A Phase I Double Blind, Placebo-Controlled, Randomized Study of the Safety and Immunogenicity of Electroporated HIV DNA with or without Interleukin 12 in Prime-Boost Combinations with an Ad35 HIV Vaccine in Healthy HIV-Seronegative African Adults.

Strategies to enhance the immunogenicity of DNA vaccines in humans include i) co-administration of molecular adjuvants, ii) intramuscular administration followed by in vivo electroporation (IM/EP) and/or iii) boosting with a different vaccine. Combining these strategies provided protection of macaques challenged with SIV; this clinical trial was designed to mimic the vaccine regimen in the SIV study.Seventy five healthy, HIV-seronegative adults were enrolled into a phase 1, randomized, double-blind, placebo-controlled trial. Multi-antigenic HIV (HIVMAG) plasmid DNA (pDNA) vaccine alone or co-administered with pDNA encoding human Interleukin 12 (IL-12) (GENEVAX IL-12) given by IM/EP using the TriGrid Delivery System was tested in different prime-boost regimens with recombinant Ad35 HIV vaccine given IM.All local reactions but one were mild or moderate. Systemic reactions and unsolicited adverse events including laboratory abnormalities did not differ between vaccine and placebo recipients. No serious adverse events (SAEs) were reported. T cell and antibody response rates after HIVMAG (x3) prime-Ad35 (x1) boost were independent of IL-12, while the magnitude of interferon gamma (IFN-γ) ELISPOT responses was highest after HIVMAG (x3) without IL-12. The quality and phenotype of T cell responses shown by intracellular cytokine staining (ICS) were similar between groups. Inhibition of HIV replication by autologous T cells was demonstrated after HIVMAG (x3) prime and was boosted after Ad35. HIV specific antibodies were detected only after Ad35 boost, although there was a priming effect with 3 doses of HIVMAG with or without IL-12. No anti-IL-12 antibodies were detected.The vaccines were safe, well tolerated and moderately immunogenic. Repeated administration IM/EP was well accepted. An adjuvant effect of co-administered plasmid IL-12 was not detected.ClinicalTrials.gov NCT01496989

Wake response to an ocean-feedback mechanism: Madeira Island case study

This discussion focused on the numerical study of a wake episode. The Weather Research and Forecasting model was used in a downscale mode. The current literature focuses the discussion on the adiabatic dynamics of atmospheric wakes. Changes in mountain height and consequently on its relation to the atmospheric inversion layer should explain the shift in wake regimes: from a 'strong-wake' to a 'weak-wake' scenario. Nevertheless, changes in SST variability can also induce similar regime shifts. Increase in evaporation, contributes to increase convection and thus to an uplift of the stratified atmospheric layer, above the critical height, with subsequent internal gravity wave activity.Comment: Under review proces

Feasibility and acceptability of a specialist clinical service for HIV-infected mineworkers in South Africa.

Occupational settings offer an ideal opportunity to provide preventive health services for HIV-infected workers. A specialized clinic was established in a mining hospital in the Free State, South Africa, with the primary aim of delivering preventive therapy such as isoniazid to those at high risk of tuberculosis (individuals with HIV infection or silicosis), and cotrimoxazole to those at highest risk for opportunistic infections. The clinic design has taken regard of the importance of minimizing stigma, protecting confidentiality, monitoring potential side effects, supporting adherence and identification of prophylaxis failure. The clinic opened in April 1999 and, by August 2001, 1773 patients had attended at least once; 1762 are HIV-infected and 11 have silicosis. Of those with HIV infection, most were asymptomatic at their first visit. The clinic has achieved high acceptability: 99% of persons who were actively recruited to the service agreed to attend. The number still attending after a median of 13 months from recruitment was 1,270 (72%) and only 48 (2.7%) have declined continued attendance. Most losses were due to termination of employment unrelated to a medical condition. The clinic has already been successfully replicated in two other regions of the mining health service in South Africa and provides a model for workplace HIV clinical services that could be used for implementation of further interventions such as antiretroviral therapy

Development of an invasively monitored porcine model of acetaminophen-induced acute liver failure

Background: The development of effective therapies for acute liver failure (ALF) is limited by our knowledge of the pathophysiology of this condition, and the lack of suitable large animal models of acetaminophen toxicity. Our aim was to develop a reproducible invasively-monitored porcine model of acetaminophen-induced ALF. Method: 35kg pigs were maintained under general anaesthesia and invasively monitored. Control pigs received a saline infusion, whereas ALF pigs received acetaminophen intravenously for 12 hours to maintain blood concentrations between 200-300 mg/l. Animals surviving 28 hours were euthanased. Results: Cytochrome p450 levels in phenobarbital pre-treated animals were significantly higher than non pre-treated animals (300 vs 100 pmol/mg protein). Control pigs (n=4) survived 28-hour anaesthesia without incident. Of nine pigs that received acetaminophen, four survived 20 hours and two survived 28 hours. Injured animals developed hypotension (mean arterial pressure; 40.8+/-5.9 vs 59+/-2.0 mmHg), increased cardiac output (7.26+/-1.86 vs 3.30+/-0.40 l/min) and decreased systemic vascular resistance (8.48+/-2.75 vs 16.2+/-1.76 mPa/s/m3). Dyspnoea developed as liver injury progressed and the increased pulmonary vascular resistance (636+/-95 vs 301+/-26.9 mPa/s/m3) observed may reflect the development of respiratory distress syndrome. Liver damage was confirmed by deterioration in pH (7.23+/-0.05 vs 7.45+/-0.02) and prothrombin time (36+/-2 vs 8.9+/-0.3 seconds) compared with controls. Factor V and VII levels were reduced to 9.3 and 15.5% of starting values in injured animals. A marked increase in serum AST (471.5+/-210 vs 42+/-8.14) coincided with a marked reduction in serum albumin (11.5+/-1.71 vs 25+/-1 g/dL) in injured animals. Animals displayed evidence of renal impairment; mean creatinine levels 280.2+/-36.5 vs 131.6+/-9.33 mumol/l. Liver histology revealed evidence of severe centrilobular necrosis with coagulative necrosis. Marked renal tubular necrosis was also seen. Methaemoglobin levels did not rise >5%. Intracranial hypertension was not seen (ICP monitoring), but there was biochemical evidence of encephalopathy by the reduction of Fischer's ratio from 5.6 +/- 1.1 to 0.45 +/- 0.06. Conclusion: We have developed a reproducible large animal model of acetaminophen-induced liver failure, which allows in-depth investigation of the pathophysiological basis of this condition. Furthermore, this represents an important large animal model for testing artificial liver support systems

Negative Symptoms in Early-Onset Psychosis and Their Association With Antipsychotic Treatment Failure.

This is the author accepted manuscript. The final version is available from OUP via the DOI in this recordThe prevalence of negative symptoms (NS) at first episode of early-onset psychosis (EOP), and their effect on psychosis prognosis is unclear. In a sample of 638 children with EOP (aged 10-17 y, 51% male), we assessed (1) the prevalence of NS at first presentation to mental health services and (2) whether NS predicted eventual development of multiple treatment failure (MTF) prior to the age of 18 (defined by initiation of a third trial of novel antipsychotic due to prior insufficient response, intolerable adverse-effects or non-adherence). Data were extracted from the electronic health records held by child inpatient and community-based services in South London, United Kingdom. Natural Language Processing tools were used to measure the presence of Marder Factor NS and antipsychotic use. The association between presenting with ≥2 NS and the development of MTF over a 5-year period was modeled using Cox regression. Out of the 638 children, 37.5% showed ≥2 NS at first presentation, and 124 (19.3%) developed MTF prior to the age of 18. The presence of NS at first episode was significantly associated with MTF (adjusted hazard ratio 1.62, 95% CI 1.07-2.46; P = .02) after controlling for a number of potential confounders including psychosis diagnostic classification, positive symptoms, comorbid depression, and family history of psychosis. Other factors associated with MTF included comorbid autism spectrum disorder, older age at first presentation, Black ethnicity, and family history of psychosis. In EOP, NS at first episode are prevalent and may help identify a subset of children at higher risk of responding poorly to antipsychotics.J.D. received supported by a Medical Research Council (MRC) Clinical Research Training Fellowship (MR/L017105/1) and Psychiatry Research Trust Peggy Pollak Research Fellowship in Developmental Psychiatry. H.D. and S.L. have received salary support from the Foundation of Professional Services to Adolescents, UK. R.D.H. was funded by an MRC Fellowship (MR/J01219X/1). R.P. was funded by an MRC CRTF (MR/K002813/1). C.A., L.P-C., and C.M.D-C. have held grants from the Spanish Ministry of Economy, Industry and Competitiveness. Instituto de Salud Carlos III, co-financed by ERDF Funds from the European Commission, “A way of making Europe,” CIBERSAM, Madrid Regional Government (S2010/BMD-2422 AGES), European Union Structural Funds and European Union Seventh Framework Program under grant agreements FP7-HEALTH-2009-2.2.1-2-241909 (EU-GEI), FP7-HEALTH-2009-2.2.1-3-242114 (OPTiMISE), FP7-HEALTH-2013-2.2.1-2-603196 (PSYSCAN)and FP7- HEALTH-2013-2.2.1-2-602478 (METSY); European Union H2020 Program under the Innovative Medicines Initiative 2 Joint Undertaking (grant agreement No-115916; PRISM); Fundación Alicia Koplowitz and Fundación Mutua Madrileña. M.H., J.H.M. and H.S. receive salary support from the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health

RIPK1-mediated immunogenic cell death promotes anti-tumour immunity against soft-tissue sarcoma.

Drugs that mobilise the immune system against cancer are dramatically improving care for many people. Dying cancer cells play an active role in inducing anti-tumour immunity but not every form of death can elicit an immune response. Moreover, resistance to apoptosis is a major problem in cancer treatment and disease control. While the term "immunogenic cell death" is not fully defined, activation of receptor-interacting serine/threonine-protein kinase 1 (RIPK1) can induce a type of death that mobilises the immune system against cancer. However, no clinical treatment protocols have yet been established that would harness the immunogenic potential of RIPK1. Here, we report the first pre-clinical application of an in vivo treatment protocol for soft-tissue sarcoma that directly engages RIPK1-mediated immunogenic cell death. We find that RIPK1-mediated cell death significantly improves local disease control, increases activation of CD8+ T cells as well as NK cells, and enhances the survival benefit of immune checkpoint blockade. Our findings warrant a clinical trial to assess the survival benefit of RIPK1-induced cell death in patients with advanced disease at limb extremities

Design considerations in a clinical trial of a cognitive behavioural intervention for the management of low back pain in primary care : Back Skills Training Trial

Background Low back pain (LBP) is a major public health problem. Risk factors for the development and persistence of LBP include physical and psychological factors. However, most research activity has focused on physical solutions including manipulation, exercise training and activity promotion. Methods/Design This randomised controlled trial will establish the clinical and cost-effectiveness of a group programme, based on cognitive behavioural principles, for the management of sub-acute and chronic LBP in primary care. Our primary outcomes are disease specific measures of pain and function. Secondary outcomes include back beliefs, generic health related quality of life and resource use. All outcomes are measured over 12 months. Participants randomised to the intervention arm are invited to attend up to six weekly sessions each of 90 minutes; each group has 6–8 participants. A parallel qualitative study will aid the evaluation of the intervention. Discussion In this paper we describe the rationale and design of a randomised evaluation of a group based cognitive behavioural intervention for low back pain

Evidence of seasonality in the diagnosis of monocytic leukaemia

Evidence of seasonality in the diagnosis of monocytic leukaemia in England and Wales is presented, with a maximum diagnosis rate in February/March and a minimum in August/September. Previous published results for monocytic leukaemia are of small sample size yet appear consistent with this finding