Friday, 27 September 2013

Is Peer Review Broken?

The centuries-old process of assessing the worth of a piece of research prior to it being published is coming under attack and calls for reassessment. All research papers submitted to a scientific journal since the 1650's have been subjected to examination by experts in the field of research that the paper addresses.

This is undertaken to ensure that the paper offers something new but also try to ensure that when someone (usually several people) who is familiar with that type of research has time to look deeply into the data presented, they cannot find and major faults or omissions. Only then is the paper published.

This gives us a minimum standard of trust in the results of that paper. If this system goes wrong and a 'rogue' paper slips through that paper can still be questioned and withdrawn if found to be at fault. Peer review has sustained scientific research for nearly 350 years and the results are difficult to argue with - science has achieved so much that it would not have been able to do without ensuring the bedrocks of the process are of high quality.

 It is however not a perfect system. In a small field there may be only a few people who could thoroughly review an article. This leads to an increase in the probability that the reviewer will know the author of the paper personally (the authors are never told who their reviewers are) and thus rumours of foul play begin to circulate as friends may mutually support each others work. This is not usually a problem of fraud (but fraud does happen measured at 0.3% of all papers) but accusations that a paper has been published in a higher ranked journal than it deserved on merit. Occasionally we hear of a suspicion from a disgruntled researcher who has had lengthy problems getting a paper published and in the meantime someone else has published the same thing or misused their early access to an original work in some other way - perhaps a reviewer has read their paper and stolen their ideas? - always very difficult to prove either way.

In our modern world the system comes under new pressures. This talk outlines some of them:




Full discussion here


Thursday, 26 September 2013

Patients & carers support, National Aspergillosis Centre, UK

The National Aspergillosis Centre holds a meeting every month that tries to inform & support people suffering from aspergillosis. The meeting is recorded and made available at Slideshare where you can watch the whole series.

You can also watch the meetings live on the third friday of the month at 1.30pm local time (UK).


Tuesday, 24 September 2013

Genome sequencing & the Special Case of Henrietta Lacks

Henrietta Lacks
Henrietta Lacks died in Johns Hopkins University Hospital in 1951 of an aggressive cancer. In itself that was not a remarkable event except for close friends and family but Mrs Lacks was not going to be forgotten and for a very special reason.

At that time cancer research was just starting to find ways to grow cancer cells to use to work on and to try to find information that might lead to medication that has since led to increase in the life expectation of many millions of cancer sufferers. Researcher George Gay took some of the cells from tumour tissue after Mrs Lacks had surgery to try to treat her cancer, and he was successful at getting it to grow outside of a human body in a laboratory for the first time. George's work was so important that within a very short time Henrietta Lacks' tumour cells (referred to as HeLa cells) were in use all over the world in cancer research labs and they continue to be to this day. A cursory search of all published articles in the medical research database Pubmed reveals that there are well over 76000 published scientific papers that prominently feature HeLa cells and without doubt many more that use Henrietta Lacks' cells to help their research.

There has been some controversy over the use of HeLa cells as Henrietta was never asked to give her permission for her cells to be used in this way. Back in 1951 that wasn't something that was thought to be necessary but today we regard it as fundamentally important, and now even more so as we are able to read the entire genome of each and every one of us quickly and efficiently.

Readers of this blog will know that we have discussed some of the ethical questions raised by this new technology before, and there are several problems including:

  1. Does the person want to know all of the possible health problems that are revealed by a complete sequencing of their genome?
  2. Should the family of the person be told? Which members? When?
In this case the family of Henrietta Lacks are faced with the entire genome sequence of HeLa cells being published without their consent last year. Should they have had to right to privacy and publication been prevented? Some researchers have stated that as HeLa cells have been in culture for so long there have been many changes to the genome sequence and as a consequence the sequence information does not resemble that of the Lacks family in any meaningful way - which is at least partially true.

Lacks family members and officials & scientists in charge of the National Institute for Health (NIH) have reached an agreement for further use of HeLa cell sequence data - a landmark agreement that once again adds to our knowledge of how we should treat genome seqiencing projects and those who have their genomes sequenced:


The HeLa Genome Use Data Agreement establishes a six-person panel—including two representatives from the Lacks family—to review applications for access to the HeLa genome and set parameters for its use.

During a press briefing this morning, NIH Director Francis Collins, NIH Deputy Director for Science, Outreach, and Policy Kathy Hudson, and three members of the Lacks family presented the Agreement and discussed the circumstances that precipitated it.

"NIH is grateful to this remarkable family for their willingness to collaborate with us on this very important issue," Collins said during the press conference. "It's fitting--given the priceless contributions Henrietta Lacks's family has made to science and medicine--that her story is now catalyzing changes in policy. We should all count Henrietta Lacks and her family as among the greatest philanthropists of our time when you consider how they contributed to the advancement of science and our health."

Under the terms of the HeLa Genome Use Data Agreement, biomedical researchers who agree to abide by the terms of the agreement will be able to apply to NIH for access to the full genome sequence data from HeLa cells. Along with representatives from the medical, scientific, and bioethics communities, two representatives of the Lacks family--David Lacks Jr., Henrietta's grandson and Veronica Spencer, Henrietta's great granddaughter--will serve on NIH’s newly formed, six-member working group that will review proposals for access to the HeLa full genome sequence data.

NIH-funded researchers who generate full genome sequence data from HeLa cells will be expected to deposit their data into the NIH HeLa dbGaP database for future sharing through this process, while other researchers are expected to respect the family’s wishes and do the same. All researchers who use or generate full genomic data from HeLa cells are formally asked to include in their publications an acknowledgement and expression of gratitude to the Lacks family for their contributions. The agreement also mandates that researchers not attempt to contact any members of the Lacks family. 


The last words of this remarkable story should perhaps go to members of Henrietta's family:

“The HeLa genome is another chapter to the never ending story of our Henrietta Lacks,” said Henrietta’s granddaughter Jeri Lacks-Whye and Lacks family spokesperson. “She is a phenomenal woman who continues to amaze the world. The Lacks family is honored to be part of an important agreement that we believe will be beneficial to everyone.”


Full story

Thursday, 19 September 2013

US Cornerback Fights Back Against Aspergillosis

Marcus Rios
Marcus Rios plays for a UCLA American Football team and had the severe misfortune of contracting one of the rare types of invasive aspergillosis that affects the sinuses.

As is usual diagnosis was quite slow - though in this case his doctors were pretty sharp and may have identified the problem quicker than perhaps many others would have, perhaps others not having access to state of the art equipment.
As a result the infection is usually well established before treatment begins. In this case Marcus suffered the loss of sight in one eye at one point and the fungus had infected his brain but his resilience is remarkable and he maintained a positive attitude throughout.

Marcus is now back playing football. Read his remarkable story in the Los Angeles Times here

Monday, 16 September 2013

Cytisine: A Cheap Way to Stop Smoking?

One of the prime causes of worsened respiratory disease (including aspergillosis) is tobacco smoking. Consequently one of the most effective

"Nearly 50 years ago, and before any smoking cessation aids were approved in the Western world, cytisine was being used in eastern and central Europe to help people quit smoking. An alkaloid with high affinity for the α4β2 nicotinic acetylcholine receptor subtype, cytisine is derived from the plant Cytisus laburnum. It was discovered in 1818, first isolated in 1865,1 and its actions were documented as “qualitatively indistinguishable from that of nicotine” in 1912.2 It was smoked as an accessible and cheap tobacco substitute by German and Russian soldiers during the second world war, and it was brought to market in 1964 as a cessation aid under the brand name Tabex, now produced by Sopharma, a Bulgarian drug company. "

The research data supporting the use of cytisine is insufficient in itself to enable us to recommend its use to help people quit smoking so more work is needed but here we have a problem - this substance is freely available and cheap, much cheaper than any other tobacco substitute and the data that we have suggests that it is at least as good as replacement products costing much more. Consequently there is relatively little potential profit for a drug company to carry out all of the required and meticulous work needed to formally bring this substance to market - in fact they would be costing themselves money as sales would be likely to fall of the commercial products manufactured by those companies.

The authors of this editorial in the British Medical Journal suggest that governments should fund this research in the public interest particularly in countries where incomes are low.

Friday, 13 September 2013

ICAAC 2013: Invasive Mycoses: Consider the Source, Consider the Host

Introduction and Overview of Host Issues

CASE STUDIES

  • HSCT Patient with a Mold Infection
  • Pediatric Patient with a Fever in the Pediatric ICU
  • SOT Patient with Suspected Fungal Infection

Program Overview
Invasive fungal infections (IFIs) remain a substantial source of morbidity and mortality. While the increasing burden of IFIs is generally seen as a byproduct of modern medicine and an increasing net state of immunosuppression, emerging data on genomics and the immunologic response of the host are informing a deeper understanding of what happens at the level of the patient. This activity will address the differences in IFIs among pediatric patients, solid organ transplant (SOT) patients, and hematopoietic stem cell transplant (HSCT) patients in terms of causative pathogens (the source), the host response to the pathogens, diagnostic considerations, and response to therapeutic interventions.

This activity will explore whether our increased understanding of these interrelated factors can lead to personalized therapy for IFIs, as is occurring in oncology. Against this backdrop, we have documented gaps in managing IFIs per evidence-based society guidelines, such as in initiating prophylactic, pre-emptive, and empiric therapy (when appropriate) and definitive treatment across these host types. Finally, as emerging diagnostics and therapeutics are developed, their efficacy in these varied host populations as well as their interactions with host factors are key considerations. All of these topics will also be addressed in this initiative using a case-based, interactive format.

More details posted here when available

Thursday, 12 September 2013

ICAAC 2013 Wednesday

Fungi-Omics: Highlighting the Recent Advances
Wednesday, 8:30 a.m.– 10:30 a.m

Speakers:
8:30 a.m.
M-423 Mycobiome and Its Impact on Diseases
Pranab K. Mukherjee; Case Western Reserve Univ. Sch. of Med.,
Cleveland, OH

9:00 a.m.
M-424 Proteomics of Filamentous Fungi
Mark R. Marten; Univ. of Maryland, Baltimore County (UMBC),
Baltimore, MD

9:30 a.m.
M-425 Genomics: Did the Genes, and Now What?
Malcolm S. Whiteway; Concordia Univ., Montreal, Canada

10:00 a.m.
M-426 Can Metabolomics Provide Approach for Fungal Diagnosis?
Mahmoud A. Ghannoum; Case Western Reserve Univ. Sch. of Med.,
Cleveland, OH

More details as we get them...

Wednesday, 11 September 2013

Sick Sea Fans May Help Treat Aspergillosis

Caribbean Sea fan corals (Gorgonia ventalina) are known to be susceptible to infection by Aspergillus - in this case Aspergillus sydowii In a period stretching from 1996 to 2004 many thousands were infected resulting in much damage or even death.
Taken from article in the ISME Journal
In contrast to invasive aspergillosis in most animals, these coral infections are easy to see (see above), causing large purple areas on the large flat coral fronds. This makes them a useful model system for a couple of purposes:

1. A model system to study why sea fans are suddenly becoming infected in large numbers and the relation of this to warming of the seas and global climate warming. Links between the two are thought to be strong - see this paper.

2. Some sea fans did not become infected and this has enabled researchers to find out why that could be, giving us clues to how we could prevent or treat infections in other organisms. Quoting from the original article:
Like all of us, corals get sick. They respond to pathogens (disease-causing microbes) and recover or die. But unlike us, they can't call a doctor for treatment.
Instead, help has arrived in the form of scientists who study the causes of the corals' disease, and the immune factors that might be important in their response and resistance.
With support from the National Science Foundation (NSF), scientists Drew Harvell and Colleen Burge of Cornell University and their colleagues have developed a catalog of genes that, the researchers say, will allow us to better understand the immune systems of corals called sea fans.
If any of these coral genes are unique this may give us insight into the development of a new type of treatment or antifungal drug, potentially helping animals or plants that have become infected

The original article goes on to talk about other infections of sea fans  and the wider implications for all undersea life of global warming.

Original article

Tuesday, 10 September 2013

ICAAC2013

ICAAC is the largest scientific meeting on antimicrobial therapy and is running this week in Denver CO, USA. One of the highlights of the first day with respect to mycology was the following:

Clinical Microbiology and Diagnosis
An Aspergillus fumigatus (AF)-Specific Breath Volatile Organic Compound (VOC) Profile is Diagnostic of Invasive Aspergillosis (IA)
Sophia Koo, MD; Brigham & Women’s Hosp., Boston, MA
Poster Session 023, Presentation M-219
The suggestion is that this research will enable us to diagnose invasive aspergillosis by testing the breath of the patient. This would be a useful tool (if reliable and accurate) as diagnosis of IA is currently slow and difficult, and even more importantly all delay in the diagnosis of invasive aspergillosis has the effect of increasing mortality rates. The sooner we are able to start treatment the better!

More details.


Scientific Program

Wednesday, 4 September 2013

Occupational Exposure to Compost and Risk of Contracting ABPA

Recent research has examined the health of a group of workers that collect and sort garden waste. These workers are exposed to high numbers of Aspergillus in their normal daily routine and previous research has limited conclusions to allergic illness in some workers, occasionally identifying cases of Allergic Bronchopulmonary Aspergillosis (ABPA).

Quoting from the original paper:
To date, there have been very few reports of illness in these workers. In a cross sectional study of 218 compost workers in Germany, there was increased job turnover, eye and upper airway irritation, chronic bronchitis, two cases of extrinsic allergic alveolitis (EAA) due to Aspergillus fumigatus and decreased lung function compared with controls. There is one case report of allergic bronchopulmonary aspergillosis (ABPA), EAA and asthma in a garbage collector in Germany; one report of ABPA in a soy sauce maker in Japan who used Aspergillus oryzae in the fermenting process and one suspected case of ABPA in a vegetable compost worker in Belgium. Two cases of EAA after spreading damp bark chippings, one of which was fatal, have been reported from Denmark.

This new paper identified two cases of ABPA in a group of 38 workers.  The prevalence of ABPA in the general population is thought to be 1 in 1000 - 1 in 3000 (Denning 2012) so frequency of 1 in 19 in this group of workers is very significant. A larger study is now required to confirm these results but perhaps precautionary measures need to be taken from now on. The authors suggest:

Until the results of large epidemiological studies of garden waste collectors and industrial compost workers are known, the few case reports of ABPA and EAA due to Aspergillus sp would indicate that workers with asthma who are sensitized to A. fumigatus or who have cystic fibrosis, bronchiectasis or are immunosuppressed should not work with garden waste or compost, unless their exposure to airborne fungi can be controlled. 
Whether asthmatics who are SPT positive or specific IgE positive to A. fumigatus will go on to develop ABPA is unknown, but they should be made aware of the
theoretical risk.
Annual health surveillance by way of a respiratory questionnaire and skin prick testing is also recommended for these workers. Other cases of ABPA or EAA in garden waste and compost workers should be sought and reported, until such time that the results of a national study of UK compost workers are known.

Monday, 2 September 2013

Fungal Crop Pathogens Moving North


A new research paper has surveyed accumulating evidence that many food pathogens are being detected in more northerly locations (in the Northern Hemisphere) as time passes, including fungal pathogens.

Quoting from the paper:
Since crop domestication 10,000 years ago, farmers have been
plagued by multitudes of pests and pathogens (hereafter termed
pests) causing starvation and social upheaval. Classic examples
include the 1840s Irish potato famine caused by the oomycete
Phytophthora infestans and the 1943 Great Bengal Famine due to the
fungus Helminthosporium oryzae. The threat persists. Between 10
and 16% of crop production is lost to pests, with similar losses postharvest. Indeed, losses of major crops to fungi and oomycetes alone amount to enough to feed 8.5% of today's population.
Problems are not just limited to old strains spreading further north, new strains are being detected:
Recently emerged strains of the rusts Puccinia graminis and
P. striiformis are among the most virulent and rapidly spreading
pathogens ever seen, and a new and invasive lineage of P. infestans
has rapidly displaced other late blight genotypes.

Since 1960 isolates of fungal pathogens are progressing northwards (away from the equator) at an average of around 20km per year (see fun. in the table above)!

This movement is bad news for our crops and therefore our food supply. The authors of the research conclude that this seem to be at least partly caused by global warming reducing the cold to the north of the range of these pathogens, and partly caused by factors such as increasing transport of food (and thus their pathogens) across the world by man for their own uses, overcoming natural barriers to spread such as large sandy deserts and cold, and potentially greater use of monoculture as crops as we progress north from Africa.




A new species - Aspergillus felis found in cats and humans, is closely related to Aspergillus fumigatus.

A. felis colonies on ME agar.
(Barrs VR et al )
A new species of aspergillus - A felis has been identified in humans and cats in Australia. Dr Vanessa Barrs lead author in the recent publication (View) from the University of Sydney said: “this all originated from spotting an unusual fungal infection in three cats I was seeing at the University’s cat treatment centre in 2006.”
“These cats presented with a tumor-like growth in one of their eye sockets, that had spread there from the nasal cavity. The fungal spores are inhaled and in susceptible cats they establish a life-threatening infection that is very difficult to treat.
The new species can reproduce both asexually and sexually - both forms were identified.
Molecular ananlysis has revealed that this new species of aspergillus is closely related to Aspergillus fumigatus, which is a well-studied cause of disease in humans. It was also identified in 2 human patients with immunocompromised immune problems. Since the study - 20 otherwise healthy cats and one dog have been identified with the new strain. It can't be transmitted from  domestic animals to humans, but the cats may provide a useful model to study effective treatments.
However, the study has shown that Aspergillus felis is intrinsically more resistant to antifungal drugs than Aspergillus fumigatus and this has important implications for therapy and prognosis.

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