Clinical Trial of Oral Nelfinavir before and during Radiation Therapy for Advanced Rectal Cancer

Purpose Nelfinavir, a PI3-kinase pathway inhibitor, is a radiosensitizer which increases tumor blood flow in preclinical models. We conducted an early-phase study to demonstrate the safety of nelfinavir combined with hypofractionated radiotherapy (RT) and to develop biomarkers of tumor perfusion and radiosensitization for this combinatorial approach. Patients and Methods Ten patients with T3-4 N0-2 M1 rectal cancer received 7 days of oral nelfinavir (1250 mg bd) and a further 7 days of nelfinavir during pelvic RT (25 Gy/5 fractions/7 days). Perfusion CT (p-CT) and DCE-MRI scans were performed pre-treatment, after 7 days of nelfinavir and prior to last fraction of RT. Biopsies taken pre-treatment and 7 days after the last fraction of RT were analysed for tumor cell density (TCD). Results There were 3 drug-related grade 3 adverse events: diarrhea, rash, lymphopenia. On DCE-MRI, there was a mean 42% increase in median Ktrans, and a corresponding median 30% increase in mean blood flow on p-CT during RT in combination with nelfinavir. Median TCD decreased from 24.3% at baseline to 9.2% in biopsies taken 7 days after RT (P=0.01). Overall, 5/9 evaluable patients exhibited good tumor regression on MRI assessed by Tumor Regression Grade (mrTRG). Conclusions This is the first study to evaluate nelfinavir in combination with RT without concurrent chemotherapy. It has shown that nelfinavir-RT is well tolerated and is associated with increased blood flow to rectal tumors. The efficacy of nelfinavir-RT versus RT alone merits clinical evaluation, including measurement of tumor blood flow

The Influence of the Internet on European Journalism

This study investigates how European journalists evaluate the changes that have occurred in their profession since the Internet has been integrated in newsrooms. How do journalists perceive the features and innovations associated with the Internet? What are the principal changes in the profession? Do practitioners believe that the quality of journalism has been raised or lowered? To answer to these research questions, we carried out a survey across 11 European countries–Cyprus, Estonia, Finland, Greece, Ireland, Italy, Lithuania, United Kingdom, Slovenia, Spain, Sweden–of 239 journalists, working for 40 of the most-read print/online news outlets in these countries. The survey shows that the opportunity to use the Internet to reinforce the social functions of journalism has not been fully recognised

GM-CSF Increases Mucosal and Systemic Immunogenicity of an H1N1 Influenza DNA Vaccine Administered into the Epidermis of Non-Human Primates

Background: The recent H5N1 avian and H1N1 swine-origin influenza virus outbreaks reaffirm that the threat of a worldwide influenza pandemic is both real and ever-present. Vaccination is still considered the best strategy for protection against influenza virus infection but a significant challenge is to identify new vaccine approaches that offer accelerated production, broader protection against drifted and shifted strains, and the capacity to elicit anti-viral immune responses in the respiratory tract at the site of viral entry. As a safe alternative to live attenuated vaccines, the mucosal and systemic immunogenicity of an H1N1 influenza (A/New Caledonia/20/99) HA DNA vaccine administered by particle-mediated epidermal delivery (PMED or gene gun) was analyzed in rhesus macaques. Methodology/Principal Findings: Macaques were immunized at weeks 0, 8, and 16 using a disposable single-shot particlemediated delivery device designed for clinical use that delivers plasmid DNA directly into cells of the epidermis. Significant levels of hemagglutination inhibiting (HI) antibodies and cytokine-secreting HA-specific T cells were observed in the periphery of macaques following 1-3 doses of the PMED HA DNA vaccine. In addition, HA DNA vaccination induced detectable levels of HA-specific mucosal antibodies and T cells in the lung and gut-associated lymphoid tissues of vaccinated macaques. Importantly, co-delivery of a DNA encoding the rhesus macaque GM-CSF gene was found to significantly enhance both the systemic and mucosal immunogenicity of the HA DNA vaccine. Conclusions/Significance: These results provide strong support for the development of a particle-mediated epidermal DNA vaccine for protection against respiratory pathogens such as influenza and demonstrate, for the first time, the ability of skindelivered GM-CSF to serve as an effective mucosal adjuvant for vaccine induction of immune responses in the gut and respiratory tract. © 2010 Loudon et al

Effectiveness of a behavioural intervention delivered by text messages (safetxt) on sexually transmitted reinfections in people aged 16-24 years: randomised controlled trial.

OBJECTIVE: To quantify the effects of a series of text messages (safetxt) delivered in the community on incidence of chlamydia and gonorrhoea reinfection at one year in people aged 16-24 years. DESIGN: Parallel group randomised controlled trial. SETTING: 92 sexual health clinics in the United Kingdom. PARTICIPANTS: People aged 16-24 years with a diagnosis of, or treatment for, chlamydia, gonorrhoea, or non-specific urethritis in the past two weeks who owned a mobile phone. INTERVENTIONS: 3123 participants assigned to the safetxt intervention received a series of text messages to improve sex behaviours: four texts daily for days 1-3, one or two daily for days 4-28, two or three weekly for month 2, and 2-5 monthly for months 3-12. 3125 control participants received a monthly text message for one year asking for any change to postal or email address. It was hypothesised that safetxt would reduce the risk of chlamydia and gonorrhoea reinfection at one year by improving three key safer sex behaviours: partner notification at one month, condom use, and sexually transmitted infection testing before unprotected sex with a new partner. Care providers and outcome assessors were blind to allocation. MAIN OUTCOME MEASURES: The primary outcome was the cumulative incidence of chlamydia or gonorrhoea reinfection at one year, assessed by nucleic acid amplification tests. Safety outcomes were self-reported road traffic incidents and partner violence. All analyses were by intention to treat. RESULTS: 6248 of 20 476 people assessed for eligibility between 1 April 2016 and 23 November 2018 were randomised. Primary outcome data were available for 4675/6248 (74.8%). At one year, the cumulative incidence of chlamydia or gonorrhoea reinfection was 22.2% (693/3123) in the safetxt arm versus 20.3% (633/3125) in the control arm (odds ratio 1.13, 95% confidence interval 0.98 to 1.31). The number needed to harm was 64 (95% confidence interval number needed to benefit 334 to ∞ to number needed to harm 24) The risk of road traffic incidents and partner violence was similar between the groups. CONCLUSIONS: The safetxt intervention did not reduce chlamydia and gonorrhoea reinfections at one year in people aged 16-24 years. More reinfections occurred in the safetxt group. The results highlight the need for rigorous evaluation of health communication interventions. TRIAL REGISTRATION: ISRCTN registry ISRCTN64390461. CORRECTION: The first two points of the what this study adds in the box should read: The safetxt intervention using a mobile phone and targeting safer sex behaviours did not reduce the incidence of chlamydia or gonorrhoea at one year; more infections occurred in the intervention group. Safetex increased some self-reported measures of sexual health, such as self-efficacy in condom use and condom use in itself

Behavioural intervention to reduce sexually transmitted infections in people aged 16–24 years in the UK: the safetxt RCT

BACKGROUND: The prevalence of genital chlamydia and gonorrhoea is higher in the 16–24 years age group than those in other age group. With users, we developed the theory-based safetxt intervention to reduce sexually transmitted infections. OBJECTIVES: To establish the effect of the safetxt intervention on the incidence of chlamydia/gonorrhoea infection at 1 year. DESIGN: A parallel-group, individual-level, randomised superiority trial in which care providers and outcome assessors were blinded to allocation. SETTING: Recruitment was from 92 UK sexual health clinics. PARTICIPANTS: Inclusion criteria were a positive chlamydia or gonorrhoea test result, diagnosis of non-specific urethritis or treatment started for chlamydia/gonorrhoea/non-specific urethritis in the last 2 weeks; owning a personal mobile phone; and being aged 16–24 years. ALLOCATION: Remote computer-based randomisation with an automated link to the messaging system delivering intervention or control group messages. INTERVENTION: The safetxt intervention was designed to reduce sexually transmitted infection by increasing partner notification, condom use and sexually transmitted infection testing before sex with new partners. It employed educational, enabling and incentivising content delivered by 42–79 text messages over 1 year, tailored according to type of infection, gender and sexuality. COMPARATOR: A monthly message regarding trial participation. Main outcomes: The primary outcome was the incidence of chlamydia and gonorrhoea infection at 12 months, assessed using nucleic acid amplification tests. Secondary outcomes at 1 and 12 months included self-reported partner notification, condom use and sexually transmitted infection testing prior to sex with new partner(s). RESULTS: Between 1 April 2016 and 23 November 2018, we assessed 20,476 people for eligibility and consented and randomised 6248 participants, allocating 3123 to the safetxt intervention and 3125 to the control. Primary outcome data were available for 4675 (74.8%) participants. The incidence of chlamydia/gonorrhoea infection was 22.2% (693/3123) in the intervention group and 20.3% (633/3125) in the control group (odds ratio 1.13, 95% confidence interval 0.98 to 1.31). There was no evidence of heterogeneity in any of the prespecified subgroups. Partner notification was 85.6% in the intervention group and 84.0% in the control group (odds ratio 1.14, 95% confidence interval 0.99 to 1.33). At 12 months, condom use at last sex was 33.8% in the intervention group and 31.2% in the control group (odds ratio 1.14, 95% confidence interval 1.01 to 1.28) and condom use at first sex with most recent new partner was 54.4% in the intervention group and 48.7% in the control group (odds ratio 1.27, 95% confidence interval 1.11 to 1.45). Testing before sex with a new partner was 39.5% in the intervention group and 40.9% in the control group (odds ratio 0.95, 95% confidence interval 0.82 to 1.10). Having two or more partners since joining the trial was 56.9% in the intervention group and 54.8% in the control group (odds ratio 1.11, 95% confidence interval 1.00 to 1.24) and having sex with someone new since joining the trial was 69.7% in the intervention group and 67.4% in the control group (odds ratio 1.13, 95% confidence interval 1.00 to 1.28). There were no differences in safety outcomes. Additional sensitivity and per-protocol analyses showed similar results. LIMITATIONS: Our understanding of the mechanism of action for the unanticipated effects is limited. CONCLUSIONS: The safetxt intervention did not reduce chlamydia and gonorrhoea infections, with slightly more infections in the intervention group. The intervention increased condom use but also increased the number of partners and new partners. Randomised controlled trials are essential for evaluating health communication interventions, which can have unanticipated effects

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

A new polygenic score for refractive error improves detection of children at risk of high myopia but not the prediction of those at risk of myopic macular degeneration

Background High myopia (HM), defined as a spherical equivalent refractive error (SER) ≤ −6.00 diopters (D), is a leading cause of sight impairment, through myopic macular degeneration (MMD). We aimed to derive an improved polygenic score (PGS) for predicting children at risk of HM and to test if a PGS is predictive of MMD after accounting for SER. Methods The PGS was derived from genome-wide association studies in participants of UK Biobank, CREAM Consortium, and Genetic Epidemiology Research on Adult Health and Aging. MMD severity was quantified by a deep learning algorithm. Prediction of HM was quantified as the area under the receiver operating curve (AUROC). Prediction of severe MMD was assessed by logistic regression. Findings In independent samples of European, African, South Asian and East Asian ancestry, the PGS explained 19% (95% confidence interval 17–21%), 2% (1–3%), 8% (7–10%) and 6% (3–9%) of the variation in SER, respectively. The AUROC for HM in these samples was 0.78 (0.75–0.81), 0.58 (0.53–0.64), 0.71 (0.69–0.74) and 0.67 (0.62–0.72), respectively. The PGS was not associated with the risk of MMD after accounting for SER: OR = 1.07 (0.92–1.24). Interpretation Performance of the PGS approached the level required for clinical utility in Europeans but not in other ancestries. A PGS for refractive error was not predictive of MMD risk once SER was accounted fo

Genome Scan Meta-Analysis of Schizophrenia and Bipolar Disorder, Part III: Bipolar Disorder

Genome scans of bipolar disorder (BPD) have not produced consistent evidence for linkage. The rank-based genome scan meta-analysis (GSMA) method was applied to 18 BPD genome scan data sets in an effort to identify regions with significant support for linkage in the combined data. The two primary analyses considered available linkage data for “very narrow” (i.e., BP-I and schizoaffective disorder–BP) and “narrow” (i.e., adding BP-II disorder) disease models, with the ranks weighted for sample size. A “broad” model (i.e., adding recurrent major depression) and unweighted analyses were also performed. No region achieved genomewide statistical significance by several simulation-based criteria. The most significant P values (<.01) were observed on chromosomes 9p22.3-21.1 (very narrow), 10q11.21-22.1 (very narrow), and 14q24.1-32.12 (narrow). Nominally significant P values were observed in adjacent bins on chromosomes 9p and 18p-q, across all three disease models on chromosomes 14q and 18p-q, and across two models on chromosome 8q. Relatively few BPD pedigrees have been studied under narrow disease models relative to the schizophrenia GSMA data set, which produced more significant results. There was no overlap of the highest-ranked regions for the two disorders. The present results for the very narrow model are promising but suggest that more and larger data sets are needed. Alternatively, linkage might be detected in certain populations or subsets of pedigrees. The narrow and broad data sets had considerable power, according to simulation studies, but did not produce more highly significant evidence for linkage. We note that meta-analysis can sometimes provide support for linkage but cannot disprove linkage in any candidate region