Lovastatin for adult patients with dengue: protocol for a randomised controlled trial.

BACKGROUND: Dengue is the most important vector-borne viral infection of man, with approximately 2 billion people living in areas at risk. Infection results in a range of manifestations from asymptomatic infection through to life-threatening shock and haemorrhage. One of the hallmarks of severe dengue is vascular endothelial disruption. There is currently no specific therapy and clinical management is limited to supportive care. Statins are a class of drug initially developed for lipid lowering. There has been considerable recent interest in their effects beyond lipid lowering. These include anti-inflammatory effects at the endothelium. In addition, it is possible that lovastatin may have an anti-viral effect against dengue. Observational data suggest that the use of statins may improve outcomes for such conditions as sepsis and pneumonia. This paper describes the protocol for a randomised controlled trial investigating a short course of lovastatin therapy in adult patients with dengue. METHODS/DESIGN: A randomised, double-blind, placebo-controlled trial will investigate the effects of lovastatin therapy in the treatment of dengue. The trial will be conducted in two phases with an escalation of dose between phases if an interim safety review is satisfactory. This is an exploratory study focusing on safety and there are no data on which to base a sample size calculation. A target sample size of 300 patients in the second phase, enrolled over two dengue seasons, was chosen based on clinical judgement and feasibility considerations. In a previous randomised trial in dengue, about 10% and 30% of patients experienced at least one serious adverse event or adverse event, respectively. With 300 patients, we will have 80% power to detect an increase of 12% (from 10% to 22%) or 16% (from 30% to 46%) in the frequency of adverse events. Furthermore, this sample size ensures some power to explore the efficacy of statins. DISCUSSION: The development of a dengue therapeutic that can attenuate disease would be an enormous advance in global health. The favourable effects of statins on the endothelium, their good safety profile and their low cost make lovastatin an attractive therapeutic candidate. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number ISRCTN03147572

A mass threshold in the number density of passive galaxies at z∼\sim2

The process that quenched star formation in galaxies at intermediate and high redshift is still the subject of considerable debate. One way to investigate this puzzling issue is to study the number density of quiescent galaxies at z~2, and its dependence on mass. Here we present the results of a new study based on very deep Ks-band imaging (with the HAWK-I instrument on the VLT) of two HST CANDELS fields (the UKIDSS Ultra-deep survey (UDS) field and GOODS-South). The new HAWK-I data (taken as part of the HUGS VLT Large Program) reach detection limits of Ks>26 (AB mag). We select a sample of passively-evolving galaxies in the redshift range 1.4<z<2.5. Thanks to the depth and large area coverage of our imaging, we have been able to extend the selection of quiescent galaxies a magnitude fainter than previous analyses. Through extensive simulations we demonstrate, for the first time, that the observed turn-over in the number of quiescent galaxies at K>22 is real. This has enabled us to establish unambiguously that the number counts of quiescent galaxies at z~2 flatten and slightly decline at magnitudes fainter than Ks~22(AB mag.). We show that this trend corresponds to a stellar mass threshold $M_*10^{10.8}\,{\rm M_{\odot}}$ below which the mechanism that halts the star formation in high-redshift galaxies seems to be inefficient. Finally we compare the observed pBzK number counts with those of quiescent galaxies extracted from four different semi-analytic models. We find that none of the models provides a statistically acceptable description of the number density of quiescent galaxies at these redshifts. We conclude that the mass function of quiescent galaxies as a function of redshift continues to present a key and demanding challenge for proposed models of galaxy formation and evolution.Comment: Accepted for publication on Astronomy and Astrophysic

Reducing the impact of emerging infections through data sharing

Data sharing has the potential to shift the paradigm of outbreak response in the public health, clinical and scientific communities. Increasing access to more data can address some of the key challenges of the limited, fragmented, poor quality data, which characterise emerging infections. To achieve this, we must design well-governed, equitable, collaborative data sharing models driven by the questions relevant to those directly affected, and ensure that the benefits of sharing are returned to them. We must also implement methodologies that maximize the usability of data to generate evidence

Targeted ablation of oligodendrocytes induces axonal pathology independent of overt demyelination

The critical role of oligodendrocytes in producing and maintaining myelin that supports rapid axonal conduction in CNS neurons is well established. More recently, additional roles for oligodendrocytes have been posited, including provision of trophic factors and metabolic support for neurons. To investigate the functional consequences of oligodendrocyte loss, we have generated a transgenic mouse model of conditional oligodendrocyte ablation. In this model, oligodendrocytes are rendered selectively sensitive to exogenously administered diphtheria toxin (DT) by targeted expression of the diphtheria toxin receptor in oligodendrocytes. Administration of DT resulted in severe clinical dysfunction with an ascending spastic paralysis ultimately resulting in fatal respiratory impairment within 22 d of DT challenge. Pathologically, at this time point, mice exhibited a loss of ∼26% of oligodendrocyte cell bodies throughout the CNS. Oligodendrocyte cell-body loss was associated with moderate microglial activation, but no widespread myelin degradation. These changes were accompanied with acute axonal injury as characterized by structural and biochemical alterations at nodes of Ranvier and reduced somatosensory-evoked potentials. In summary, we have shown that a death signal initiated within oligodendrocytes results in subcellular changes and loss of key symbiotic interactions between the oligodendrocyte and the axons it ensheaths. This produces profound functional consequences that occur before the removal of the myelin membrane, i.e., in the absence of demyelination. These findings have clear implications for the understanding of the pathogenesis of diseases of the CNS such as multiple sclerosis in which the oligodendrocyte is potentially targeted

Avoiding data dumpsters - Toward equitable and useful data sharing.

The potential health benefits from sharing participant-level clinical research data for the purpose of secondary analysis or meta-analysis have been widely touted. Although some researchers remain wary about sharing data, recent policies and proposals by funders, scientific journals, research institutions, and international health organizations mean that data sharing, in one form or another, is inevitable. Now is therefore the time to focus on developing practices for data sharing that are effective, efficient, equitable, and ethical. In the process, we may need to question the assumption that more is better. Simply making more data openly available may not lead to analyses that are relevant and that are actually applied to improve health

Secondary analysis and participation of those at the data source

Your Editorial Closing the door on parachutes and parasites (June 2018) offers poignant insight on key issues in authorship of manuscripts resulting from secondary data analysis. As global health researchers who believe in the ethical and scientific imperative to maximise health gains from existing data, we strongly support the need to get this right. The discourse is not only important to develop sound publication practice, but also to promote equity, effectiveness, and sustainability of global health research collaboration. We agree that policy on academic authorship must evolve to avoid undermining these objectives

Clinical evaluation of dengue and identification of risk factors for severe disease: protocol for a multicentre study in 8 countries

Background: The burden of dengue continues to increase globally, with an estimated 100 million clinically apparent infections occurring each year. Although most dengue infections are asymptomatic, patients can present with a wide spectrum of clinical symptoms ranging from mild febrile illness through to severe manifestations of bleeding, organ impairment, and hypovolaemic shock due to a systemic vascular leak syndrome. Clinical diagnosis of dengue and identification of which patients are likely to develop severe disease remain challenging. This study aims to improve diagnosis and clinical management through approaches designed a) to differentiate between dengue and other common febrile illness within 72 h of fever onset, and b) among patients with dengue to identify markers that are predictive of the likelihood of evolving to a more severe disease course. Method/Design: This is a prospective multi-centre observational study aiming to enrol 7–8000 participants aged ≥ 5 years presenting with a febrile illness consistent with dengue to outpatient health facilities in 8 countries across Asia and Latin America. Patients presenting within 72 h of fever onset who do not exhibit signs of severe disease are eligible for the study. A broad range of clinical and laboratory parameters are assessed daily for up to 6 days during the acute illness, and also at a follow up visit 1 week later. Discussion: Data from this large cohort of patients, enrolled early with undifferentiated fever, will be used to develop a practical diagnostic algorithm and a robust clinical case definition for dengue. Additionally, among patients with confirmed dengue we aim to identify simple clinical and laboratory parameters associated with progression to a more severe disease course. We will also investigate early virological and serological correlates of severe disease, and examine genetic associations in this large heterogeneous cohort. In addition the results will be used to assess the new World Health Organization classification scheme for dengue in practice, and to update the guidelines for “Integrated Management of Childhood Illness” used in dengue-endemic countries. Trial registration: NCT01550016. Registration Date: March 7, 201

Intensified Antituberculosis Therapy in Adults with Tuberculous Meningitis

BACKGROUND Tuberculous meningitis is often lethal. Early antituberculosis treatment and adjunctive treatment with glucocorticoids improve survival, but nearly one third of patients with the condition still die. We hypothesized that intensified antituberculosis treatment would enhance the killing of intracerebral Mycobacterium tuberculosis organisms and decrease the rate of death among patients. METHODS We performed a randomized, double-blind, placebo-controlled trial involving human immunodeficiency virus (HIV)-infected adults and HIV-uninfected adults with a clinical diagnosis of tuberculous meningitis who were admitted to one of two Vietnamese hospitals. We compared a standard, 9-month antituberculosis regimen (which included 10 mg of rifampin per kilogram of body weight per day) with an intensified regimen that included higher-dose rifampin (15 mg per kilogram per day) and levofloxacin (20 mg per kilogram per day) for the first 8 weeks of treatment. The primary outcome was death by 9 months after randomization. RESULTS A total of 817 patients (349 of whom were HIV-infected) were enrolled; 409 were randomly assigned to receive the standard regimen, and 408 were assigned to receive intensified treatment. During the 9 months of follow-up, 113 patients in the intensified-treatment group and 114 patients in the standard-treatment group died (hazard ratio, 0.94; 95% confidence interval, 0.73 to 1.22; P=0.66). There was no evidence of a significant differential effect of intensified treatment in the overall population or in any of the subgroups, with the possible exception of patients infected with isoniazid-resistant M. tuberculosis. There were also no significant differences in secondary outcomes between the treatment groups. The overall number of adverse events leading to treatment interruption did not differ significantly between the treatment groups (64 events in the standard-treatment group and 95 events in the intensified-treatment group, P=0.08). CONCLUSIONS Intensified antituberculosis treatment was not associated with a higher rate of survival among patients with tuberculous meningitis than standard treatment. (Funded by the Wellcome Trust and the Li Ka Shing Foundation; Current Controlled Trials number, ISRCTN61649292.)

Open source clinical science for emerging infections

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