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COMPUTERS 1,000 TIMES FASTER? QUICK-CHANGE MATERIALS BREAK SILICON SPEED LIMIT FOR COMPUTERS

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Faster, smaller, greener computers, capable of processing information up to 1,000 times faster than currently available models, could be made possible by replacing silicon with materials that can switch back and forth between different electrical states.

The present size and speed limitations of computer processors and memory could be overcome by replacing silicon with ‘phase-change materials’ (PCMs), which are capable of reversibly switching between two structural phases with different electrical states – one crystalline and conducting and the other glassy and insulating – in billionths of a second.

Modelling and tests of PCM-based devices have shown that logic-processing operations can be performed in non-volatile memory cells using particular combinations of ultra-short voltage pulses, which is not possible with silicon-based devices.

In these new devices, logic operations and memory are co-located, rather than separated, as they are in silicon-based computers. These materials could eventually enable processing speeds between 500 and 1,000 times faster than the current average laptop computer, while using less energy. The results are published in the journal Proceedings of the National Academy of Sciences.

The processors, designed by researchers from the University of Cambridge, the Singapore A*STAR Data-Storage Institute and the Singapore University of Technology and Design, use a type of PCM based on a chalcogenide glass, which can be melted and recrystallized in as little as half a nanosecond (billionth of a second) using appropriate voltage pulses.

The calculations performed by most computers, mobile phones and tablets are carried out by silicon-based logic devices. The solid-state memory used to store the results of such calculations is also silicon-based. “However, as demand for faster computers continues to increase, we are rapidly reaching the limits of silicon’s capabilities,” said Professor Stephen Elliott of Cambridge’s Department of Chemistry, who led the research.

The primary method of increasing the power of computers has previously been to increase the number of logic devices which they contain by progressively reducing the size of the devices, but physical limitations for current device architectures mean that this is quickly becoming nearly impossible to continue.

Currently, the smallest logic and memory devices based on silicon are about 20 nanometres in size – approximately 4000 times thinner than a human hair – and are constructed in layers. As the devices are made ever smaller in order to increase their numbers on a chip, eventually the gaps between the layers will get so small that electrons which are stored in certain regions of flash non-volatile memory devices will be able to tunnel out of the device, resulting in data loss. PCM devices can overcome this size-scaling limit since they have been shown to function down to about two nanometres.

An alternative for increasing processing speed without increasing the number of logic devices is to increase the number of calculations which each device can perform, which is not possible using silicon, but the researchers have demonstrated that multiple calculations are possible for PCM logic/memory devices.
First developed in the 1960s, PCMs were originally used in optical-memory devices, such as re-writable DVDs. Now, they are starting to be used for electronic-memory applications and are beginning to replace silicon-based flash memory in some makes of smartphones.

The PCM devices recently demonstrated to perform in-memory logic do have shortcomings: currently, they do not perform calculations at the same speeds as silicon, and they exhibit a lack of stability in the starting amorphous phase.

However, the Cambridge and Singapore researchers found that, by performing the logic-operation process in reverse – starting from the crystalline phase and then melting the PCMs in the cells to perform the logic operations – the materials are both much more stable and capable of performing operations much faster.

The intrinsic switching, or crystallization, speed of existing PCMs is about ten nanoseconds, making them suitable for replacing flash memory. By increasing speeds even further, to less than one nanosecond (as demonstrated by the Cambridge and Singapore researchers in 2012), they could one day replace computer dynamic random-access memory (DRAM), which needs to be continually refreshed, by a non-volatile PCM replacement.

In a silicon-based system, information is shuffled around, costing both time and energy. “Ideally, we’d like information to be both generated and stored in the same place,” said Dr Desmond Loke of the Singapore University of Technology and Design, the paper’s lead author. “Silicon is transient: the information is generated, passes through and has to be stored somewhere else. But using PCM logic devices, the information stays in the place where it is generated.”

“Eventually, what we really want to do is to replace both DRAM and logic processors in computers by new PCM-based non-volatile devices,” said Professor Elliott. “But for that, we need switching speeds approaching one nanosecond. Currently, refreshing of DRAM leaks a huge amount of energy globally, which is costly, both financially and environmentally. Faster PCM switching times would greatly reduce this, resulting in computers which are not just faster, but also much ‘greener’.”

The research was part-funded by the UK Engineering and Physical Sciences Research Council (EPSRC).

Ring and bracelet system designed to help the hearing-impaired.

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Take rings, add a bracelet, and you have a helping mechanism for the hearing-impaired in a novel design. For people who have hearing handicaps and do not know sign language, the ring and bracelet system can help them out, both in communicating what they need to say and in getting messages they can read. First, a Sign Language Ring behaves as a translating device that picks up motion and gestures and translates them into words, delivered through voice by the bracelet. The bracelet can translate spoken words into its readable display panel for the wearer to read. After use, the rings can be set into the bracelet for storage.

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The design was inspired by Buddhist prayer beads. The name of the entire system is the Sign Language Ring, which is actually a set of rings and a bracelet. In all, six gesture-detecting finger rings can be snapped and stored on the bracelet. The user can program certain gestures to a specific word if desired. The speaker box and readable display are wrapped around the bracelet. After use, the rings can be set into the for storage.

Sign Language Ring is a 2013 winner of the red dot award for design concept. The red dot award for design concept is an annual design competition for design concept and prototypes. Winning concepts are exhibited at the red dot museum in Singapore for at least one year.

This attempt comes at a time when wearable technologies market watchers are recognizing a subset that carries ample opportunities for growth, and that is wearables as disability technologies for the deaf, blind, paralyzed, and elderly. In turn, there is interest in “hear ware,” which would include embedding jewelry with technologies that can help those who have hearing difficulties.

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In a GigaOm Pro article titled “The wearable computing market: a global analysis by Jody Ranck, the author made note of the 2006 event in London, where the Victoria and Albert Museum hosted an exhibition on hear ware. These were technologies developed in response to a call from the UK Design Council to rethink the hearing aid. The result, said the author, was a fascinating array of wearable technologies outfitted with sensors and hearing devices.

Brain tumour genes identified.

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The team was led by Professor Brandon Wainwright, Dr Laura Genovesi and Dr Melissa Davis from The University of Queensland’s Institute for Molecular Bioscience.

Professor Brandon Wainwright said these genes provided potential targets for treatment.

“Brain tumours are the most common cause of cancer death in children,” Professor Wainwright said.

“Those who do survive often experience significant neurological, intellectual and physical disabilities as a result of their treatment, which involves surgical removal of the tumour followed by radiotherapy and chemotherapy.

“We clearly need more effective and less invasive options to treat medulloblastoma and improve outcomes for both children and adults with this devastating disease.”

There are four different sub-types of medulloblastoma, each with their own molecular signature.

The researchers identified underlying genetic regulatory networks that were present in all of the sub-types, a discovery that Professor Wainwright said was important in advancing treatments.

“We are now searching for existing drugs that may block these gene networks and act as viable treatment alternatives for medulloblastoma.”

The team, which included researchers from Australia, Singapore, Canada, the United Kingdom and the United States, made the discovery after screening 85 tumours.

The results were published in the highly prestigious scientific journal Proceedings of the National Academy of Sciences USA.

Cheaper solar material explained.

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In the near future, solar panels will not only be more efficient but also a lot cheaper and affordable for everyone, thanks to research by Nanyang Technological University (NTU) scientists.

This next generation solar cell, made from organic-inorganic hybrid perovskite materials, is about five times cheaper than current thin-film solar cells, due to a simpler solution-based manufacturing process.

Perovskite is known to be a remarkable solar cell material as it can convert up to 15 per cent of sunlight to electricity, close to the efficiency of the current solar cells, but scientists did not know why or how, until now.

In a paper published in the world’s most prestigious academic journal, Science, NTU’s interdisciplinary research team was the first in the world to explain this phenomenon.

The team of eight researchers led by Assistant Professor Sum Tze Chien and Dr Nripan Mathews had worked closely with NTU Visiting Professor Michael Grätzel, who currently holds the record for perovskite solar cell efficiency of 15 per cent, and is a co-author of the paper. Prof Grätzel, who is based at the Swiss Federal Institute of Technology in Lausanne (EPFL), has won multiple awards for his invention of dye-sensitised solar cells.

The high sunlight-to-electricity efficiency of perovskite solar cells places it in direct competition with thin film solar cells which are already in the market and have efficiencies close to 20 per cent.

The new knowledge on how these solar cells work is now being applied by the Energy Research Institute @ NTU (ERI@N), which is developing a commercial prototype of the perovskite solar cell in collaboration with Australian clean-tech firm Dyesol Limited (ASX: DYE).

Asst Prof Sum said the discovery of why perovskite worked so well as a solar cell material was made possible only through the use of cutting-edge equipment and in close collaboration with NTU engineers.

“In our work, we utilise ultrafast lasers to study the perovskite materials. We tracked how fast these materials react to light in quadrillionths of a second (roughly 100 billion times faster than a camera flash),” said the Singaporean photophysics expert from NTU’s School of Physical and Mathematical Sciences.

“We discovered that in these perovskite materials, the electrons generated in the material by sunlight can travel quite far. This will allow us to make thicker solar cells which absorb more light and in turn generate more electricity.”

The NTU physicist added that this unique characteristic of perovskite is quite remarkable since it is made from a simple solution method that normally produces low quality materials.

His collaborator, Dr Nripan Mathews, a senior scientist at ERI@N, said that their discovery is a great example of how investment in fundamental research and an interdisciplinary effort, can lead to advances in knowledge and breakthroughs in applied science.

“Now that we know exactly how perovskite materials behave and work, we will be able to tweak the performance of the new solar cells and improve its efficiency, hopefully reaching or even exceeding the performance of today’s thin-film solar cells,” said Dr Mathews, who is also the Singapore R&D Director of the Singapore-Berkeley Research Initiative for Sustainable Energy (SinBeRISE) NRF CREATE programme.

“The excellent properties of these materials, allow us to make light weight, flexible solar cells on plastic using cheap processes without sacrificing the good sunlight conversion efficiency.”

Professor Subodh Mhaisalkar, the Executive Director of ERI@N said they are now looking into building prototype solar cell modules based on this exciting class of materials.

“Perovskite-based solar cells have the potential to reach 20 per cent solar cell efficiencies and another great benefit of these materials is their amenability to yield different translucent colours, such as red, yellow or brown. Having such colourful solar glass will create new opportunities for architectural design,” he added.

The NTU team, consisting of six scientists, one postgraduate and one undergraduate, took six months to complete this fundamental research project, which was funded by NTU and the National Research Foundation, Prime Minister’s Office, Singapore.

The nun teaching taekwondo to sick children.

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Sister Linda Sim gave up taekwondo when she joined a convent. Years later, she’s dusted off her black belt at a Singaporean hospice to teach children recovering from cancer.

When she was much younger, Linda Sim wanted to join the army, but was told she was too small.

“Next I thought I could be a policewoman – to protect people,” she says, but she didn’t make the weight requirements for the police force, either.

Instead, she discovered taekwondo in 1971, and it seemed to fulfil her need to help other people. “If I had a black belt I thought I could be a bodyguard and protect somebody.” Within a few years, she achieved just that.

Though the sport gave her great mental strength, she didn’t find a practical use for her martial art for more than three decades.

Much to the chagrin of her parents, Sim met the Franciscan Missionaries of the Divine Motherhood, and decided to join them by becoming a Catholic nun.

“Being the only daughter, my mum was very upset when I said I would give my life to God and be a missionary,” she says. Her parents had hoped she would provide them with grandchildren.

Since the group’s headquarters were on the other side of the world in Britain, she would disappoint them further by leaving Singapore.

“I spent 17 years in England and three more in Africa, where I ran a hospital in Zimbabwe,” she says.

During her absence, a relationship developed between the Singapore Taekwondo Federation and Mount Alvernia hospital in the centre of the country.

Ming Wong, secretary general of the federation explains that an employee of the hospital thought some of its patients – young children being treated for cancer – could benefit from the sport. They were “stuck inside playing snakes and ladders”, she says, and the organisation agreed to provide training sessions for them.

Linda Sim with students

It was not until 2004, when Sim’s mother was diagnosed with Alzheimer’s disease, that she felt she had to return to Singapore.

When she saw the classes taking place, she knew she wanted to be involved. “That was what I had to leave behind in order to be a sister, and so I thought ‘now I’m reunited’,” she says.

Today she runs a weekly class for about 20 people, all of whom have brain tumours or childhood leukaemia. Most are young children, although three are now in their 20s, having trained under Sim for many years.

One of the older students, Ng Wei Hau, was diagnosed with a brain tumour at the age of 12 and given just six months to live by his doctors. “When I first met him he was in a wheelchair. When he reached 21 he was walking with a frame, when he reached 23 he had a stick, and now he walks unaided,” she says. Despite being partially deaf and blind, Wei Hau became a black belt last year under Sim’s tutelage.

“These children try to do their best however they can, despite their sickness,” says Wong. “I think because they want to live life for the fullest because they want to enjoy whatever time they have.”

The federation’s charitable work is not just limited to children from the hospital. The organisation works with children’s homes and other disadvantaged groups to offer free taekwondo classes to others who would not usually come into contact with the sport.

For Sim, religion is central to her motivation. Whereas most sisters teach religious education in quite a traditional way, she thinks the taekwondo classes allow her to lead by example instead.

“For me I can actually be a presence and a witness to God’s love without actually quoting scripture,” she says. “It gives me a lot of peace and satisfaction. It’s about evangelising without having to mention going to church.”

Neurological complications of dengue virus infection.

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Dengue is the second most common mosquito-borne disease affecting human beings. In 2009, WHO endorsed new guidelines that, for the first time, consider neurological manifestations in the clinical case classification for severe dengue. Dengue can manifest with a wide range of neurological features, which have been noted—depending on the clinical setting—in 0·5—21% of patients with dengue admitted to hospital. Furthermore, dengue was identified in 4—47% of admissions with encephalitis-like illness in endemic areas. Neurological complications can be categorised into dengue encephalopathy (eg, caused by hepatic failure or metabolic disorders), encephalitis (caused by direct virus invasion), neuromuscular complications (eg, Guillain-Barré syndrome or transient muscle dysfunctions), and neuro-ophthalmic involvement. However, overlap of these categories is possible. In endemic countries and after travel to these regions, dengue should be considered in patients presenting with fever and acute neurological manifestations.

Diagnosis

Clinical suspicion is essential for diagnosis of dengue because many symptoms are non-specific. Various methods are available for laboratory confirmation. During the first days of infection, dengue virus is present in blood; thus, at that time, detection of NS1 antigen or RNA by RT-PCR and viral culture are appropriate diagnostic methods.1 Dengue virus-specific IgM antibodies are present in serum samples 3—10 days after disease onset.1 IgM capture (MAC)-ELISA is the most widely used serological test. Antibodies against other flaviviruses (eg, Japanese encephalitis, West Nile virus, yellow fever) might cross-react with dengue virus, leading to false-positive reactions.136

In endemic countries, or among travellers who recently (<14 days) returned from such regions, dengue should be ruled out in patients with fever and neurological features (panel 2). If possible, lumbar puncture should be done and CSF analysed for abnormalities and for dengue virus-specific antibodies, NS1 antigen, or dengue virus RNA, depending on available laboratory facilities. Differential diagnosis in patients with febrile encephalopathy includes malaria, tuberculosis, leptospirosis, rickettsial infection, and other bacterial or viral diseases (caused by, for example, Japanese encephalitis, West Nile virus, or herpes simplex virus [HSV]), depending on the local epidemiology. In a prospective hospital-based study in Vietnam, most children with acute encephalitis of presumed viral origin were infected with Japanese encephalitis (26%), followed by enteroviruses (9%) and dengue virus (5%).30 In adults and adolescents in Brazil, dengue was the leading cause of viral encephalitis (47%), followed by infections with HSV-1.31

To differentiate dengue encephalitis from encephalopathy, detection of dengue virus, NS1 antigen, or dengue virus-specific IgM antibodies in CSF is helpful. Nevertheless, sensitivity of serological techniques can be low. Dengue virus-specific IgM antibodies have been recorded in CSF of 22—33% of patients diagnosed with dengue encephalitis (Table 1, Table 2).90Detection of dengue virus in CSF could be hampered by low sensitivity of RT-PCR in CSF, compared with findings in serum, because of a lower viral load.137 Moreover, measurement of IgM antibodies in CSF might not be a reliable diagnostic marker of dengue CNS involvement, owing to low titres in CSF.138 Abnormalities in CSF—such as lymphocytic pleocytosis—support the diagnosis of dengue encephalitis, but they are not always present (Table 1, Table 2, Table 3). A mild increase in CSF protein has been recorded.28 In a series of patients with neurological complications of dengue, four of seven with encephalitis had no alterations in CSF.90 Therefore, normal CSF cellularity should not exclude dengue encephalitis.

The case definitions in panel 2 are designed to be used epidemiologically and clinically and to guide diagnosis and prognosis. Although we propose criteria for a classification scheme, a topic as challenging and as controversial as dengue encephalitis needs to be addressed in a standard way. Prospective studies are needed to assess the specificity and sensitivity of the proposed case definitions and to generate supporting evidence. Cases fulfilling neither the definition for encephalitis nor that for encephalopathy—eg, without CSF testing or when categories are overlapping—can be categorised as other or non-specified dengue CNS involvement.

Neuroimaging might provide additional clues in the diagnosis of neurological complications of dengue. In dengue encephalitis, brain MRI can be normal or show focal parenchymal abnormalities.22, 41 Nevertheless, no specific MRI findings suggestive of dengue encephalitis have been reported. Neuroimaging features of patients with dengue are diverse, with cerebral oedema the most commonly reported finding.77 Meningeal enhancement on post-contrast MRI has been reported occasionally as well.77

Finally, EEG abnormalities can be seen in dengue patients with neurological complications. In a study of 23 patients with dengue virus infection and neurological symptoms, EEG abnormalities were recorded in 12 people.139 Slowing on EEG can be seen, but this finding is unspecific and could be attributable to seizures, intracranial haemorrhage, and viral infection per se, besides encephalopathy.77

Management

Currently, no effective antiviral agents are available to treat symptomatic dengue virus infection.140 Therefore, management remains supportive. In mild cases, antipyretic drugs and oral fluids could be useful. Acetyl-salicylic derivatives and other non-steroidal anti-inflammatory drugs should be avoided. Management of haemorrhagic complications should be initially conservative. Precise management of intravenous fluids is needed, and blood or platelet transfusion is only necessary when severe bleeding takes place.1

In patients with severe dengue and signs of plasma leakage, prompt fluid resuscitation is imperative, with close monitoring of packed-cell volume to avoid fluid overload. Isotonic crystalloid solutions should be used, with isotonic colloid solutions reserved for patients presenting with profound shock or those who do not have a response to initial crystalloid treatment.140, 141 In a randomised controlled trial from Vietnam,142 use of oral prednisolone during the early acute phase of dengue infection was not associated with a reduction in the development of shock or other recognised complications of dengue virus infection.

For supportive management of patients with neurological manifestations, possible underlying causes such as intracranial bleeding, liver failure, hyponatraemia, hypokalaemia, or metabolic acidosis should be ruled out and—if possible—corrected. Management of dengue encephalitis remains supportive and should include adequate hydration, nutrition, monitoring of consciousness, and maintenance of airways.143 Symptomatic seizures should be treated with non-hepatotoxic anticonvulsants. Decompressive craniotomy and cerebral haematoma evacuation were done in two patients with dengue after correction of prothrombin time and platelet count.92 Nevertheless, prognosis is not good and, in one case series, two of five patients died.92 At this moment, haematoma surgery cannot be proposed as a routine treatment for dengue virus intracranial bleeding.

Some clinicians recommend treatment of immune-mediated dengue CNS involvement with pulses of intravenous methylprednisolone for several days.50, 69, 72 However, up to now, no randomised controlled trial has been undertaken to show the efficacy of this approach in patients with dengue myelitis or acute disseminated encephalomyelitis. High doses of intravenous immunoglobulin might be useful to treat post-dengue Guillain-Barré syndrome. Supportive treatment—including hydration and analgesic drugs—is used for myalgia and transitory muscle dysfunction. The effectiveness of corticosteroids in dengue myositis remains to be proven.

No treatment has been approved for neuro-ophthalmic manifestations of dengue. Steroids have been administered previously because of possible underlying immune mechanisms, although up to now no randomised trials have been done. Topical steroids have been used to treat anterior uveitis, whereas pulsed intravenous methylprednisolone or systemic oral steroids might be indicated for extensive retinal vasculitis.120

Currently, no vaccine is available for protection against dengue. However, several vaccine candidates are in development.

Conclusions and future research

Dengue should be included in the differential diagnosis of acute febrile disease with neurological manifestations in dengue-endemic countries and in patients with a recent travel history to an endemic region. Many neurological manifestations of dengue have been recorded, ranging—with substantial overlap—from encephalitis and encephalopathy to immune-mediated syndromes and muscle involvement. Recent evidence suggests that dengue virus has neuroinvasive capacity. In several studies in endemic areas, a large proportion of viral encephalitis was caused by dengue virus.26—32 However, even though CNS involvement is included now as a criterion for severe dengue in the 2009 WHO case classification,1 no standardised case definitions or diagnostic criteria for dengue encephalitis or encephalopathy have been agreed, which leads to inconsistent use of these terms in published work.

An updated WHO dengue guideline should include a case definition for dengue encephalitis and encephalopathy, to guide clinicians and clinical epidemiological researchers into this topic. A case classification—such as the one proposed in panel 2—could serve as a starting point, which could be reviewed by WHO, agreed by consensus and best available current evidence, and refined as additional data become available from prospective studies. For this reason, assessment of CSF in patients with suspected neurological manifestations of dengue should be standardised. Very few published reports present findings of CSF testing for dengue virus, dengue virus-specific IgM antibodies, or NS1 antigen combined with CSF cellularity and confirmation of dengue in serum samples in a consistent way. Further epidemiological and neuropathological studies are needed to ascertain the true incidence and burden of neurological complications of dengue, to elucidate the underlying pathophysiology, and to assess the sensitivity and specificity of diagnostic markers for dengue encephalitis.

Source: Lancet

Effect of double dose oseltamivir on clinical and virological outcomes in children and adults admitted to hospital with severe influenza: double blind randomised controlled trial.

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Abstract

Objective To investigate the validity of recommendations in treatment guidelines to use higher than approved doses of oseltamivir in patients with severe influenza.

Design Double blind randomised trial.

Setting Thirteen hospitals in Indonesia, Singapore, Thailand, and Vietnam.

Participants Patients aged ≥1 year admitted to hospital with confirmed severe influenza.

Interventions Oral oseltamivir at double dose (150 mg twice a day/paediatric equivalent) versus standard dose (75 mg twice a day/paediatric equivalent).

Main outcome measure Viral status according to reverse transcriptase polymerase chain reaction (RT-PCR) for influenza RNA in nasal and throat swabs on day five.

Results Of 326 patients (including 246 (75.5%) children aged <15), 165 and 161 were randomised to double or standard dose oseltamivir, respectively. Of these, 260 (79.8%) were infected with influenza virus A (133 (40.8%) with A/H3N2, 72 (22.1%) with A/H1N1-pdm09, 38 (11.7%) with seasonal A/H1N1, 17 (5.2%) with A/H5N1) and 53 (16.2%) with influenza virus B. A further 3.9% (13) were false positive by rapid antigen test (negative by RT-PCR and no rise in convalescent haemagglutination inhibition titers). Similar proportions of patients were negative for RT-PCR on day five of treatment: 115/159 (72.3%, 95% confidence interval 64.9% to 78.7%) double dose recipients versus 105/154 (68.2%, 60.5% to 75.0%) standard dose recipients; difference 4.2% (−5.9 to 14.2); P=0.42. No differences were found in clearance of virus in subgroup analyses by virus type/subtype, age, and duration of illness before randomisation. Mortality was similar: 12/165 (7.3%, 4.2% to 12.3%) in double dose recipients versus 9/161 (5.6%, 3.0% to 10.3%) in standard dose recipients. No differences were found between double and standard dose arms in median days on supplemental oxygen (3 (interquartile range 2-5) v 3.5 (2-7)), in intensive care (4.5 (3-6) v 5 (2-11), and on mechanical ventilation (2.5 (1-16) v 8 (1-16)), respectively. No important differences in tolerability were found.

Conclusions There were no virological or clinical advantages with double dose oseltamivir compared with standard dose in patients with severe influenza admitted to hospital.

Discussion

In this large randomised controlled trial of antiviral treatment in patients with severe influenza we found that double dose oseltamivir was well tolerated but did not confer additional virological or clinical benefits over standard dose treatment in patients in South East Asia. There were no differences between the treatment arms in detection of viral RNA or infectious virus on day five, and there were also no differences in clinical failure rates, mortality in hospital, or rates of adverse events between the dose regimens on day five. We enrolled a heterogeneous population that included mostly children and also those infected with avian H5N1 or H1N1-pdm09 viruses. While subgroup analyses based on age cohorts, virus type and subtype, and time to treatment did not suggest additional virological efficacy of double dose oseltamivir in any subgroup, these results should be interpreted with caution as the study was not powered for these analyses.

Our patients presented relatively late after the onset of illness, a median of five days overall (seven days for H5N1). Despite administration of oseltamivir, about 30% of those enrolled remained positive for viral RNA (the primary endpoint) after five days of treatment. Timing of oseltamivir treatment is important as several studies have shown that early treatment confers greater virological and clinical benefits.4 5 6 32 33 34 In particular, later viral clearance has been noted with delayed treatment with oseltamivir compared with treatment within two to three days after onset of symptoms in observational reports from patients with H1N1-pdm09, especially those with severe illness.35 36 37 38 39 40 In the current trial, 73 (22.4%) patients presented within three days of illness, but even in this subpopulation, double dose oseltamivir was not associated with more rapid viral RNA clearance. Over a quarter of patients received neuraminidase inhibitors before enrolment, which could have influenced the effect size and contributed to the low proportion of patients shedding virus at day five in both treatment groups.

Although viral RNA detection in samples from the upper respiratory tract might not accurately reflect viral replication in the lower respiratory tract, especially in those with severe illness,39 prolonged viral RNA detection in upper respiratory tract samples has been shown to correlate with inpatient morbidity and prolonged hospital stay. In our study viral detection on day five was observed at about twofold the frequency in those meeting the criteria for clinical failure, although lack of clinical failure was not a surrogate for cessation of viral detection. Thus in our study the delays in starting treatment with oseltamivir also probably contributed to the substantial rates of admission to intensive care (18%), use of supplemental oxygen (30%), mechanical ventilation (12%), and mortality in hospital of 6.4%. Although our study was not placebo controlled for ethical reasons, other studies indicate that early oseltamivir treatment in people with severe influenza is associated with both clinical benefits and more rapid viral clearance from upper respiratory tract samples.4 8 14 36 37 38 39 40 41

Possible reasons for findings

It is unclear why double dose oseltamivir does not seem to offer benefit over standard dose in patients with severe influenza. Blood trough concentrations of oseltamivir carboxylate from 75 mg or 150 mg twice daily in influenza exceed the IC50 (inhibitory concentration) of influenza viruses.42 43 Inhibition of viral neuraminidase by oseltamivir might be a saturable process, and maximal inhibition might be achieved with a standard dose; exceeding these concentrations might not produce an additional clinical or virological effect. In this regard, a randomised oseltamivir controlled study of intravenous peramivir (BioCryst Pharmaceuticals, Durham, NC), which reaches over 20-fold higher peak blood concentrations of active metabolite than oseltamivir carboxylate, found similar viral reductions in patients with influenza A virus admitted to hospital.44 Further studies of peramivir and other intravenous neuraminidase inhibitors currently in progress should provide additional evidence regarding this hypothesis.

Infection with avian H5N1 virus, higher baseline viral load, and severity of disease were independently associated with longer viral RNA detection. The association between avian H5N1, severe illness, and prolonged shedding has been well described.14 The clearance kinetics of influenza viruses, both without antiviral treatment and with oseltamivir treatment,32 41 could explain longer viral RNA detection with higher baseline viral loads. It is unclear whether the independent association with disease severity might be related to impaired mechanisms of viral clearance or higher intrinsic rates of viral replication or both in these patients. Severe chronic comorbidities are seen commonly in industrialised countries and are related to prolonged viral shedding but most of our patients lacked these comorbidities.40 41

The heterogeneous population characteristics, geographical differences in recruitment (most patients were from Vietnam but there were no significant differences between Vietnam and other sites), and the variety of infecting viruses in our trial reflect the clinical circumstances in South East Asia during our study but might be viewed as a limitation. Most of these patients were children and had low or normal BMI, and for all patients only about a fifth reported a chronic underlying medical condition. Thus, our findings are applicable primarily to the region where the study was conducted and other settings with similar characteristics of influenza epidemiology. We did not have many adults in our study and results were inconclusive but indicate no difference in efficacy between the two oseltamivir regimens. We would caution the extension of our results to, for example, morbidly obese adults with severe influenza and those who could have underlying chronic illnesses. We conducted several statistical comparisons and inevitably subgroup analyses involved small numbers; thus power was limited and some significant results could have resulted by chance. Additionally, as all patients were randomised to an active treatment, our study was not designed to evaluate the efficacy of oseltamivir in severe influenza nor in H5N1 infections. This large randomised trial did, however, examine an important clinical and public health question and showed a lack of a clinical or virological benefit of double dose compared with standard dose oseltamivir in patients admitted to hospital with severe influenza. Our results and other observational reports from avian H5N110 and H1N1-pdm0911 36 infections do not support routine use of double dose oseltamivir to treat severe influenza. These findings have implications for both clinical management and pandemic preparedness including during the current H7N9 epidemic.16 17 18

What is already known on this topic

  • Clinical trials in patients with uncomplicated influenza have shown that treatment with oseltamivir has clinical and virological benefit when administered within 48 hours of onset of symptoms
  • Observational studies in severe influenza have shown that oseltamivir treatment, if given early, is associated with reduced mortality and shorter length of hospital stay. Reduced mortality has also been reported for patients with H5N1 influenza treated with oseltamivir
  • Several authorities have suggested the use of double dose oseltamivir for severe influenza, although there is no clinical evidence to support this
  • In the largest randomised trial on the treatment of severe influenza, no clinical or virological benefit of double dose oseltamivir over standard dose was found
  • These findings have implications for both clinical management of severe influenza and for pandemic preparedness of emerging influenza viruses including the current H7N9 epidemic

What this study adds

 

Source: BMJ