Wednesday, 26 September 2012

Preventing Cold Housing Can Cause Mould in the Home

Housing authorities and governments over the last 40 years have gone to great trouble to improve the standard of housing in their countries by installing insulation, better heating and removing draughts - this news article from New Zealand is typical and many homeowners speaks of the potential benefits of a warmer home with less condensation.

Unfortunately after a short period of improvement in living conditions as more heat is retained within living areas we have found that condensation is far from 'cured'. The amount of moisture in the air can rise as warmer air can hold more water than cold air, but ultimately moisture must be exhausted out of the property somehow otherwise it will inevitably reappear, especially during the night as the heating goes off and air cools. Once moisture starts to settle on walls and furnishing moulds will quickly follow as it is not warmer air that prevents moulds growing - it is the absence of moisture.

If all draughts are plugged and ventilation grids are blocked up, including old chimney's then there is nowhere for all the moisture generated in a building by its occupants (washing, clothes drying, breathing) to go. Installation of insulation has to be done so as to retain ventilation, insulating materials must not be biodegradable (shredded paper, sheep's wool) and the occupants need to be made aware of the potential problems with mould if they do not change the way they live a little - a warm home comes with responsibilities! Ventilation that ensure good flow of fresh air into a house must be installed if not present - and their are devices which will retain most of the heat in a house as damp air is removed.

The Institute of Specialist Surveyers and Engineers (ISSE) and the National Aspergillosis Centre, Manchester, UK are investigating a partnership to help prevent moulds growing in homes and other properties. There is to be a series of qualifications to help train building inspectors and remediators with damp as a main focus, and a national awareness campaign to help educate all interested parties.

Tuesday, 25 September 2012

Newsbite: Aflatoxin Widespread in US Mid West Drought

This year has been one of very little rain in the American MidWest (64% of the lower 48 states are in serious drought - a new record (U.S. Drought Monitor)), promoting growth of Aspergillus. As crops dry out (mainly corn/maize) the plants become highly stressed in the dry heat and are vulnerable to infection. Once the crop is infected Aspergillus itself becomes stressed as moisture is short and it starts to defend itself by producing mycotoxins which contaminate the crop. If the contamination exceeds 20 parts per billion it cannot be used for human or dairy cattle consumption. Consequent shortages effect both human food needs and food needed for cattle. more...

Monday, 24 September 2012

Newsbite: Rarity of Aspergillosis Claims Another Victim

Invasive aspergillosis is so rare (especially in people with healthy immune systems) there are many doctors who have never seen a case. Aspergillosis is also good at mimicking other types of infection so accurate diagnosis is difficult and tends to be slow, leading to a poorer outcome. We have already reported in this blog several fatalities caused by these problems (1, 2, 3, 4, 5) and this case is another - the lead surgeon had never seen a case in 25 years of practice. The only solution for this will be to increase awareness of aspergillosis and to improve diagnostic tools.
In addition NOTE that this case was only uncovered after an autopsy was performed - this vital learning tool is underused as discussed in an earlier blog more...

Friday, 21 September 2012

Europe Dominates World Research into Fungi

The online journal and European news journal Lab Times periodically releases analyses of the citation ranking of countries of the world in order of the number of publication that are referred to by other researchers in a particular field.
Citations are a form of performance measurement for academics as arguably the number of times a research paper is cited by other authors reflects its importance in that field more accurately than simply counting the number of papers published by a researcher or research group.

This is because some research papers are more important than others. Those which are amongst the first to describe a finding will be cited by all of those following and will get a high number of citations. Those that merely make a minor point in an already established field of research will attract relatively few citations.

Citation indexes are routinely collated and used by journals as a measure of their importance and are included as one factor in calculating impact factor.

 Lab Times calculates a citation 'league table' for scientists in each field of research - effectively a league table of importance of each researcher in each field of research.

Their most recent analysis is for the field of fungal research and interestingly it shows that Europe dominates the world in this category, particularly powered by major fungal research centres in Germany, Holland and England, closely followed by France and Spain. Taken together the EU claims nearly twice as many citations as the US and nearly ten times as many as Japan.

Within Europe Germany dominates closely followed by Holland but it might be worth noting that the UK is divided up into its component countries. If this had not happened UK might well edge out Germany for first place as there are prolific centres of excellence in fungal research in both Scotland (currently led by Aberdeen University) and Wales (Cardiff University).

This success is said to largely reflect the size of the CBS Fungal Biodiversity Centre  in Holland, the Pasteur Institute in France as well as multiple smaller Universities throughout Europe but perhaps most remarkable is the research prominence of the University of Manchester in this field. Professors David Denning and Stephen Oliver are placed first and third in the league table for authorship of papers and both work in Manchester.

Thursday, 20 September 2012

Newsbite: First Recorded Case of Antifungal Resistant Aspergillus Strain Originating in the Environment

Recent studies have shown that antifungal-resistant strains of Aspergillus can be found outside of hospitals and other non-clinical environments. It is assumed that agricultural use of antifungal azole drugs (very similar to those used to treat infected patients) could be promoting the development of these resistant strains and it has been suggested that some of the resistant organisms found in clinical samples may be the result of a patients breathing in resistant Aspergillus. The first case where it has been proven that a resistant clinical specimen has originated in the environment has now been published more...

Wednesday, 19 September 2012

Newsbite: Fungal Paper Celebrates Rare 10,000th Citation

Scientific papers are carefully managed as much rests on their impact. A paper that is referred to in another publication (cited) is clearly important or significant enough for another research group to quote its findings. Most scientific papers might be cited 10 - 100 times. The paper memorably entitled "Amplification and direct sequencing of fungal ribosomal RNA genes for phylogenetics" recently achieved the rare accolade of being cited over 10 000 times more...

Tuesday, 18 September 2012

Aspergillosis and the Role of Misdiagnosis in Morbidity and Mortality

A recent US study systematically surveyed 31 reports giving a total of nearly 6000 autopsies. Of these cases anything from 6 - 100% showed evidence of misdiagnosis - indicating that the doctors diagnosed and treated incorrectly, presumably often contributing to death (mortality).
28% of all autopsies revealed evidence of at least one missed diagnosis and 8% evidence of a Class I (Goldman criteria) error which means that the misdiagnosis could have contributed to or directly caused death (the most common of which were heart attack, pulmonary embolism, artery blockage in the lungs, pneumonia and aspergillosis).

About two thirds of all missed diagnoses are thought to have not contributed to death

This is clearly a serious issue and as a result of this study an estimate for the United States is that 40 500 deaths occur in intensive care units every year as a result of misdiagnosis. Given that aspergillosis is one of the most common of these (up to 30% of Class I misdiagnoses - though the paper isn't clear on this) this could account for up to 13 000 deaths a year. For a rare infection such as aspergillosis that represents a substantial increase in the number of recorded fatal infections per year.

Why so many? What can we do about it?

The report mentions several factors involved and many are mentioned in this slide presentation by the author (Winters suggested hospitals consider employing intensivists to monitor their ICUs, as well as improving nurse-to-patient ratios) but a major factor is the lack of autopsies now carried out to discover the true cause of death. In the US and throughout the EU the rate of autopsies has been falling for years, consequently doctors can no longer learn from comparing what they diagnosed with what actually killed a patient - or at least they can do far less than they used to. Under-representation of aspergillosis as a cause of death is one consequence.

Monday, 17 September 2012

Fungi are Effective at Helping Make a New Generation of Stradivarius Violins

Physisporinus vitreus
One of the most famous and sought after musical instrument over the last few years has been one of the violins made by Stradivarius in his workshops in Italy in the late 1600's and early 1700's. Enthusiasts declare that those violins have no equal and modern attempts to replicate those instruments can never quite meet the sound produced by a Stradivarius. Consequently they sell for many millions of dollars.

Theories abounded as to what was special about this instrument - ranging from the blend of woods to special treatments applied to the wood but essentially it seems to have been concluded that the key is a specific batch of wood that he used. Grown during a particularly cold spell in the 1650-1750's the wood was less dense than normal - but such wood is no longer available.

It should be mentioned that there has been great difficulty measuring much difference between a Stradivarius and more modern violins - even when panels of human experts are tried they often fail to identify the right instrument. Nevertheless they are still highly prized.

Insofar as I have been able to understand the low density of the wood allows the sound to travels through the wood easily, while at the same time its stiffness produced the tone. Modern woods are denser than those picked by Stradivarius but perhaps they could be lightened?

xylaria longipes
In his after dinner speech at the 1st ECRC "Franz-Volhard" Symposium of the Max Delbrück Center for Molecular Medicine (MDC) and Charité -- Universitätsmedizin on Sept. 7, 2012 in Berlin-Buch, Professor Francis W. M. R. Schwarze (Empa, Swiss Federal Laboratories for Materials Science and Technology, St. Gallen, Switzerland) reported that he had treated modern wood with two types of fungus (Physisporinus vitreus and Xylaria longipes) and that the slow digestion of the wood by these fungi had adequately replicated the wood used by Stradivarius.

Tests of violins made with this wood failed to distinguish the new violin from the old (though we know that even with a non-treated violin that is far from easy). Enthusiasts claim that this may make the sound quality of a famous classical instrument accessible to far more people, and encourage young musicians by working with better instruments.

Friday, 14 September 2012

Medical Ethics and Genome Research: Aspergillosis

We have already debated in this blog the difficulties many people who suffer from chronic infection may have when they or their family are thinking about having their genome fully sequenced. Once sequenced the information contained within a genome can tell us many things about that persons vulnerability to disease & disorder in their future life, consequently various parties will immediately have a profound interest in that information

  • the patient
  • their children
  • other genetic relatives (siblings, parents, more distant relatives)
  • person considering having a family with the patient
  • NHS (Government)
  • Mortgage providers
  • Life Insurance companies
  • many more!
Who should know, what should people be told?
Doctors are struggling with the ethics of finding out far more about a patient than they originally intended when they ask for a genome to be sequenced - should they have an agreement with the patient before offering the test if the new information indicates a high probability that the patient will develop an incurable illness? What about if that illness can be cured if the doctor treated the patient before any symptoms developed?

In this article we find that similar ethical dilemma's are not restricted to doctors treating the patient. Researchers currently routinely take samples of tissue from patients after asking for consent and getting a signed agreement off the patients that allows the researcher to proceed (Informed Consent). In some research samples are passed to other researchers, some of who may also be medical doctors.

In one example case genome sequencing was carried out for research purposes on the DNA of a young woman who was planning a double mastectomy to prevent herself getting breast cancer. There was a strong family history of breast cancer in this case so in the absence of any further information this was a sensible precaution albeit drastic. It is likely that the research was to investigate what genetic factors cause breast cancer to run in families, and how they work - some factors would be already known and others not. It is normal practice for this to be done anonymously to protect all parties involved, so the researchers do not know the identity of the tissue donor unless the donor permits that to be known.

As a result of being able to read this person's DNA code the researchers soon realised that this person was one of the lucky family members who were not at risk of breast cancer - but they had also discovered by chance that she planned drastic surgery. Researchers were horrified that the information they had meant she did not have to have the surgery - but they were bound by law not to break the original research agreement with the patients not to disclose the information. The outcome was that a way was found to tell the patient to prevent the surgery and that necessarily triggered a series of similar conversations with all of the family.

Not many people would say that the research team should not have contacted the person considering radical surgery - but where do we draw the line that defines where we must break confidentiality? Many other women in that research project would also have been found to be not at risk of breast cancer but as the researchers did not know anything about those people they did not make contact - was that wrong? In all probability the samples were given for research purposes and not as part of the clinical care of those people - such research could not have gone ahead if the original attention was to disclose the results of the tests to the people involved and future research will not go ahead if that is changed. 

Thursday, 13 September 2012

Intravenous posaconazole passes key test in patients

Whilst oral posaconazole has been licensed since 2006, development of an intravenous formulation has been challenging and slow.
At the recent ICAAC meeting in San Francisco, Professor Johan Maertens and colleagues from Leuven, Belgium and collaborators in Germany described the pharmacokinetics of 2 doses of intravenous (IV)  posaconazole. The 55 patient volunteers all had leukaemia and low white cell counts and were given IV posaconazole to prevent fungal infection. Usually oral posaconazole is administered but this is often poorly absorbed and so can be ineffective. Maertens compared 200mg and 300mg given once daily and found good tolerance and higher protective blood levels of posaconazole from the 300mg dose. The average blood level at 14 days was 1430ng/ml which is associated with good efficacy and protection, the minimum effective level was seen in 95% of patients. Posaconazole is formulated in a novel cyclodextrin product for IV use, similar to voriconazole and itraconazole.

Merck supported this study and will now advance IV posaconazole into randomised clinical studies. This complements a parallel development of an oral tablet of posaconazole.  Since posaconazole is the most broad spectrum antifungal available, limited primarily by poor bioavailablity in highly susceptible patients and occasional resistance, these formulation improvements will help to deliver improved therapy for many patients.

Wednesday, 12 September 2012

Astellas unveils a second generation echinocandin antifungal

At ICAAC  in San Francisco, Dr Souichirou Akamatsu from Astellas summarised the latest data on a second generation echinocandin called ASP9726. The potency of ASP9726 was slightly more than that of first generation echincandin antifungals micafungin and caspofungin in the lab, even when combined with serum. Direct observation of how Aspergillus grows showed marked prevention of filamentous growth compared with the first generation echinocandins. In experimentally infected mice, guinea pigs and rabbits with invasive aspergillosis, ASP9726 greatly improved survival. ASP9726 was also effective against common Candida species and greatly increased survival in a Candida glabrata model, using an isolate resistant to caspofungin. 

The echinocandins are now the leading IV antifungal class in critically ill patients worldwide for treatment of both Candida and Aspergillus infections. Worldwide sales exceed $1,300 million annually and given the only modest efficacy for aspergillosis and resistance emergence in Candida -  are strong arguments for developing  improved echinocandin compounds.
Of the echinocandin family,  Astellas have discovered and developed micafungin, Merck markets caspofungin and Pfizer  has acquired anidulafungin which was originally developed by Lilly.

Friday, 7 September 2012

Pont-Saint-Esprit Mass Poisoning, August 1951

Leon Armunier - The first victim
There is much focus in the media on the possibility of poisoning by fungal toxins - much of it in the context of the home or in damp/mouldy places of work. In those cases it is often presumed that the toxins are breathed in along with numbers of fungal spores and allergens and there is little to show that acutely toxic quantities can be received via that route. Chronic exposure is the subject of current research.

In contrast there is no dispute that sufficient quantities of mycotoxins can be acquired via eating mouldy food - massive quantities can be present on foods that are infected with toxin and those eating it can be unaware of the presence of the toxins, or be forced to eat what food they have as there is nothing else to eat. In fact prior to 1950 there was no good understanding of mycotoxins and what they could do as the toxins had not been isolated or characterised up until then, though the toxic effects of certain fungi were noted and had been the subject of some experimentation (link).

Many mysterious bouts of illness have been noted going back a long way into history - thousands of years in fact and include poisonings referred to as ergot. We now think many of these are consistent with mycotoxin poisoning but proof is impossible.

As recently as 1951 there was an incident in the French village of Pont-Saint-Esprit where hundreds of people started to behave in a highly unusual way (e.g. obsessively counting window panes, attempting to fly) and seven died. The authorities decided that there had been a faulty batch of bread which was made using flour contaminated with a mercury-based fungicide, though that finding has been questioned several times as it does not precisely fit the symptoms observed.

More bizarrely an article was discussed on the BBC in 2010 claiming the the US Central Intelligence Agency (CIA) had been experimenting with the drug LSD on the townspeople of Pont-Saint-Esprit!

This more recent commentary suggests that in fact the poisoning was most likely caused by Aspergillus fumigatus and its toxins (originally suggested by Moreau in 1982) - particularly because the mill that produced the infected flour was reported to have been flooded earlier in the same year - providing excellent conditions for fungal growth withing the flour or stored grain.

We will never what happened at Pont-Saint-Esprit for sure but this one incident illustrates how difficult it is to pin down cases of mycotoxin poisoning, even in relatively modern day cases. Suggested alternative causes can be numerous and unusual and the affected individuals in 1951 found it as hard to prove what caused their illness as they do nowadays when trying to prove in court the existence of a mycotoxin illness caused by inhaled mycotoxin - only one survivor was ever compensated.

Wednesday, 5 September 2012

One in four ICU patients may have a missed diagnosis at death

A new publication from The John Hopkins University studying acute care patients has revealed that up to 28% of adult ICU patients may have one or more misdiagnoses at death. In the US that means as many as 40,500 adult ICU patients in the country may die with a misdiagnosis every year.

The study reviewed more than 5,800 postmortems, researchers found that 28 percent of patients had a missed diagnosis the main ones including : heart attack, pulmonary embolism, artery blockage of the lungs, pneumonia and aspergillosis. Potentially these diagnostic errors could have contributed to or directly caused the patient's death.

The study was published in BMJ Quality and Safety and the research took into account that autopsies are more commonly performed on complex patients.
 Bradford Winters (Associate Professor at John Hopkins) said that although diagnostic errors in the intensive care unit (ICU) may claim as many lives each year as breast cancer, they remain an under-appreciated cause of preventable patient harm.  If diagnosed in time they very  likely would have changed treatment, researchers say.

 Infections and vascular maladies, such as heart attack and stroke, accounted for more than three-quarters of those fatal flaws.
Even though two-thirds of misdiagnosed cases may not have contributed to death, the authors note that the errors could lead to longer hospital stays, unnecessary surgery and poorer quality of life for the patients who survive.
Dr Winters concluded that "we need to develop better cognitive tools that can take into account the 7,000 or more pieces of information that critical care physicians are bombarded with each day to ensure we’re not ruling out potential diagnoses,” Winters says. 
 The study points to the need for additional research to pinpoint the causes of misdiagnosis and identify tools to help diagnosticians more accurately assess patients in the ICU setting.

Newsbite: F2G Ltd Completes $30 Million Financing Round to Fund Pre-clinical and Clinical Development of Novel Anti-fungal Compounds

F2G Limited, an antifungal drug discovery and development company, today announced the completion of a $30 million equity financing round in which two new investors (Advent Life Sciences and Novartis Bioventures) joined the existing syndicate (Sunstone Capital, Merifin Capital, K Nominees, and Astellas Venture Fund). These funds will be used to select a clinical candidate from the F3 series of advanced preclinical analogs and proceed to first in man studies. more...

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