Effectiveness of influenza vaccine in children in preventing influenza associated hospitalisation, 2018/19, England.

2013/14 saw the start of the introduction of a new live attenuated influenza vaccine (LAIV) programme for children in England. 2018/19 saw co-circulation of both A(H1N1)pdm09 and A(H3N2), when LAIV was offered to all healthy children 2-9 years of age. LAIV effectiveness against influenza hospitalisation is not well described. This paper presents the 2018/19 end-of-season adjusted vaccine effectiveness (aVE) against laboratory confirmed influenza related hospitalisation in children aged 2-17. The test negative case control approach was used to estimate aVE by influenza A subtype and vaccine type. Cases and controls were selected from a sentinel laboratory surveillance system which collates details of individuals tested for influenza with reverse-transcription polymerase chain reaction (RT-PCR) on respiratory samples. Vaccine and clinical history was obtained from general practitioners of study participants. There were 307 hospitalised cases and 679 hospitalised controls. End-of-season influenza aVE was 53.0% (95% CI: 33.3, 66.8) against influenza confirmed hospitalisation; 63.5% (95% CI: 34.4, 79.7) against influenza A(H1N1)pdm09 hospitalisation and 31.1% (95% CI: -53.9, 69.2) against influenza A(H3N2). LAIV aVE was 49.1% (95% CI: 25.9, 65.0) for any influenza and 70.7% (95% CI: 41.8, 85.3) for A(H1N1)pdm09, whereas for those receiving quadrivalent inactivated influenza vaccine (QIV), aVE was 64.4% (95% CI: 29.4, 82.0) and 44.4% (95% CI: -51.9, 79.6) respectively. We provide evidence of overall significant VE for both LAIV and QIV against influenza associated hospitalisation in children 2-17 years of age, most notably against influenza A(H1N1)pdm09, with non-significant protection against A(H3N2).

Integration of copy number and transcriptomics provides risk stratification in prostate cancer: A discovery and validation cohort study.

BACKGROUND: Understanding the heterogeneous genotypes and phenotypes of prostate cancer is fundamental to improving the way we treat this disease. As yet, there are no validated descriptions of prostate cancer subgroups derived from integrated genomics linked with clinical outcome. METHODS: In a study of 482 tumour, benign and germline samples from 259 men with primary prostate cancer, we used integrative analysis of copy number alterations (CNA) and array transcriptomics to identify genomic loci that affect expression levels of mRNA in an expression quantitative trait loci (eQTL) approach, to stratify patients into subgroups that we then associated with future clinical behaviour, and compared with either CNA or transcriptomics alone. FINDINGS: We identified five separate patient subgroups with distinct genomic alterations and expression profiles based on 100 discriminating genes in our separate discovery and validation sets of 125 and 103 men. These subgroups were able to consistently predict biochemical relapse (p = 0.0017 and p = 0.016 respectively) and were further validated in a third cohort with long-term follow-up (p = 0.027). We show the relative contributions of gene expression and copy number data on phenotype, and demonstrate the improved power gained from integrative analyses. We confirm alterations in six genes previously associated with prostate cancer (MAP3K7, MELK, RCBTB2, ELAC2, TPD52, ZBTB4), and also identify 94 genes not previously linked to prostate cancer progression that would not have been detected using either transcript or copy number data alone. We confirm a number of previously published molecular changes associated with high risk disease, including MYC amplification, and NKX3-1, RB1 and PTEN deletions, as well as over-expression of PCA3 and AMACR, and loss of MSMB in tumour tissue. A subset of the 100 genes outperforms established clinical predictors of poor prognosis (PSA, Gleason score), as well as previously published gene signatures (p = 0.0001). We further show how our molecular profiles can be used for the early detection of aggressive cases in a clinical setting, and inform treatment decisions. INTERPRETATION: For the first time in prostate cancer this study demonstrates the importance of integrated genomic analyses incorporating both benign and tumour tissue data in identifying molecular alterations leading to the generation of robust gene sets that are predictive of clinical outcome in independent patient cohorts.

N-acetyl-L-aspartyl-L-glutamate peptidase-like 2 is overexpressed in cancer and promotes a pro-migratory and pro-metastatic phenotype.

N-acetyl-L-aspartyl-L-glutamate peptidase-like 2 (NAALADL2) is a member of the glutamate carboxypeptidase II family, best characterized by prostate-specific membrane antigen (PSMA/NAALAD1). Using immunohistochemistry (IHC), we have shown overexpression of NAALADL2 in colon and prostate tumours when compared with benign tissue. In prostate cancer, NAALADL2 expression was associated with stage and Grade, as well as circulating mRNA levels of the NAALADL2 gene. Overexpression of NAALADL2 was shown to predict poor survival following radical prostatectomy. In contrast to PSMA/NAALAD1, NAALADL2 was localized at the basal cell surface where it promotes adhesion to extracellular matrix proteins. Using stable knockdown and overexpression cell lines, we have demonstrated NAALADL2-dependent changes in cell migration, invasion and colony-forming potential. Expression arrays of the knockdown and overexpression cell lines have identified nine genes that co-expressed with NAALADL2, which included membrane proteins and genes known to be androgen regulated, including the prostate cancer biomarkers AGR2 and SPON2. Androgen regulation was confirmed in a number of these genes, although NAALADL2 itself was not found to be androgen regulated. NAALADL2 was also found to regulate levels of Ser133 phosphorylated C-AMP-binding protein (CREB), a master regulator of a number of cellular processes involved in cancer development and progression. In combination, these data suggest that changes in expression of NAALADL2 can impact upon a number of pro-oncogenic pathways and processes, making it a useful biomarker for both diagnosis and prognosis.

Peroxiredoxin-3 is overexpressed in prostate cancer and promotes cancer cell survival by protecting cells from oxidative stress.

OBJECTIVE: We have previously identified peroxiredoxin-3 (PRDX-3) as a cell-surface protein that is androgen regulated in the LNCaP prostate cancer (PCa) cell line. PRDX-3 is a member of the peroxiredoxin family that are responsible for neutralising reactive oxygen species. EXPERIMENTAL DESIGN: PRDX-3 expression was examined in tissue from 32 patients using immunohistochemistry. Subcellular distribution was determined using confocal microscopy. PRDX-3 expression was determined in antiandrogen-resistant cell lines by western blotting and quantitative RT-PCR. The pathways of PRDX-3 overexpression and knockdown on apoptosis and response to oxidative stress were investigated using protein arrays. RESULTS: PRDX-3 is upregulated in a number of endocrine-regulated tumours; in particular in PCa and prostatic intraepithelial neoplasia. Although the majority of PRDX-3 is localised to the mitochondria, we have confirmed that PRDX-3 at the cell membrane is androgen regulated. In antiandrogen-resistant LNCaP cell lines, PRDX-3 is upregulated at the protein but not RNA level. Resistant cells also possess an upregulation of the tricarboxylic acid (TCA) pathway and resistance to H2O2-induced apoptosis through a failure to activate pro-apoptotic pathways. Knockdown of PRDX-3 restored H2O2 sensitivity. CONCLUSION: Our results suggest that PRDX-3 has an essential role in regulating oxidation-induced apoptosis in antiandrogen-resistant cells. PRDX-3 may have potential as a therapeutic target in castrate-independent PCa.

Use of the self-controlled case-series method in vaccine safety studies: review and recommendations for best practice.

The self-controlled case-series method was originally developed to investigate potential associations between vaccines and adverse events, and is now commonly used for this purpose. This study reviews applications of the method to vaccine safety investigations in the period 1995-2010. In total, 40 studies were reviewed. The application of the self-controlled case-series method in these studies is critically examined, with particular reference to the definition of observation and risk periods, control of confounders, assumptions and potential biases, methodological and presentation issues, power and sample size, and software. Comparisons with other study designs undertaken in the papers reviewed are also highlighted. Some recommendations are presented, with the emphasis on promoting good practice.

Nuclear LYRIC/AEG-1 interacts with PLZF and relieves PLZF-mediated repression.

LYRIC/AEG-1 and its altered expression have been linked to carcinogenesis in prostate, brain and melanoma as well as promoting chemoresistance and metastasis in breast cancer. LYRIC/AEG-1 function remains unclear, although LYRIC/AEG-1 is activated by oncogenic HA-RAS, through binding of c-myc to its promoter, which in turn regulates the key components of the PI3-kinase and nuclear factor-kappaB pathways. We have identified the transcriptional repressor PLZF as an interacting protein of LYRIC/AEG through a yeast two-hybrid screen. PLZF regulates the expression of genes involved in cell growth and apoptosis including c-myc. Coexpression of LYRIC/AEG-1 with PLZF leads to a reduction in PLZF-mediated repression by reducing PLZF binding to promoters. We have confirmed that nuclear LYRIC/AEG-1 and PLZF interact in mammalian cells via the N- and C termini of LYRIC/AEG-1 and a region C terminal to the RD2 domain of PLZF. Both proteins colocalize to nuclear bodies containing histone deacetylases, which are known to promote PLZF-mediated repression. Our data suggest one mechanism for cells with altered LYRIC/AEG-1 expression to evade apoptosis and increase cell growth during tumourigenesis through the regulation of PLZF repression.

Measures of disassortativeness and their application to directly transmitted infections.

We propose a measure of disassortativeness to summarize contact patterns relevant to the transmission of directly transmitted infections. We discuss the properties of this measure, describe standardization relative to homogeneous mixing, and generalize it to multivariate contact structures. We explore some of its properties and apply our methods to serological surveys of close contact infections and surveys of self-reported social contacts obtained in several European countries.

A novel mutation in the human androgen receptor suggests a regulatory role for the hinge region in amino-terminal and carboxy-terminal interactions.

CONTEXT: The androgen insensitivity syndrome (AIS) is caused by molecular defects in the androgen receptor (AR). Clinically, the partial AIS has a variable phenotype. Many mechanisms explain the phenotype in the AIS. A crucial step in AR action is the interaction of the N and C termini. OBJECTIVE: The role of the hinge region of the AR is not as well understood as other parts of the receptor. We aim to study the role of this region in the N/C-termini interaction. PATIENT AND METHOD: We report a patient with severe undermasculinization and poor response to exogenous androgens. Androgen binding was performed, and the AR gene was sequenced. The mutation was recreated and transfected in COS-1 cells. Transactivation was studied. N/C-termini interaction was studied using a mammalian two-hybrid assay. A nuclear localization study was performed. RESULTS: Androgen binding was normal, and a novel mutation (Arg629Trp) in the AR hinge region was identified. Mutant AR transactivation was 40% higher compared with wild type (WT). A 3-fold increase in transcription occurred when both WT N and C-terminal domains were cotransfected; no response occurred when the mutated region of the AR was included (P < 0.001). Cells with mutant AR showed a comparable nuclear localization to the WT AR. CONCLUSIONS: A mutation in the hinge region impaired N/C-domain interaction in the presence of normal AR binding and nuclear localization. It resulted in severe undermasculinization at birth and resistance to androgens. The findings confirm a unique regulatory role for the hinge region in AR function.

Discovery and evaluation of single nucleotide polymorphisms (SNPs) for Haliotis midae: a targeted EST approach.

In this study, we describe the first set of SNP markers for the South African abalone, Haliotis midae. A cDNA library was constructed from which ESTs were selected for the screening of SNPs. The observed frequency of SNPs in this species was estimated at one every 185 bp. When characterized in wild-caught abalone, the minor allele frequencies and F(ST) estimates for every SNP indicated that these markers may potentially be useful for population analysis, parentage assignment and linkage mapping in Haliotis midae. No linkage disequilibrium was observed between SNPs originating from different EST sequences. These SNPs, together with additional SNPs currently being developed, will provide a useful complementary set of markers to the currently available genetic markers in abalone.

Hepatitis B vaccination and first central nervous system demyelinating events: reanalysis of a case-control study using the self-controlled case series method.

The hypothesis that hepatitis B vaccination is a risk factor for multiple sclerosis has been discussed at length. The data from an earlier case-control study were reanalyzed using the self-controlled case series method. Using the matched cases from the case-control study, we found a relative incidence of 1.68, 95% CI (0.77-3.68) for the 0-60-day post-vaccination risk period; this compares to an odds ratio of 1.8, 95% CI (0.7-4.6). When an additional 53 unmatched cases not used in the case-control study were included, the relative incidence was 1.35, 95% CI (0.66-2.79). Our results throw further light on the methodological aspects of the case series method. We recommend that, when case-control studies of vaccination and adverse events are planned, case series analyses based on the cases are also undertaken when appropriate.

Pathogenesis of prostate cancer and hormone refractory prostate cancer.

Prostate cancer is the second most common malignancy in males and the leading cause of cancer death. Prostate cancer is initially androgen dependent and relies upon the androgen receptor (AR) to mediate the effects of androgens. The AR is also the target for therapy using antiandrogens and LHRH analogues. However, all cancers eventually become androgen independent, often referred to as hormone refractory prostate cancer. The processes involved in this transformation are yet to be fully understood but research in this area has discovered numerous potential mechanisms including AR amplification, over-expression or mutation and alterations in the AR signaling pathway. This review of the recent literature examines the current knowledge and developments in the understanding of the molecular biology of prostate cancer and hormone refractory prostate cancer, summarizing the well characterized pathways involved as well as introducing new concepts that may offer future solutions to this difficult problem.

Mechanisms of androgen receptor repression in prostate cancer.

Anti-androgens used in prostate cancer therapy inhibit AR (androgen receptor) activity via largely unknown mechanisms. Although initially successful in most cases, they eventually fail and the disease progresses. We need to elucidate how anti-androgens work to understand why they fail, and prolong their effects or design further therapies. Using a cellular model, we found different anti-androgens have diverse effects on subcellular localization of AR, revealing that they work via different mechanisms and suggesting that an informed sequential treatment regime may benefit patients. In the presence of the anti-androgens bicalutamide and hydroxyflutamide, a significant proportion of the AR is translocated to the nucleus but remains inactive. Receptor inhibition under these conditions is likely to involve recruitment of co-repressor proteins, which interact with antagonist-occupied receptor but inhibit receptor-dependent transcription. Which co-repressors are required in vivo for AR repression by anti-androgens is not clear, but one candidate is the Notch effector Hey1. This inhibits ligand-dependent activity of the AR but not other steroid receptors. Further, it is excluded from the nucleus in most human prostate cancers, suggesting that abnormal subcellular distribution of co-repressors may contribute to the aberrant hormonal responses observed in prostate cancer. A decrease in co-repressor function is one possible explanation for the development of anti-androgen-resistant prostate cancer, and this suggests that it may not occur at the gross level of protein expression.

Does concurrent prescription of selective serotonin reuptake inhibitors and non-steroidal anti-inflammatory drugs substantially increase the risk of upper gastrointestinal bleeding?

BACKGROUND: A 15-fold increased risk of gastrointestinal bleeding has been reported with concurrent use of selective serotonin reuptake inhibitors and non-steroidal anti-inflammatory drugs. Recent guidance cautions against concurrent prescription, particularly in older people. AIM: To quantify the risk of gastrointestinal bleeding associated with current exposure to non-steroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors, and both drugs concurrently. METHODS: We conducted a case-control analysis of 11,261 cases with upper gastrointestinal bleeding and 53,156 controls matched by gender, age and general practice from computerized primary care data. We coupled this with self-controlled case series analysis. RESULTS: Both drugs were associated with a twofold increased risk of gastrointestinal bleeding (odds ratio =2.38, 95% confidence interval 2.08-2.72 for selective serotonin reuptake inhibitors and odds ratio = 2.15, 95% confidence interval 2.02-2.28 for non-steroidal anti-inflammatory drugs). This increased risk was marginally higher for concurrent prescription (odds ratio = 2.93, 95% confidence interval 2.25-3.82). The self-controlled analysis showed a greater incidence rate ratio for gastrointestinal bleeding with non-steroidal anti-inflammatory drugs (2.71, 95% confidence interval 2.51-2.91) and lower incidence rate ratio with selective serotonin reuptake inhibitors (1.71, 95% confidence interval 1.48-1.98). The incidence rate ratio when both drugs were combined was 3.25, 95% confidence interval 1.95-5.42. Estimates were similar after restricting to people over 80 years of age. Increased risk of gastrointestinal bleeding was not specifically related to class of non-steroidal anti-inflammatory drugs and was similar when we looked at tricyclic anti-depressants. CONCLUSIONS: Our study suggests that the risk of gastrointestinal bleeding is not substantially increased when non-steroidal anti-inflammatory drugs and selective serotonin reuptake inhibitors are prescribed together, compared with their use alone.

Infections with varying contact rates: application to varicella.

We develop methods for the analysis of infectious disease data when age-specific contact rates vary over time. Our methods are valid when contact rates vary slowly on the time scale of the infection process, and are applicable to a variety of data types including serial seroprevalence surveys and case reports. The methods exploit approximate endemic equilibria, and require numerical solution of an associated integral equation in age and time. We also estimate summary statistics such as time-dependent analogs of the basic reproduction number and critical immunization threshold. We illustrate the methods with data on varicella (chickenpox) in the United Kingdom.

Estimation of infectious disease parameters from serological survey data: the impact of regular epidemics.

Serological surveys are a useful source of information about epidemiological parameters for infectious diseases. In particular they may be used to estimate contact rates, forces of infection, the reproduction number and the critical vaccination threshold. However, these estimation methods require the assumption that the infection is in endemic equilibrium. Such equilibria seldom exist in practice: for example, many common infections of childhood exhibit regular epidemic cycles. In this paper, we investigate whether ignoring such cycles produces biased estimates. We apply the methods to data on mumps and rubella in the U.K. prior to the introduction of the combined measles, mumps, rubella (MMR) vaccine. We conclude that past epidemics have only a marginal effect on estimates, and that standard methods that do not adjust for regular epidemics are valid.

Estimation of effective reproduction numbers for infectious diseases using serological survey data.

The effective reproduction number of an infection, denoted Re, may be used to monitor the impact of a vaccination programme. If Re is maintained below 1, then sustained endemic transmission of the infection cannot occur. In this paper we discuss methods for estimating Re from serological survey data, allowing for age and individual heterogeneity. We describe semi-parametric and parametric models, and obtain an upper bound on Re when vaccine coverage and efficacy are not known. The methods are illustrated using data on mumps and rubella in England and Wales.

Jean-Baptiste Bouillaud, Claude-François Lallemand, and the role of the frontal lobe: location and mislocation of language in the early 19th century.

In 1825, Jean-Baptiste Bouillaud read a paper at the Royal Academy of Medicine in Paris supporting Franz Gall's theory of a relation between speech and the frontal lobes. Bouillaud argued that if the frontal lobes are crucial to speech, 2 conditions must be satisfied: when the frontal lobes are affected, speech must also be affected; conversely, when the frontal lobes are spared, speech is also spared. Following these principles, he tested and argued in support of Gall's theory by analyzing the data from 2 neuropathological casebooks (Lallemand, 1820-1823; Rostan, 1820 and 1823). We now know that Bouillaud was wrong, since the crucial dichotomy is between the left and right hemispheres and not between the anterior and posterior areas. What is interesting is that the actual data refute Bouillaud's conclusion. We replicated his experiment by reanalyzing the 147 clinical cases described by Lallemand. There were, of course, some cases with frontal lesions and speech disorders; other cases, however, had speech disorders with lesions outside the frontal lobes, and still others had frontal lesions without speech disorders. Although Bouillaud did not notice it, as we expected, almost all patients with speech disorders had a left hemisphere lesion.