Parenteral and oral antibiotic duration for treatment of pediatric osteomyelitis: a systematic review protocol

BACKGROUND: Pediatric osteomyelitis is a bacterial infection of bones requiring prolonged antibiotic treatment using parenteral followed by enteral agents. Major complications of pediatric osteomyelitis include transition to chronic osteomyelitis, formation of subperiosteal abscesses, extension of infection into the joint, and permanent bony deformity or limb shortening. Historically, osteomyelitis has been treated with long durations of antibiotics to avoid these complications. However, with improvements in management and antibiotic treatment, standard of care is moving towards short durations of intravenous antibiotics prior to enteral antibiotics. METHODS/DESIGN: The authors will perform a systematic review based on PRISMA guidelines in order to evaluate the literature, looking for evidence to support the optimal duration of parenteral and enteral therapy. The main goals are to see if literature supports shorter durations of either parenteral antibiotics and/or enteral antibiotics. Multiple databases will be investigated using a thorough search strategy. Databases include Medline, Cochrane, EMBASE, SCOPUS, Dissertation Abstracts, CINAHL, Web of Science, African Index Medicus and LILACS. Search stream will include medical subject heading for pediatric patients with osteomyelitis and antibiotic therapy. We will search for published or unpublished randomized and quasi-randomized controlled trials. Two authors will independently select articles, extract data and assess risk of bias by standard Cochrane methodologies. We will analyze comparisons between dichotomous outcomes using risk ratios and continuous outcomes using mean differences. 95% confidence intervals will be computed. DISCUSSION: One of the major dilemmas of management of this disease is the duration of parenteral therapy. Long parenteral therapy has increased risk of serious complications and the necessity for long therapy has been called into question. Our study aims to review the currently available evidence from randomized trials regarding duration of both parenteral and oral therapy for pediatric acute osteomyelitis. TRIAL REGISTRATION: CRD4201300232

Growth Faltering and Developmental Delay in HIV-Exposed Uninfected Ugandan Infants: A Prospective Cohort Study

BACKGROUND: HIV-exposed but uninfected (HEU) infants are at increased risk of impaired early linear growth and cognitive development. We examined associations between prenatal and postnatal growth and subsequent neurodevelopment in Ugandan HEU infants, hypothesizing that early insults may explain alterations in both somatic growth and brain development. METHODS: We prospectively followed a cohort of HEU infants from birth to 18 months of age, and measured length/height, weight, head, and arm circumference longitudinally. The Malawi Development Assessment Tool (MDAT, 12 and 18 months) and the Color Object Association Test (18 months) were used for developmental assessments. RESULTS: Among 170 HEU infants, the prevalence of low-birth weight and failure to thrive was 7.6% and 37%, respectively. HEU infants had MDAT scores that were similar to the reference population. The mean (SD) score on the Color Object Association Test was 5.5 (3.1) compared with 6.9 (5.3) in developmentally normal children. Developmental ability at age 18 months showed strong cross-sectional correlation with weight-for-age (ρ = 0.36, P < 0.0001), length/height-for-age (ρ = 0.41, P < 0.0001), head circumference-for-age (ρ = 0.26, P = 0.0011), and mid-upper arm circumference-for-age (ρ = 0.34, P = 0.0014). There was a statistically significant correlation between birth weight and MDAT z-score at 18 months (ρ = 0.20, P = 0.010). Failure to thrive was associated with lower MDAT z-score [median -0.13 (IQR -0.75 to +0.14) versus +0.14 (IQR -0.44 to +0.63), P = 0.042]. CONCLUSION: Growth faltering in HEU infants was associated with lower attainment of developmental milestones at age 18 months. Our findings point to a simple screening method for identifying HEU infants at risk for developmental intervention

Pediatric malignancies presenting as a possible infectious disease

<p>Abstract</p> <p>Background</p> <p>The clinical, laboratory, and radiological features of malignancy can overlap with those of infection. The purpose of this study was to determine the findings in children who were initially thought to have an infectious disease but ultimately proved to have a malignancy.</p> <p>Methods</p> <p>The database of patients diagnosed with a malignancy in the Northern Alberta Children's Cancer Program (NACCP) January 1, 1993 to December 31, 2003 was merged with the database of inpatients referred to the infectious diseases service at the Stollery Children's Hospital and charts were reviewed on all patients referred to the infectious diseases consult service prior to the diagnosis of malignancy.</p> <p>Results</p> <p>An infectious diseases consultation for diagnosis was requested in 21 of 561 patients prior to the confirmation of malignancy, and 3 of these 21 patients had both infection and malignancy (leukemia (N = 13), lymphoma (N = 3), rhabdomyosarcoma (N = 1), Langerhan's cell histiocytosis (N = 1), fibrous histicocytosis (N = 1), ependymoma (N = 1), and neuroblastoma (N = 1). The most common reason for infectious diseases consultation was suspected muskuloskeletal infection (N = 9). A palpable or radiographically enlarged spleen was noted in 11 patients (52%). All but 2 patients had abnormal hematologic parameters while an elevated lactate dehydrogenase (LDH) occurred in 10 patients (48%). Delay of diagnosis because of investigation or therapy for an infectious disease occurred in only 2 patients.</p> <p>Conclusion</p> <p>It is not common for treatment of pediatric malignancies to be delayed because infection is thought to be the primary diagnosis. However, pediatric infectious diseases physicians should consider malignancy in the differential diagnosis when they see patients with fever and bone pain, unexplained splenomegaly or abnormal complete blood cell counts. Other clues may include hepatomegaly or elevated LDH.</p

Paediatric Investigators Collaborative Network on Infections in Canada (PICNIC) study of aseptic meningitis

BACKGROUND: The seasonality, clinical and radiographic features and outcome of aseptic meningitis have been described for regional outbreaks but data from a wider geographic area is necessary to delineate the epidemiology of this condition. METHODS: A retrospective chart review was completed of children presenting with aseptic meningitis to eight Canadian pediatric hospitals over a two-year period. RESULTS: There were 233 cases of proven enteroviral (EV) meningitis, 495 cases of clinical aseptic meningitis and 74 cases of possible aseptic meningitis with most cases occurring July to October. Headache, vomiting, meningismus and photophobia were more common in children ≥ 5 years of age, while rash, diarrhea and cough were more common in children < 5 years of age. Pleocytosis was absent in 22.3% of children < 30 days of age with proven EV meningitis. Enterovirus was isolated in cerebrospinal fluid (CSF) from 154 of 389 patients (39.6%) who had viral culture performed, and a nucleic acid amplification test for enterovirus was positive in CSF from 81 of 149 patients (54.3%). Imaging of the head by computerized tomography or magnetic resonance imaging was completed in 96 cases (19.7%) and 24 had abnormal findings that were possibly related to meningitis while none had changes that were definitely related to meningitis. There was minimal morbidity and there were no deaths. CONCLUSION: The clinical presentation of aseptic meningitis varies with the age of the child. Absence of CSF pleocytosis is common in infants < 30 days of age. Enterovirus is the predominant isolate, but no etiologic agent is identified in the majority of cases of aseptic meningitis in Canadian children

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Integrated Genomic Analysis of the Ubiquitin Pathway across Cancer Types

Protein ubiquitination is a dynamic and reversibleprocess of adding single ubiquitin molecules orvarious ubiquitin chains to target proteins. Here,using multidimensional omic data of 9,125 tumorsamples across 33 cancer types from The CancerGenome Atlas, we perform comprehensive molecu-lar characterization of 929 ubiquitin-related genesand 95 deubiquitinase genes. Among them, we sys-tematically identify top somatic driver candidates,including mutatedFBXW7with cancer-type-specificpatterns and amplifiedMDM2showing a mutuallyexclusive pattern withBRAFmutations. Ubiquitinpathway genes tend to be upregulated in cancermediated by diverse mechanisms. By integratingpan-cancer multiomic data, we identify a group oftumor samples that exhibit worse prognosis. Thesesamples are consistently associated with the upre-gulation of cell-cycle and DNA repair pathways, char-acterized by mutatedTP53,MYC/TERTamplifica-tion, andAPC/PTENdeletion. Our analysishighlights the importance of the ubiquitin pathwayin cancer development and lays a foundation fordeveloping relevant therapeutic strategies