibody positive compared to 44% without, p=0.026. Levels of 14 of 37 cytokines/chemokines (IL-1RA, IL-2RA, IL-6, IL-8, TNF-α, IL-10, IL-15, IL-18, MCP-1, IP-10, MIP-1α, MCP-2, MIP-1β, Eotaxin) were significantly higher in children with MIS-C compared to those without, irrespective of age or sex (FDR&lt;0.05; p&lt;0.05). Conclusions The distinct pattern of heightened cytokine/chemokine dysregulation observed with MIS-C, compared with acute COVID-19, occurs across the pediatric age spectrum and with similar levels of nasopharyngeal SARS-CoV-2 RNA.

Background: Mycoplasma pneumoniae (MP) is a major cause of community-acquired upper and lower respiratory infections in school-age children; however, there is increasing recognition that younger children are also affected. Clinical manifestations vary from asymptomatic, to severe complicated pneumonia sometimes with extrapulmonary manifestations. Methods: We reviewed the medical records of all MP positive pediatric patients admitted to the Hadassah-Hebrew University Medical Center. MP positive case was defined if MP polymerase chain reaction was positive from an oropharyngeal swab sent from 2007 to 2017. Results: During the study period, we identified 353 MP positive pediatric cases, of which 51.3% (181 of 353) were younger than 6 years old. Full clinical data were available for 332 of 353 (94%). The median age was 5.7 years (range, 3 weeks to 18 years). Disease presentation differed between younger and older children. Children older than 6 years were more likely to have chest radiograph confirmed pneumonia (66% vs. 52%; P = 0.009), while younger children were more likely to have other respiratory manifestations (37% vs. 25%; P = 0.017). The duration of hospitalization and pediatric intensive care unit admission rate, however, did not differ between age groups. The rate of extrapulmonary manifestations were also similar. Conclusions: MP-associated infection is a significant cause of hospitalization in the pediatric population including younger children (<6 years old). However, the clinical presentation in younger age is less typical than is thought. These findings should prompt clinicians to consider MP infections also in children younger than 6 admitted with fever even without pneumonia.