Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children

BACKGROUND: Neuraminidase inhibitors (NIs) are stockpiled and recommended by public health agencies for treating and preventing seasonal and pandemic influenza. They are used clinically worldwide. OBJECTIVES: To describe the potential benefits and harms of NIs for influenza in all age groups by reviewing all clinical study reports of published and unpublished randomised, placebo-controlled trials and regulatory comments. SEARCH METHODS: We searched trial registries, electronic databases (to 22 July 2013) and regulatory archives, and corresponded with manufacturers to identify all trials. We also requested clinical study reports. We focused on the primary data sources of manufacturers but we checked that there were no published randomised controlled trials (RCTs) from non-manufacturer sources by running electronic searches in the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE (Ovid), EMBASE, Embase.com, PubMed (not MEDLINE), the Database of Reviews of Effects, the NHS Economic Evaluation Database and the Health Economic Evaluations Database. SELECTION CRITERIA: Randomised, placebo-controlled trials on adults and children with confirmed or suspected exposure to naturally occurring influenza. DATA COLLECTION AND ANALYSIS: We extracted clinical study reports and assessed risk of bias using purpose-built instruments. We analysed the effects of zanamivir and oseltamivir on time to first alleviation of symptoms, influenza outcomes, complications, hospitalisations and adverse events in the intention-to-treat (ITT) population. All trials were sponsored by the manufacturers. MAIN RESULTS: We obtained 107 clinical study reports from the European Medicines Agency (EMA), GlaxoSmithKline and Roche. We accessed comments by the US Food and Drug Administration (FDA), EMA and Japanese regulator. We included 53 trials in Stage 1 (a judgement of appropriate study design) and 46 in Stage 2 (formal analysis), including 20 oseltamivir (9623 participants) and 26 zanamivir trials (14,628 participants). Inadequate reporting put most of the zanamivir studies and half of the oseltamivir studies at a high risk of selection bias. There were inadequate measures in place to protect 11 studies of oseltamivir from performance bias due to non-identical presentation of placebo. Attrition bias was high across the oseltamivir studies and there was also evidence of selective reporting for both the zanamivir and oseltamivir studies. The placebo interventions in both sets of trials may have contained active substances. Time to first symptom alleviation. For the treatment of adults, oseltamivir reduced the time to first alleviation of symptoms by 16.8 hours (95% confidence interval (CI) 8.4 to 25.1 hours, P 1000) and nausea whilst on treatment (RD 4.15%, 95% CI 0.86 to 9.51); NNTH = 25 (95% CI 11 to 116). AUTHORS' CONCLUSIONS: Oseltamivir and zanamivir have small, non-specific effects on reducing the time to alleviation of influenza symptoms in adults, but not in asthmatic children. Using either drug as prophylaxis reduces the risk of developing symptomatic influenza. Treatment trials with oseltamivir or zanamivir do not settle the question of whether the complications of influenza (such as pneumonia) are reduced, because of a lack of diagnostic definitions. The use of oseltamivir increases the risk of adverse effects, such as nausea, vomiting, psychiatric effects and renal events in adults and vomiting in children. The lower bioavailability may explain the lower toxicity of zanamivir compared to oseltamivir. The balance between benefits and harms should be considered when making decisions about use of both NIs for either the prophylaxis or treatment of influenza. The influenza virus-specific mechanism of action proposed by the producers does not fit the clinical evidence

Postexposure Treatment and Animal Rabies, Ontario, 1958-2000

This paper investigates the relationship between animal rabies and postexposure treatment (PET) in Ontario by examining the introduction of human diploid cell vaccine (HDCV) in 1980 and the initiation of an oral rabies vaccination program for wildlife in 1989. Introducing HDCV led to an immediate doubling of treatments. Both animal rabies and human treatments declined rapidly after the vaccination program was introduced, but human treatments have leveled off at approximately 1,000 per year

Dynamics of bacterial communities in relation to soil aggregate formation during the decomposition of 13C-labelled rice straw

The addition of fresh organic matter is known to modify both microbial community structure and soil aggregation. The objective of this study was to understand the relationship between the dynamics of the soil microbial community structure in relation to that of their habitats during the decomposition of straw. Soil samples, ground (2000 μm) were measured. Fatty acid methyl ester (FAME) profiling was used to determine total bacterial community structure and FAME based stable isotope probing (FAME-SIP) was used to characterise the straw degrader communities. The mineralisation rate of the native C and the CStraw was high. The formation of macroaggregates (>2000 μm) occurred within 2 days in amended and unamended samples but did so to a greater extent in the amended samples. The CStraw was mainly located in fractions >200 μm, where degraders were the most abundant. The ¹³C-FAME profiles followed the same trends as total FAME profiles through time and within soil fractions, suggesting common dynamics between straw degraders and total bacterial communities: Gram-negative were more important in fraction >200 μm and during the early stages of the incubation while Gram-positive and actinobacteria dominated in fine fractions and at the end of the incubation. Bacterial community structure changed rapidly (within 2 days) in conjunction with the formation of new microbial habitats, suggesting that the relationship between the two is very close

Eliciting human intelligence: police source handlers' perceptions and experiences of rapport during covert human intelligence sources (CHIS) interactions

Rapport is an integral part of interviewing, viewed as fundamental to the success of intelligence elicitation. One collection capability is human intelligence (HUMINT), the discipline charged with eliciting intelligence through interactions with human sources, such as covert human intelligence sources (CHIS). To date, research has yet to explore the perceptions and experiences of intelligence operatives responsible for gathering HUMINT within England and Wales. The present study consisted of structured interviews with police source handlers (N = 24). Rapport was perceived as essential, especially for maximising the opportunity for intelligence elicitation. Participants provided a range of rapport strategies while highlighting the importance of establishing, and maintaining, rapport. The majority of participants believed rapport could be trained to some degree. Thus, rapport was not viewed exclusively as a natural skill. However, participants commonly perceived some natural attributes are required to build rapport that can be refined and developed through training and experience

Cardiovascular autonomic control in patients undergoing left ventricular assist device (LVAD) support and pharmacologic therapy

Objectives The objective of the study is to determine cardiac autonomic control in patients undergoing assessment for and/or LVAD therapy. Methods Heart rate variability (HRV) was measured in 17 explanted LVAD, 17 implanted LVAD and 23 NYHA III-IV classified chronic heart failure (CHF) patients and ten healthy matched controls under three conditions: supine free breathing, standing and supine controlled breathing. Five measures of HRV were assessed: mean R-R interval (mR-R), high frequency (HF) and low frequency (LF) spectral power, LF in normalised units (LFnu), and LF to HF (LF:HF) ratio. Results Repeat measures ANOVA showed significant (p < 0.05) differences in HRV between all three conditions within groups. Lower values were observed in CHF for LF(in log natural units) compared with explanted patients (- 1.4 [95% CI - 2.6 to - 0.7], p = 0.04) and controls (- 2.1 [- 3.5 to - 0.7], p = 0.001) and for LF:HF compared with implanted patients under paced breathing conditions (z = - 2.7, p = 0.007) and controls in standing (z = - 2.9, p = 0.004) and paced breathing conditions (z = - 2.3, p = 0.02). However, no significant differences were seen between explanted, implanted and control groups under any condition. Conclusions Patients implanted with an LVAD and explanted from a LVAD following myocardial recovery demonstrate a more normal dynamic response to autonomic stimuli and have a lower HRV risk profile compared to CHF patients. © 2013 Elsevier Ireland Ltd

The impact of rapport on intelligence yield: police source handler telephone interactions with covert human intelligence sources

Covert Human Intelligence Sources (CHIS) provide unique access to criminals and organised crime groups, and their collection of intelligence is vital to understanding England and Wales’ threat picture. Rapport is essential to the establishment and maintenance of effective professional relationships between source handlers and their CHIS. Thus, rapport-based interviewing is a fundamental factor to maximising intelligence yield. The present research gained unprecedented access to 105 real-life audio recorded telephone interactions between England and Wales police source handlers and CHIS. This research quantified both the rapport component behaviours (e.g., attention, positivity, and coordination) displayed by the source handler and the intelligence yielded from the CHIS, in order to investigate the frequencies of these rapport components and their relationship to intelligence yield. Overall rapport, attention and coordination significantly correlated with intelligence yield, while positivity did not. Attention was the most frequently used component of rapport, followed by positivity, and then coordination

Source handler's perceptions of the interviewing process employed with Informants

The collection of accurate, detailed, and timely intelligence buttresses critical law enforcement decision-making. However, the quality and quantity of the intelligence gathered relies heavily upon the interviewing techniques that are used to retrieve it. The perceptions of intelligence practitioners are key to developing an understanding of practices concerning intelligence collection. Yet, to date, no research has been undertaken that explores the United Kingdom’s Source Handlers’ perceptions of the interviewing processes employed with informants. The present study interviewed 24 Source Handlers from Counter Terrorism Dedicated Source Units in the United Kingdom. Five themes emerged from the interviews, (i) a comparison between interviewing and debriefing; (ii) the PEACE model in intelligence interviews; (iii) the importance of effective communication; (iv) Source Handlers’ use of cognitive retrieval techniques; and, (v) Source Handler interview training. The perceived commonalities between interviewing and debriefing provided support for the transferability of investigative interviewing research and practices into the collection of Human Intelligence (HUMINT), reiterating themes (ii), (iii), and (iv). Finally, participants highlighted a need for additional training concerning intelligence gathering techniques, as police officers who are responsible for gathering HUMINT could benefit from further professional development based on investigative interviewing research and professional practices

Microglial VPAC1R mediates a novel mechanism of neuroimmune-modulation of hippocampal precursor cells via IL-4 release

Neurogenesis, the production of new neurons from neural stem/progenitor cells (NSPCs), occurs throughout adulthood in the dentate gyrus of the hippocampus, where it supports learning and memory. The innate and adaptive immune systems are increasingly recognized as important modulators of hippocampal neurogenesis under both physiological and pathological conditions. However, the mechanisms by which the immune system regulates hippocampal neurogenesis are incompletely understood. In particular, the role of microglia, the brains resident immune cell is complex, as they have been reported to both positively and negatively regulate neurogenesis. Interestingly, neuronal activity can also regulate the function of the immune system. Here, we show that depleting microglia from hippocampal cultures reduces NSPC survival and proliferation. Furthermore, addition of purified hippocampal microglia, or their conditioned media, is trophic and proliferative to NSPCs. VIP, a neuropeptide released by dentate gyrus interneurons, enhances the proliferative and pro-neurogenic effect of microglia via the VPAC1 receptor. This VIP-induced enhancement is mediated by IL-4 release, which directly targets NSPCs. This demonstrates a potential neuro-immuno-neurogenic pathway, disruption of which may have significant implications in conditions where combined cognitive impairments, interneuron loss, and immune system activation occurs, such as temporal lobe epilepsy and Alzheimer's disease

Elimination of Arctic Variant Rabies in Red Foxes, Metropolitan Toronto

To control the arctic variant of rabies virus in red foxes, 332,257 bait doses containing live, attenuated Evelyn-Rokitnicki-Abelseth rabies vaccine were distributed in greater metropolitan Toronto during 1989–1999. Human and pet contact with bait was minimal, and no adverse reactions to the vaccine were noted. Significantly fewer rabid foxes were found during the 17 years after fox baiting (5 cases during 1990–2006) than in the 17 years before (96 cases during 1973–1989). The last report of a rabid fox in metropolitan Toronto was in 1996 (reporting period through September 2006), which confirms that distributing oral rabies vaccine bait is a feasible tactic for the control of rabies in foxes in urban environments