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Wilms' tumor--lessons and outcomes--a 25-year single center UK experience.
Wilms' tumor (WT) is a common childhood renal cancer. A 25-year single center UK experience is reported. During 1985-2010, 97 children underwent immediate nephrectomy or delayed resection of tumor after chemotherapy. Survival, morbidity, and late effects following treatment are described. Tumor distribution was: Stage I, 25.7% (n = 25); Stage II, 24.7% (n = 24); Stage III, 26.8% (n = 26); Stage IV, 17.5% (n = 17); and Stage V, 5.2% (n = 5). Immediate nephrectomy was performed in 39% (n = 38) patients with elective delayed resection in 61% (n = 59) cases. Ten patients had cavotomy to excise tumor involving vena cava territory. Two cases required cardiopulmonary bypass. Tumor rupture was recorded in eight (8.5%) total operated cases-after immediate (n = 5/37), 13.5% vs delayed nephrectomy-(n = 3/57), 5.2%; X(2) P = .154. From 2001 onwards, one case of tumor rupture was recorded at this center after the universal adoption of UKW3 and SIOP guidelines advocating preoperative chemotherapy and delayed nephrectomy for all WT. Three treatment-related deaths occurred-hepatic veno-occlusive disease (n = 2) with actinomycin D and a single WT fatality due to vascular injury. Overall survival was 84.5% (82/97 cases). Two patients developed "late malignancies" -thyroid cancer and a basal cell carcinoma. This study demonstrates excellent survival for WT comparable with national outcomes and international cooperative studies. Adverse events with chemotherapy and surgery, including "late onset," second malignancies deserve special consideration.
The impact of the H1N1 influenza pandemic on clinical presentations and viral epidemiology of acute respiratory infection in preschool children in Brazil.
We assessed the impact of the H1N1 influenza pandemic on acute respiratory infection in young children from low-income families in Brazil. Influenza (specifically H1N1) detection in acute respiratory infection quintupled during the pandemic and, during its peak, it was associated with 30% of all acute respiratory infection visits to the emergency department. H1N1 was also associated with increased risk of hospitalization and coinfection.
Malrotation: Age-Related Differences in Reoperation Rate.
OBJECTIVE: Intestinal malrotation classically presents in the neonatal period with bilious vomiting. However, population studies suggest that up to two-thirds of these patients are diagnosed later in childhood or in adulthood. Increased morbidity in the adult population has been reported. Local experience suggested that surgery was technically more difficult in older children and led to the hypothesis that it would be associated with increased morbidity. METHODS: A retrospective case note analysis was performed on all children presenting with intestinal malrotation to a tertiary referral center between January 2002 and November 2014. Case notes and operation records were reviewed and those who underwent laparotomy for confirmed malrotation were included. Children were grouped as infants (< 1 year) and older (> 1 year). The primary outcome was total emergency reoperation rate. Secondary outcomes were requirement for a bypass at reoperation and mortality. RESULTS: A total of 131 children with malrotation were identified (104 infants, 27 older children; 78 males; age range, 0-16 years). Overall, 13 patients had emergency reoperation following initial Ladd procedure (6 infants and 7 older children). Risk for reoperation was significantly higher in older children (p = 0.005) and additionally a bypass procedure was more often required in older children than infants (4 children, 2 infants, p = 0.016). Adhesiolysis was required on four occasions and redo Ladd procedure in two; these were evenly distributed between both groups. One child was found to have distal bowel obstruction at reoperation. There were three deaths (2.3%), all in the infant group. One was directly associated with malrotation with extensive bowel necrosis. The other two died of unrelated sepsis several months later. CONCLUSIONS: Malrotation surgery in older children is associated with a significantly higher emergency reoperation rate. The primary duodenal bypass procedure should always be considered with longstanding chronic intermittent obstruction associated with malrotation if the simple Ladd procedure is deemed inadequate.
Rhinovirus-C detection in children presenting with acute respiratory infection to hospital in Brazil.
Human rhinovirus (RV) is a common cause of acute respiratory infection (ARI) in children. We aimed to characterize the clinical and demographic features associated with different RV species detected in children attending hospital with ARI, from low-income families in North-east Brazil. Nasopharyngeal aspirates were collected from 630 children <5 years with ARI. Clinical diagnosis and disease severity were also recorded. Samples were analyzed by multiplex PCR for 18 viral and atypical bacterial pathogens; RV positive samples underwent partial sequencing to determine species and type. RV was the fourth commonest pathogen accounting for 18.7% of pathogens detected. RV was commonly detected in children with bronchiolitis, pneumonia, and asthma/episodic viral wheeze (EVW). Species and type were assigned in 112 cases (73% RV-A; 27% RV-C; 0% RV-B). Generally, there were no differences in clinical or demographic characteristics between those infected with RV-A and RV-C. However, in children with asthma/EVW, RV-C was detected relatively more frequently than RV-A (23% vs. 5%; P = 0.04). Our findings highlight RV as a potentially important pathogen in this setting. Generally, clinical and demographic features were similar in children in whom RV-A and C species were detected. However, RV-C was more frequently found in children with asthma/EVW than RV-A.
Emergency abdominal wall defects in neonates: saved by distress.
This report presents two cases of neonatal patients with abdominal wall defects requiring emergency intervention, a closing gastroschisis and a pedunculated exomphalos with eviscerated liver. Both presented as pre-partum fetal distress and were delivered in a tertiary centre, where they received antenatal care. Coordination in the multidisciplinary team and prompt surgical intervention prevented loss of the eviscerated abdominal contents and prevented mortality in both cases.
Identifying cross-disease components of genetic risk across hospital data in the UK Biobank.
Genetic risk factors frequently affect multiple common human diseases, providing insight into shared pathophysiological pathways and opportunities for therapeutic development. However, systematic identification of genetic profiles of disease risk is limited by the availability of both comprehensive clinical data on population-scale cohorts and the lack of suitable statistical methodology that can handle the scale of and differential power inherent in multi-phenotype data. Here, we develop a disease-agnostic approach to cluster the genetic risk profiles for 3,025 genome-wide independent loci across 19,155 disease classification codes from 320,644 participants in the UK Biobank, representing a large and heterogeneous population. We identify 339 distinct disease association profiles and use multiple approaches to link clusters to the underlying biological pathways. We show how clusters can decompose the variance and covariance in risk for disease, thereby identifying underlying biological processes and their impact. We demonstrate the use of clusters in defining disease relationships and their potential in informing therapeutic strategies.
Distinct determinants of human immunodeficiency virus type 1 RNA and DNA loads in vaginal and cervical secretions.
The relationship between human immunodeficiency virus type 1 (HIV-1) viral RNA and proviral DNA load in vagina and cervix and that found in the plasma and peripheral blood mononuclear cells (PBMC) was investigated in 28 HIV-1-infected women. Of the patients, 64% had > or = 1 HIV-1 RNA-positive genital sample, while 71% had > or = 1 DNA-positive sample. The higher the cervical HIV load, the more widespread was the virus in the genital tract. A strong correlation was found between viral RNA load in plasma and the genital tract, whereas the association between proviral DNA load in PBMC and the genital tract was less evident. Cervical HIV-1 DNA correlated with a viral RNA load > or = 50,000 copies/mL. Cervical HIV-1 RNA levels ranged from 10% to 100% of the plasma levels. Thus, a continuous transmission risk from untraumatized genital epithelium exists in the majority of HIV-1-infected women at all stages of infection.
HIV-1 Adaptation to Antigen Processing Results in Population-Level Immune Evasion and Affects Subtype Diversification
The recent HIV-1 vaccine failures highlight the need to better understand virus-host interactions. One key question is why CD8+ Tcell responses to two HIV-Gag regions are uniquely associated with delayed disease progression only in patients expressing a few rare HLA class I variants when these regions encode epitopes presented by ~30 more common HLA variants. By combining epitope processing and computational analyses of the two HIV subtypes responsible for ~60% of worldwide infections, we identified a hitherto unrecognized adaptation to the antigen-processing machinery through substitutions at subtype-specific motifs. Multiple HLA variants presenting epitopes situated next to a given subtype-specific motif drive selection at this subtype-specific position, and epitope abundances correlate inversely with the HLA frequency distribution in affected populations. This adaptation reflects the sum of intrapatient adaptations, is predictable, facilitates viral subtype diversification, and increases global HIV diversity. Because low epitope abundance is associated with infrequent and weak Tcell responses, this most likely results inboth population-level immune evasion and inadequate responses in most people vaccinated with natural HIV-1 sequence constructs. Our results suggest that artificial sequence modifications at subtype-specific positions invitro could refocus and reverse the poor immunogenicity of HIV proteins. © 2014 The Authors.
HIV-1 adaptation to antigen processing results in population-level immune evasion and affects subtype diversification.
The recent HIV-1 vaccine failures highlight the need to better understand virus-host interactions. One key question is why CD8(+) T cell responses to two HIV-Gag regions are uniquely associated with delayed disease progression only in patients expressing a few rare HLA class I variants when these regions encode epitopes presented by ~30 more common HLA variants. By combining epitope processing and computational analyses of the two HIV subtypes responsible for ~60% of worldwide infections, we identified a hitherto unrecognized adaptation to the antigen-processing machinery through substitutions at subtype-specific motifs. Multiple HLA variants presenting epitopes situated next to a given subtype-specific motif drive selection at this subtype-specific position, and epitope abundances correlate inversely with the HLA frequency distribution in affected populations. This adaptation reflects the sum of intrapatient adaptations, is predictable, facilitates viral subtype diversification, and increases global HIV diversity. Because low epitope abundance is associated with infrequent and weak T cell responses, this most likely results in both population-level immune evasion and inadequate responses in most people vaccinated with natural HIV-1 sequence constructs. Our results suggest that artificial sequence modifications at subtype-specific positions in vitro could refocus and reverse the poor immunogenicity of HIV proteins.
Presence of multiple HIV subtypes and a high frequency of subtype chimeric viruses in heterosexually infected women.
The HIV-1 subtype distribution was determined in 41 HIV-positive women (-8% of all HIV-infected women in Denmark) belonging to different risk groups. HIV p17 gag and env gene subtypes were determined by DNA sequence analysis. Five different HIV subtypes were detected across all patients. Most HIV-1-positive women of Danish origin carried subtype B viruses, and a minority had virus belonging to subtypes A or C. All injecting drug users (IDUs) were infected with HIV subtype B viruses, whereas all non-B subtypes were present in cases linked to heterosexual transmission. In contrast, all women of African origin carried non-B HIV subtypes (subtypes A, C, D, or G) regardless of transmission mode. Of these women, 21% infected with non-B HIV subtypes appeared to be infected by subtype chimeric viruses and 7% were jointly infected with viruses belonging to two different subtypes (A and C). Data demonstrate a preferential representation of non-B HIV subtypes in women infected through heterosexual contact, as well as a high degree of recombination between viruses derived from endemic areas in which several HIV subtypes predominate. Combined with the increased incidence of heterosexual transmission of HIV, the results imply that an increased subtype diversity can be anticipated in newly infected individuals.
The Drosophila homologue of MEGF8 is essential for early development.
Mutations of the gene MEGF8 cause Carpenter syndrome in humans, and the mouse orthologue has been functionally associated with Nodal and Bmp4 signalling. Here, we have investigated the phenotype associated with loss-of-function of CG7466, a gene that encodes the Drosophila homologue of MEGF8. We generated three different frame-shift null mutations in CG7466 using CRISPR/Cas9 gene editing. Heterozygous flies appeared normal, but homozygous animals had disorganised denticle belts and died as 2nd or 3rd instar larvae. Larvae were delayed in transition to 3rd instars and showed arrested growth, which was associated with abnormal feeding behaviour and prolonged survival when yeast food was supplemented with sucrose. RNAi-mediated knockdown using the Gal4-UAS system resulted in lethality with ubiquitous and tissue-specific Gal4 drivers, and growth defects including abnormal bristle number and orientation in a subset of escapers. We conclude that CG7466 is essential for larval development and that diminished function perturbs denticle and bristle formation.
Bayesian analysis of genetic association across tree-structured routine healthcare data in the UK Biobank.
Genetic discovery from the multitude of phenotypes extractable from routine healthcare data can transform understanding of the human phenome and accelerate progress toward precision medicine. However, a critical question when analyzing high-dimensional and heterogeneous data is how best to interrogate increasingly specific subphenotypes while retaining statistical power to detect genetic associations. Here we develop and employ a new Bayesian analysis framework that exploits the hierarchical structure of diagnosis classifications to analyze genetic variants against UK Biobank disease phenotypes derived from self-reporting and hospital episode statistics. Our method displays a more than 20% increase in power to detect genetic effects over other approaches and identifies new associations between classical human leukocyte antigen (HLA) alleles and common immune-mediated diseases (IMDs). By applying the approach to genetic risk scores (GRSs), we show the extent of genetic sharing among IMDs and expose differences in disease perception or diagnosis with potential clinical implications.
A plasmid-encoded peptide from Staphylococcus aureus induces anti-myeloperoxidase nephritogenic autoimmunity.
Autoreactivity to myeloperoxidase (MPO) causes anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), with rapidly progressive glomerulonephritis. Here, we show that a Staphylococcus aureus peptide, homologous to an immunodominant MPO T-cell epitope (MPO409-428), can induce anti-MPO autoimmunity. The peptide (6PGD391-410) is part of a plasmid-encoded 6-phosphogluconate dehydrogenase found in some S. aureus strains. It induces anti-MPO T-cell autoimmunity and MPO-ANCA in mice, whereas related sequences do not. Mice immunized with 6PGD391-410, or with S. aureus containing a plasmid expressing 6PGD391-410, develop glomerulonephritis when MPO is deposited in glomeruli. The peptide induces anti-MPO autoreactivity in the context of three MHC class II allomorphs. Furthermore, we show that 6PGD391-410 is immunogenic in humans, as healthy human and AAV patient sera contain anti-6PGD and anti-6PGD391-410 antibodies. Therefore, our results support the idea that bacterial plasmids might have a function in autoimmune disease.
Assessing similarity to primary tissue and cortical layer identity in induced pluripotent stem cell-derived cortical neurons through single-cell transcriptomics.
Induced pluripotent stem cell (iPSC)-derived cortical neurons potentially present a powerful new model to understand corticogenesis and neurological disease. Previous work has established that differentiation protocols can produce cortical neurons, but little has been done to characterize these at cellular resolution. In particular, it is unclear to what extent in vitro two-dimensional, relatively disordered culture conditions recapitulate the development of in vivo cortical layer identity. Single-cell multiplex reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) was used to interrogate the expression of genes previously implicated in cortical layer or phenotypic identity in individual cells. Totally, 93.6% of single cells derived from iPSCs expressed genes indicative of neuronal identity. High proportions of single neurons derived from iPSCs expressed glutamatergic receptors and synaptic genes. And, 68.4% of iPSC-derived neurons expressing at least one layer marker could be assigned to a laminar identity using canonical cortical layer marker genes. We compared single-cell RNA-seq of our iPSC-derived neurons to available single-cell RNA-seq data from human fetal and adult brain and found that iPSC-derived cortical neurons closely resembled primary fetal brain cells. Unexpectedly, a subpopulation of iPSC-derived neurons co-expressed canonical fetal deep and upper cortical layer markers. However, this appeared to be concordant with data from primary cells. Our results therefore provide reassurance that iPSC-derived cortical neurons are highly similar to primary cortical neurons at the level of single cells but suggest that current layer markers, although effective, may not be able to disambiguate cortical layer identity in all cells.
Systematic classification of shared components of genetic risk for common human diseases
Disease classification is fundamental to clinical practice, but current taxonomies do not necessarily reflect the pathophysiological processes that are common or unique to different disorders, such as those determined by genetic risk factors. Here, we use routine healthcare data from the 500,000 participants in the UK Biobank to map genome-wide associations across 19,628 diagnostic terms. We find that 3,510 independent genetic risk loci affect multiple clinical phenotypes, which we cluster into 629 distinct disease association profiles. We use multiple approaches to link clusters to different underlying biological pathways and show how these clusters define the genetic architecture of common medical conditions, including hypertension and immune-mediated diseases. Finally, we demonstrate how clusters can be utilised to re-define disease relationships and to inform therapeutic strategies. One sentence summary Systematic classification of genetic risk factors reveals molecular connectivity of human diseases with clinical implications
HLA variation and disease.
Fifty years since the first description of an association between HLA and human disease, HLA molecules have proven to be central to physiology, protective immunity and deleterious, disease-causing autoimmune reactivity. Technological advances have enabled pivotal progress in the determination of the molecular mechanisms that underpin the association between HLA genetics and functional outcome. Here, we review our current understanding of HLA molecules as the fundamental platform for immune surveillance and responsiveness in health and disease. We evaluate the scope for personalized antigen-specific disease prevention, whereby harnessing HLA-ligand interactions for clinical benefit is becoming a realistic prospect.