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Prof Graeme Suthers
  • Clinical Articles

Studying Chromosomes In 2017

Examining the structure of chromosomes The first studies in human genetics were done in the early 1900s, well before we had any idea of the structure of DNA or chromosomes. It was not until the late 1950s that the double helix was deciphered, that we realised that chromosomes were large bundles of DNA, and that we were able to visualise the number and shape of chromosomes under the microscope.In just a few years, numerous clinical disorders were identified as being due to abnormalities in the number or shape of chromosomes, and the field of “cytogenetics” was born.Over the next five decades, techniques improved.With the right sample and a good microscope, the laboratory could detect an abnormal gain or loss that was as small as 5-10 million base pairs of DNA on a specific chromosome. The light microscope reigned supreme as the ultimate tool for genetic analysis!

Examining the mass of chromosomes

In the last 10-15 years, a different technology called “microarrays” has challenged the supremacy of the microscope in genetic analysis.There are many different implementations of microarrays, but in essence they are all based on breaking the chromosomes from a tissue sample into millions of tiny DNA fragments, thereby destroying the structural cues used in microscopy.Each fragment then binds to a particular location on a prepared surface, and the amount of bound fragment is measured. The prepared surface, a “microarray”, is only a centimetre across and can have defined locations for millions of specific DNA fragments.The relative amounts of specific fragments can indicate tiny chromosomal regions in which there is a relative deficiency or excess of material. For example, in a person with Down syndrome (trisomy 21), the locations on the microarray that bind fragments derived from chromosome 21 will have 1 ½ times the number of fragments as locations which correspond to other chromosomes (three copies from chromosome 21 versus two copies from other chromosomes). The microarray could be regarded as examining the relative mass, rather than the shape, of specific chromosomal regions.Current microarrays can identify loss or gain of chromosomal material that is 10-100 times smaller than would be visible with the microscope. This has markedly improved the diagnostic yield in many situations but, as described below, conventional cytogenetics by light microscopy still has a role to play.

Microarrays in paediatrics

Conventional cytogenetics will identify a chromosome abnormality in 3-5% of children with intellectual disability or multiple malformations. A microarray will identify the same abnormality in those children, plus abnormalities in a further 10-15% i.e. the yield from microarray studies is approximately 15-20% (1).For this reason, microarray studies are the recommended type of cytogenetic analysis in the investigation of children or adults with intellectual disability or multiple malformations.There is a specific Medicare item for “diagnostic studies of a person with developmental delay, intellectual disability, autism, or at least two congenital abnormalities” by microarray. Requestors should request microarray analysis (item 73292) rather than use the less specific request for chromosome studies (item 73289).There are three cautions about microarray studies in this setting.First, a microarray will not detect every familial disorder. Intellectual disability due to a single gene disorder e.g. fragile X syndrome, will not be detected by a microarray.Second, experience with microarrays has demonstrated that some gains and losses of genetic material are benign and familial. It may be necessary to test the parents as well as the child to clarify the clinical significance of an uncommon change identified by microarray; the laboratory would provide guidance in such instances.And third, a microarray may identify an unexpected abnormality that has clinical consequences other than those which triggered the investigation.

Microarrays in antenatal care

The use of microarrays to investigate children with multiple malformations has now been extended to the investigation of fetuses with malformations.By using microarrays rather than conventional microscopy, the diagnostic yield from antenatal cytogenetics has increased by 6%(2). The cautions noted above still apply i.e. a microarray cannot detect every genetic cause of malformations, and determining the clinical significance of an uncommon finding may require additional studies.Microarrays can also be useful in the investigation of miscarriage and stillbirth.Most miscarriages are due to chromosome abnormalities which occur during the formation of the sperm or egg, or during early embryogenesis(3). These abnormalities are not inherited from either parent and hence do not constitute a hazard in subsequent pregnancies. Many clinicians and couples wish to confirm that a miscarriage was due to a sporadic chromosome abnormality that carries little risk for a subsequent pregnancy.This analysis can be done by either microarray or microscopic analysis of the products of conception. Microscopic analysis requires viable tissue, and up to 30% of studies may fail. Microarray analysis is preferred because it has better resolution and does not require living cells; as a result, the yield from microarray analysis is much higher(2). Requesters should specifically request microarray analysis, utilising the non-specific MBS item (73287).

Situations in which microarrays should not be used

There are two important antenatal situations in which microarrays should not be used: preconception screening, and investigation after a high risk non-invasive prenatal testing (NIPT) result.As noted above, a microarray measures the relative amount of genetic material from a specific location on a chromosome; it does not evaluate the shape of that chromosome.Approximately 1:1,000 healthy people has a balanced translocation i.e. part of one chromosome is attached to a different chromosome. The overall amount of genetic material is normal and there is usually no clinical consequence of this rearrangement. A balanced translocation would not be detected by microarray because there is not net gain or loss of chromosomal material.Microscopic analysis is likely to detect the translocation because of the change in shape of the two chromosomes involved.A person with a translocation can produce eggs or sperm that are unbalanced, having an abnormal gain or loss of chromosome material. This can cause infertility, recurrent miscarriages, or the birth of a child with intellectual disability or malformations. The unbalanced abnormality in the child would be detected by microarray, but the balanced precursor in the parent would not.For this reason, cytogenetic investigation of infertility and recurrent miscarriages requires microscopic cytogenetic studies of both partners (MBS item 73289).Approximately 4% of couples with recurrent miscarriages are found to have a balanced translocation in one or both partners.For similar reasons, microarray testing is not recommended for follow-up studies of CVS or amniotic fluid after a high risk result from NIPT. A microarray would identify the trisomy, but may not detect the rare instance of trisomy due to a familial translocation. Prenatal testing for autosomal trisomy requires microscopic cytogenetic studies (MBS item 73287).

The future of microarrays

Rapid developments in DNA sequencing have raised the possibility that microarrays will themselves be displaced as the preferred method of cytogenetic analysis(4). It is already possible to replicate many of the functions of a microarray by advanced sequencing methods. However, the microarray currently has the advantages of precision, reproducibility, and affordability that will ensure its continuing use for at least the next few years. And, as already demonstrated above, there may still be clinical questions that require the older methods. Cytogenetics is changing, but it is not dead.Sonic Genetics offers cytogenetic studies by both microscopic and microarray methods. General Practice Pathology is a new fortnightly column each authored by an Australian expert pathologist on a topic of particular relevance and interest to practising GPs. The authors provide this editorial, free of charge as part of an educational initiative developed and coordinated by Sonic Pathology.References
  1. Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010 May 14;86(5):749–64.
  2. Dugoff L, Norton ME, Kuller JA. The use of chromosomal microarray for prenatal diagnosis. Am J Obstet Gynecol. 2016;215(4):B2–9.
  3. van den Berg MMJ, van Maarle MC, van Wely M, Goddijn M. Genetics of early miscarriage. Biochim Biophys Acta - Mol Basis Dis. 2012;1822(12):1951–9.
  4. Downie L, Donoghue S, Stutterd C. Advances in genomic testing. Aust Fam Physician. 2017;46(4):200–4.
By Prof Graeme Suthers
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Dr Linda Calabresi
  • Clinical Articles

Zika Now In Fiji

In what could represent a major blow to tourism in the region, the US Centers for Disease Control have, this week, issued a level 2 warning that mosquitoes in Fiji have been found to be infected with Zika virus and have transmitted the infection to humans.Because of the strong link between Zika virus infection and severe birth defects, the CDC is strongly advising against women who are pregnant or who are even planning on becoming pregnant travelling to the area.And as the virus can also be transmitted through the sex, the advice for pregnant women whose partner has travelled to Fiji is to use condoms or refrain from sex for the duration of the pregnancy.The warning also signals an alert for Australian doctors to consider Zika virus in patients who present with symptoms such as fever, rash and headache following travel to Fiji. However, one of the major problems in curtailing the spread of this virus has been the fact that infected adults may display very few if any symptoms and maybe unaware that have contracted the disease.What’s more an infected male can harbour the Zika virus in his semen for much longer than in other bodily fluids, so the CDC recommends that men travelling to a Zika-prone country, that now includes Fiji, avoid conceiving a child for six months after leaving the area or from the time they develop symptoms if they indeed do develop symptoms. Women clear the virus more quickly and therefore the recommendation from the CDC is that they avoid falling pregnant two months after potential exposure or from when symptoms appear, assuming their partner did not travel.For those people, including pregnant women who can’t avoid travel Fiji or other Zika-prone area, the CDC advises they take precautions to avoid mosquito bites and continue these precautions for three weeks after returning home. These include the use of specific insect repellents and the wearing of long-sleeved clothing.Ref: https://wwwnc.cdc.gov/travel/notices/alert/zika-virus-fiji

By Dr Linda Calabresi
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Dr Ri Scarborough
  • Clinical Articles

Why Animal Trial Results Aren’t The Final Word

Throughout the era of modern medicine, animals have been used extensively to develop and test therapies before they are tested in humans. Virtually every medical therapy in use today – including drugs, vaccines, surgical techniques, devices such as pacemakers and joint prostheses, radiation therapy – owes its existence, at some level, to animal experiments.Animals have played a pivotal role in countless life-saving discoveries in the modern era. For example, in crude experiments in the 1800s, dogs were injected with extracts made from the pancreases of other animals, which led to insulin therapy for human diabetes. Much more recently, genetically modified mice were used to develop revolutionary cancer immunotherapy drugs, such as that credited with curing advanced melanoma in AFL footballer Jarryd Roughead.
Read more: How we’re arming the immune system to help fight cancer
In developing and testing drugs for human use, animal trials give us extremely valuable information that is impossible to get from test tube or petri dish experiments alone. They tell us how a drug is absorbed and spread around the body in a living animal and how it affects the targeted, and other, tissues. They also tell us how the body processes and eliminates a drug – for most drugs, this is primarily done by the liver and kidneys.These studies help decide whether to progress the drug to human trials and, if so, what a reasonable starting dose for a human might be. However, because of species differences, something that is effective and safe in an animal might not be so in a human.

What’s the strike rate?

The late Judah Folkman, a cancer researcher at Children’s Hospital in Boston, discovered a compound in the 1990s that eliminated a range of tumours in laboratory mice. Unlike traditional chemotherapies, there were no apparent side effects and the tumours developed no resistance to the treatment. Mass media outlets heralded a miracle cancer cure, but Folkman knew that what happens in the laboratory often fails to translate to the bedside. He famously quipped:
If you have cancer and you are a mouse, we can take good care of you.
The compound, endostatin, went on to human trials and was well tolerated in patients. But its effect on tumour growth was minimal and inconsistent, and results were described as “lukewarm”. Endostatin has since been reformulated and shows some promise in managing certain cancers, especially when combined with other therapies, but it’s not the wonder drug it at first appeared to be.Scientific journal publications on animal studies usually include a disclaimer along the lines of “this effect has only been demonstrated in animals and may not be replicated in humans”. And with very good reason. A 2006 review looked at studies where medical interventions were tested on animals and whether the results were replicated in human trials.It showed that of the most-cited animal studies in prestigious scientific journals, such as Nature and Cell, only 37% were replicated in subsequent human randomised trials and 18% were contradicted in human trials. It is safe to assume that less-cited animal studies in lesser journals would have an even lower strike rate.Another review found the treatment effect (benefit or harm) from six medical interventions carried out in humans and animals was similar for only half the interventions. That is, the results of animal and human trials disagreed half the time.

Costs of failure

The mismatch between animal trials and human trials can cause big problems. Developing a drug to the animal trial phase is already incredibly expensive, but taking it to human clinical trials adds enormous cost, often tens or hundreds of millions of dollars. If a promising drug fails to impress in human trials, it can mean a lot of money, time and effort wasted.But far more problematic is a drug that seems safe in animal trials, but turns out to be unsafe in humans. The consequences can be tragic. For instance, thalidomide (a drug to treat morning sickness) does not cause birth defects when given to pregnant rats and mice, but in humans it caused an international epidemic of birth defects, including severe limb malformations, in the 1950s and 1960s.
Read more: Remind me again, what is thalidomide and how did it cause so much harm?
More recently, a drug designed to treat leukaemia, TGN1412, was tested in monkeys – in many senses the closest laboratory model to humans – and was well tolerated. But when just 1/500th of the safe monkey dose was given to six healthy young men in the first phase of clinical (human) trials in 2006, they immediately developed fever, vomiting and diarrhoea. Within hours, they were in an intensive care unit with multiple organ failure. They only narrowly escaped death.Another drug, fialuridine, developed to treat people with hepatitis B, tested well in mice, rats, dogs, woodchucks and primates. But a subsequent human trial in 1993 caused seven people to develop liver failure. Five died and the other two were saved through liver transplants.

Mice and men differences

So, why do human and animal drug trials sometimes disagree so spectacularly? It boils down to the way the body absorbs and processes the drug and the way the drug affects the body. Often these processes are the same or very similar across species, but occasionally they are different enough that a substance that is benign in one species is deadly in another.Similarly, a cat that ingests even a small amount of paracetamol is a veterinary emergency, as cats lack the liver enzymes required to safely break down paracetamol. Instead, they convert it to a chemical that is toxic to their red blood cells.This will not surprise pet owners, who know a block of chocolate can kill a dog. Dog livers are poor at breaking down the chemicals caffeine and theobromine, found in chocolate, so it doesn’t take much for toxic levels to build up in a dog’s bloodstream.Hindsight has taught us where the human and animal differences lie for thalidomide, TGN1412 and fialuridine, too. Rats and mice not only break down thalidomide much faster than humans, but their embryos also have more antioxidant defences than human embryos.In the case of TGN1412, at least part of the problem was that the drug’s target – a protein on certain immune cells – differs slightly between the monkey and human versions. The drug binds more strongly to the human immune cells and triggers a rapid release of massive amounts of chemicals involved in inflammation.And the reason fialuridine is toxic to humans is because we have a unique transporter molecule deep in our cells that allows the drug to penetrate and disrupt our mitochondria, which act as cells’ internal energy generators. So fialuridine effectively switches off the power supply to human cells, causing cell death. This transporter is not present in any of the five test animal species, so the drug did not affect their mitochondria.Despite the shortcomings of animal models, and the profound ethical questions around subjecting animals to suffering for human benefit – an issue that concerns all researchers despite their commitment to improving human well-being – animal experimentation remains an invaluable tool in developing drugs.The ConversationThe challenges, and indeed the obligations, for medical researchers are to use animals as sparingly as possible, to minimise suffering where experimentation is required and to maximise their predictive value for subsequent human trials. If we can increase the predictive value of animal trials – by being smarter about which animals we use, and when and how we use them – we will use fewer animals, waste less time and money testing drugs that don’t work, and make clinical trials safer for humans.Ri Scarborough, Manager, Cancer Research Program, Monash UniversityThis article was originally published on The Conversation. Read the original article.
By Dr Ri Scarborough
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A/Prof Ian M. Mackay
  • Clinical Articles

Flu Season Pretty Bad

This year, the number of laboratory-confirmed influenza (flu) virus infections began rising earlier than usual and hit historic highs in some Australian states. If you have been part of any gathering this winter, this is probably not news.States in the south-east (central and southern Queensland, New South Wales, Victoria, Tasmania and South Australia) are more inflamed by flu than those in the north and west. For example, Queensland has seen more hospital admissions than in the last five years, mostly among an older population, while younger demographics more often test positive without needing hospitalisation.Meanwhile, flu numbers in New Zealand and elsewhere in the Pacific have not matched the same elevated levels. But is Australia really experiencing the biggest flu season on record in 2017, or are we just testing more and using better tools?This is hard to answer for certain because the information we need is not usually reported until later and public databases only show the past five years. We can say for sure that 2017 is on track to be a historically big flu year.
Read more: Have you noticed Australia’s flu seasons seem to be getting worse? Here’s why

Really, a big flu season

Flu can be a nasty illness. Sometimes it’s deadly. Other times it can be mild. But even for cases that fall in the middle you may not be able to work for days, or you’ll have to look after ill children home from school, or visit the very sick who have been hospitalised.Years ago, detection of influenza viruses mostly relied on slow, finicky methods such as testing for virus in artificial cell cultures. But, in Australia today, most laboratories use either sensitive tools to detect viral gene sequences in samples from the patient’s airway, or less sensitive but rapid dipstick methods, where a special strip is placed in a sample to detect viral proteins.These tools have been in use since 2007 in the larger Australian laboratories, so it’s unlikely we are just seeing more positives in 2017. While newer versions of these tests are being rolled out this year, they are unlikely to detect more cases. Equally, it’s unlikely more people with suspected flu decided to change their behaviour in 2017 and get tested, compared to 2016, or the year before.As in all years, there are many people in the community with flu who don’t get tested. The proportion of people with flu who are tested likely remains roughly the same year to year.State-wide flu reports provide reliable, laboratory-confirmed results. By looking at them, we can also be confident that “man flu” and severe common colds aren’t contributing to this specific and large increase in flu. We’re very likely seeing a truly huge flu season.

Why so bad this year?

Flu, caused by infection with an influenza virus, is mostly a disease with an epidemic peak during July and August in non-tropical countries. Flu viruses are broadly grouped into two types: Influenza-A and Influenza-B. Influenza-B viruses have two main sub-types while the Influenza-A viruses are more variable.The Influenza-As you get each year are usually A/H3N2 (the main player so far this season) or A/H1N1, which lingers on from its 2009 “swine flu” pandemic. Multiple flu viruses circulate each year and serial infections with different strains in the same person in a single season are possible.H3N2 has played a big role in the past five flu seasons. When it clearly dominates we tend to have bigger flu seasons and see cases affecting the elderly more than the young.H3N2 is a more changeable beast than the other flu viruses. New variants can even emerge within a season, possibly replacing older variants as the season progresses. This may be happening this winter, driving the bigger-than-normal season, but we won’t know for certain until many more viruses are analysed.Outside winter, flu viruses still spread among us. This year, in particular, we’re being encouraged to get vaccinated even during the peak of flu season. Vaccines are a safe way to decrease the risk that we or loved ones will get a full-blown case of the flu.Yet Australian flu vaccination rates are low. Data are scant but vaccination rates have increased in adults and some at-risk groups, but remain lower than for childhood vaccines.
Read more: Disease risk increasing with unvaccinated Australian adults

The flu vaccine

Each season new flu vaccines are designed based on detailed characterisation of the flu viruses circulating in the previous season. But the viruses that end up dominating the next season may change in the meantime.It is not clear whether that was a factor for this year’s high numbers in Australia this year or precisely what the vaccine uptake has been in 2017. Much of this detail will not be reported until after the epidemic ends. Some testing suggests this year’s vaccine is well matched to the circulating viruses.The flu vaccine is not the most effective of vaccines, but it is safe and the only preventive option we have for now. Of those vaccinated, 10-60% become immune to flu virus.
Read more: Flu vaccine won’t definitely stop you from getting the flu, but it’s more important than you think
Future flu vaccines promise to account for the ever-changing nature of flu virus, reducing the current need for yearly vaccination. Until they are available, though, it remains really important to book an appointment with your vaccine provider and get a quick, safe vaccination, because we are unarguably in the midst of the biggest flu season Australia has seen in years.The ConversationWe have both vaccines and drugs to help us prevent and minimise disease and the extra load on hospitals caused by flu. The young, elderly, those with underlying disease and Indigenous Australian people are most at risk of the worst outcomes and this is reflected by government-funded vaccination for these groups.Ian M. Mackay, Adjunct assistant professor, The University of Queensland and Katherine Arden, Virologist, The University of QueenslandThis article was originally published on The Conversation. Read the original article.
By A/Prof Ian M. Mackay, Dr Katherine Arden
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Dr Linda Calabresi
  • Clinical Articles

Rectal Exams Still Important – Sorry

Most GPs of a certain vintage would have heard the old adage “if you don’t put your finger in, you put your foot in.”It refers of course to the digital rectal examination and its importance as part of a thorough physical examination especially when symptoms indicate some potential pathology in that area.However it would be fair to say that most doctors, let alone patients are not particularly enthusiastic about this particular test. Indeed you could almost hear the collective sigh of relief when the authoritative guidelines suggested regular DRE was not useful as a means of screening for prostate cancer.The downside of this change in recommendation and general avoidance behaviour is that one can become deskilled in this examination, potentially missing an opportunity to diagnose a variety of conditions from prostate abnormalities to cancer.In the latest MJA, Dr Christopher Pokorny from the South Western Sydney Medical School at UNSW gives a synopsis of indications for DRE and a run through of the appropriate technique.“About 25% of colorectal cancers occur in the rectum and up to half can be palpated, but accuracy depends on training, experience, examination technique and the length of the examining finger,” Dr Pokorny writes.His list of indications for the procedure include the more obvious symptoms such as PR bleeding or mucus, change in bowel habit and prostatic symptoms but also a history of faecal urgency, difficult defaecation, faecal incontinence and anorectal pain (with the caveat that DRE should be avoided if there is an obvious anal fissure).Placing the patient in the left lateral position for the procedure is recommended with the patient drawing their knees to their chest and assuming that the patient is safe from falling off the examination couch.Assessment is made of the skin around the anus – looking for fissures, fistulae, skin tags, skin diseases such as warts or psoriasis, abscesses and haemorrhoids. The well-lubricated, gloved finger is then gently inserted, rotated in a clockwise direction into the rectum. Dr Pokorny suggests a systematic examination of the rectal mucosa anteriorly, posteriorly and laterally for masses that should be described as soft, hard, irregular or smooth. Prostatic abnormalities in men and ovarian or uterine abnormalities in women may be noted being careful not to confuse a palpable cervix in a woman with a mass.Finally, the doctor needs to check for any blood, including malaena on the glove.Dr Pokorny does concede the value of this examination is limited by the body habitus of the patient, and the length of the examiner’s fingers. Nonetheless, it is unwise to miss this diagnostic opportunity in general practice.“DRE is an often neglected but important part of the physical examination and should be performed whenever symptoms suggest anorectal or prostatic pathology,” he concludes.MJA doi:10.5694/mja17.00373

By Dr Linda Calabresi
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Dr Linda Calabresi
  • Clinical Articles

Poo Transplants Beat Antibiotics

Faecal transplantation has been gaining momentum as a mainstream treatment over recent years, but now a systematic review published in the MJA puts it ahead of antibiotics in effectiveness against Clostridium difficile-associated diarrhoea.The literature search examined all the randomised controlled trials on the topic up until February this year, including some recently published studies, and concluded there was moderate quality evidence that faecal microbiota transplantation is more effective in patients with Clostridium difficile-associated diarrhoea than either vancomycin or placebo.The review also found that samples that had been frozen and then thawed prior to transplantation were as effective as fresh samples.“Our systematic review also highlights the fact that frozen/thawed transplants – a more convenient approach that reduces the burden on a donor to supply a sample on the day it is needed – is as effective as fresh [faecal microbiota transplant],” the authors said.However, there was less clarity about the optimal method of administering the transplanted microbiota.“Our analysis indicates that naso-duodenal and colonoscopic application may be more effective than retention enemas, but this conclusion relies on indirect comparisons of subgroups,” they concluded suggesting that further research was needed to determine the best route of administration.There also needs to be more evidence into the most appropriate donor – whether they should be related, unrelated or anonymous, or whether ‘pooling stool from several donors’ would be the best way to go.“Over the past 20 years the worldwide incidence of [Clostridium difficile-associated diarrhoea] has more than doubled, and outbreaks have been associated with greater morbidity and mortality, although to a lesser extent in Australia,” the study authors said.Even though recent guidelines from Europe and North America now recommend these transplants to treat antibiotic-resistant Clostridium difficile-associated diarrhoea, the international authors of the review said these recommendations were based on relatively poor evidence.It is expected this systematic review that includes more scientifically robust clinical trials will inform future guidelines on the topic, particularly in Australia and New Zealand whose guidelines on treating Clostridium difficile-associated diarrhoea currently need updating.Ref: doi: 10.5694/mja17.00295

By Dr Linda Calabresi
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Prof Gabrielle Belz
  • Clinical Articles

Man flu is real, but women get more autoimmune diseases and allergies

Men and women respond differently to diseases and treatments for biological, social and psychological reasons. In this series on Gender Medicine, experts explore these differences and the importance of approaching treatment and diagnosis through a gender lens.
We know that sex hormones drive characteristic male and female traits such as breast enlargement and hip widening in women, or increased muscle mass and growth of facial hair in men. But now we also recognise they have a major impact on the immune system - our body’s inbuilt mechanism that helps fight and protect us against disease.Research suggests this has an evolutionary basis: survival of the species may mean men are harder hit by viruses, but a woman’s reactive immune system leaves her more susceptible to autoimmune diseases and allergies.

Viruses see men as weaker

Men die significantly more often from infectious diseases than women. For instance, men are 1.5 times more likely to die from tuberculosis, and twice as likely to develop Hodgkin’s lymphoma following Epstein–Barr virus (EBV) infection. Men are also five times more likely to develop cancer after infection with human papillomavirus (HPV), than women.This is because women’s immune systems mount a stronger response against foreign invaders, particularly viruses. While the male hormone testosterone tends to dampen immune responses, the female hormone oestrogen increases the number of immune cells and the intensity of their response. So women are able to recover more quickly from an infection.All this may reflect a sneaky evolutionary trick used by viruses to enable their survival. Women have developed multiple mechanisms to transmit infections; mainly through passing bugs from mother to child during gestation or birth, or through breastfeeding. So women are better vessels for viruses.Meanwhile, viruses have singled men out as the weaker sex. While popular culture has come up with the term “man flu”, suggesting men are over-dramatising flu symptoms, evidence suggests they may in reality be suffering more due to this dampening down of their immune responses.
Read more - Health Check: is man flu real?
However, this increased susceptibility of men to infection may not be an advantage for the long-term (over tens of thousands of years) survival of a disease-causing organism (pathogen), if it induces such severe disease that it results in the death of the host.Pathogens modify themselves so they can be transmitted by women during pregnancy, birth or breast feeding. Because of this, many have adapted to be less aggressive in women allowing wider infection, generally across a population.However, this feature alone is not likely to be sufficient to ensure the ongoing survival of a virus. The fitness of both sexes is necessary to reproduce long-term and thus provide new hosts for invading pathogens. Thus, the hit to the male sex must somehow be balanced by other advantages to their immune system.

Autoimmune diseases

Autoimmune diseases occur when the immune system turns on and attacks the body’s own cells or tissues, initiating a chronic cycle that results in damage or destruction of specific organs. These diseases include type 1 diabetes, lupus, rheumatoid arthritis, multiple sclerosis, and up to 80 different diseases that affect systems such as the intestine, bones, joints and nervous systems.The most striking sex differences in the immune system are seen in autoimmune diseases. Autoimmune disease affects about 8% of the population, but 78% of those affected are women. Women are three times more likely than men to develop these types of disease.
Read more - Explainer: what are autoimmune diseases?
In the case of lupus, the immune system mistakenly attacks the person’s own DNA (the structure that carries a person’s genetic code) causing damage to multiple organs that will lead to weight loss, anemia and eventually heart and kidney failure. Nine out of ten patients with lupus are women and clinical observations suggest that, again, hormones are the culprits.These differences of susceptibility between males and females tend to appear after puberty, and flare-ups increase during pregnancy. On the contrary, menopause is associated with a lower disease severity.Studies have linked oestrogen levels with the exacerbation of lupus. Oestrogens directly act on a particular immune cell (called the plasmacytoid dendritic cell) to promote their capacity to secrete inflammatory signals, which exacerbate lupus symptoms. Although these dendritic cells are generally important for fighting viral infections, in the context of lupus and multiple sclerosis, they cause significant harm.

Hormones and allergies

One in nine Australians (more than 2.5 million in total) suffer from asthma – a disease that causes swelling and narrowing of the airways. This makes it difficult to breathe when we encounter environmental allergens such as pollen.Twice as many women develop asthma compared to men. Interestingly, males are more susceptible to asthma before to the onset of puberty but, after puberty, females are more affected and develop more severe asthma than men. Until now, the reasons for this were not obvious, but hormones were speculated to play a role.In a recent study, we showed that high levels of testosterone in males protect them against the development of allergic asthma. During puberty, the level of testosterone increases.Testosterone acts as a potent inhibitor of a recently discovered immune cell called an innate lymphoid cell (ILC2), which accumulates in the lungs and initiates asthma. ILC2 cells release inflammatory signals that drive the swelling and airway narrowing characteristic of asthma when people are exposed to pollen, dust mites, grass or other common allergens. Testosterone reduces the numbers of ILC2 in the lungs of males, while female hormones provide no protective effect.
Read more: Do kids grow out of childhood asthma?
Immunity and sex are far more intricately linked than we had previously appreciated. More research needs to be done to better understand the triggers involved in the different responses of males and females. But the recent discoveries open the door for tactics to potentially target hormonal pathways or receptors that are preferentially expressed on male or female immune cells.
The ConversationRead the first article in our Gender Medicine series - Medicine’s gender revolution: how women stopped being treated as ‘small men’Gabrielle Belz, Professor, Molecular Immunology, Walter and Eliza Hall Institute and Cyril Seillet, Senior research scientist, Walter and Eliza Hall InstituteThis article was originally published on The Conversation. Read the original article.
By Prof Gabrielle Belz, Dr Cyril Seillet
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Dr Linda Calabresi
  • Clinical Articles

Do Not Order These Tests On Pregnant Women

Hot on the heels of the Choosing Wisely campaign of “do nots” for GPs, the Royal Australasian College of Physicians has released a new list of tests doctors should avoid ordering on pregnant women.The recommendations come from the Society of Obstetric Medicine in Australia and New Zealand (SOMANZ), and include the advice that the D-dimer test should not be used to diagnose venous thromboembolism in pregnant women as it is unreliable.Even though women are five times more likely to develop venous thromboembolism in pregnancy, other investigative tests should be used if a clot is suspected as D-dimer concentrations normally rise in pregnancy regardless of whether thrombosis has occurred, making abnormal results ‘incredibly unreliable’.Another recommendation included in the RACP’s top five low value practices and interventions is to not test for inherited thrombophilia in women who have a history of placenta-mediated complications of pregnancy such as stillbirth, recurrent miscarriages or placental abruption.The rationale behind the recommendation is that while some older, retrospective studies had suggested there might be an association with an inherited clotting disorder and these complications, more recent and more robust evidence has shown there is no link and what’s more, taking low molecular weight heparin is not useful as a preventive measure.The experts also advise not to do repeat tests for proteinuria in women with established  pre-eclampsia. Even though proteinuria is an important diagnostic marker for pre-eclampsia it is has no prognostic value. The level of the proteinuria does not correlate with the severity of the maternal complications, so repeated testing does not help management.MTHFR testing has become popular in certain, mainly allied health circles and is controversial. SOMANZ has made a strong recommendation to not undertake MTHFR polymorphism tests as part of a routine evaluation for thrombophilia in pregnancy.“Patients with the thermolabile variant of the methylenetetrahydrofolate reductase (MTHFR) polymorphism are at higher risk of hyperhomocysteinaemia which has been associated with venous thrombosis. However, these associations appear to hold only in countries lacking grain products nutritionally fortified as a public health measure.”They also say testing may lead to many anxiety-provoking false positives, as up to 15% of the population have homozygous variants, which in most instances appear to have no deleterious effects.The final test on the list is the erythrocyte sedimentation rate. The experts advise do not measure ESR in pregnancy as the levels can vary widely depending on factors such as gestational age and haemoglobin concentrations and therefore the test cannot reliably distinguish between healthy and unhealthy women in pregnancy.The list is the latest publication put out as part of the physician-led Evolve initiative run by the RACP. The aim of the initiative is to help ensure high quality patient care by identifying those practices and interventions that represent poor value to patients in terms of improving their clinical outcome and may even cause harm. According to the media release there are now 17 Evolve lists that have been published across a range of medical specialties, and there are another 15 in development.Ref: https://evolve.edu.au/published-lists/society-of-obstetric-medicine-of-australia-and-new-zealand

By Dr Linda Calabresi
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Studying Chromosomes In 2017

Examining the structure of chromosomes The first studies in human genetics were done in the early 1900s, well before we had any idea of the structure of DNA or chromosomes. It was not until the late 1950s that the double helix was deciphered, that we realised that chromosomes were large bundles of DNA, and that we were able to visualise the number and shape of chromosomes under the microscope.In just a few years, numerous clinical disorders were identified as being due to abnormalities in the number or shape of chromosomes, and the field of “cytogenetics” was born.Over the next five decades, techniques improved.With the right sample and a good microscope, the laboratory could detect an abnormal gain or loss that was as small as 5-10 million base pairs of DNA on a specific chromosome. The light microscope reigned supreme as the ultimate tool for genetic analysis!

Examining the mass of chromosomes

In the last 10-15 years, a different technology called “microarrays” has challenged the supremacy of the microscope in genetic analysis.There are many different implementations of microarrays, but in essence they are all based on breaking the chromosomes from a tissue sample into millions of tiny DNA fragments, thereby destroying the structural cues used in microscopy.Each fragment then binds to a particular location on a prepared surface, and the amount of bound fragment is measured. The prepared surface, a “microarray”, is only a centimetre across and can have defined locations for millions of specific DNA fragments.The relative amounts of specific fragments can indicate tiny chromosomal regions in which there is a relative deficiency or excess of material. For example, in a person with Down syndrome (trisomy 21), the locations on the microarray that bind fragments derived from chromosome 21 will have 1 ½ times the number of fragments as locations which correspond to other chromosomes (three copies from chromosome 21 versus two copies from other chromosomes). The microarray could be regarded as examining the relative mass, rather than the shape, of specific chromosomal regions.Current microarrays can identify loss or gain of chromosomal material that is 10-100 times smaller than would be visible with the microscope. This has markedly improved the diagnostic yield in many situations but, as described below, conventional cytogenetics by light microscopy still has a role to play.

Microarrays in paediatrics

Conventional cytogenetics will identify a chromosome abnormality in 3-5% of children with intellectual disability or multiple malformations. A microarray will identify the same abnormality in those children, plus abnormalities in a further 10-15% i.e. the yield from microarray studies is approximately 15-20% (1).For this reason, microarray studies are the recommended type of cytogenetic analysis in the investigation of children or adults with intellectual disability or multiple malformations.There is a specific Medicare item for “diagnostic studies of a person with developmental delay, intellectual disability, autism, or at least two congenital abnormalities” by microarray. Requestors should request microarray analysis (item 73292) rather than use the less specific request for chromosome studies (item 73289).There are three cautions about microarray studies in this setting.First, a microarray will not detect every familial disorder. Intellectual disability due to a single gene disorder e.g. fragile X syndrome, will not be detected by a microarray.Second, experience with microarrays has demonstrated that some gains and losses of genetic material are benign and familial. It may be necessary to test the parents as well as the child to clarify the clinical significance of an uncommon change identified by microarray; the laboratory would provide guidance in such instances.And third, a microarray may identify an unexpected abnormality that has clinical consequences other than those which triggered the investigation.

Microarrays in antenatal care

The use of microarrays to investigate children with multiple malformations has now been extended to the investigation of fetuses with malformations.By using microarrays rather than conventional microscopy, the diagnostic yield from antenatal cytogenetics has increased by 6%(2). The cautions noted above still apply i.e. a microarray cannot detect every genetic cause of malformations, and determining the clinical significance of an uncommon finding may require additional studies.Microarrays can also be useful in the investigation of miscarriage and stillbirth.Most miscarriages are due to chromosome abnormalities which occur during the formation of the sperm or egg, or during early embryogenesis(3). These abnormalities are not inherited from either parent and hence do not constitute a hazard in subsequent pregnancies. Many clinicians and couples wish to confirm that a miscarriage was due to a sporadic chromosome abnormality that carries little risk for a subsequent pregnancy.This analysis can be done by either microarray or microscopic analysis of the products of conception. Microscopic analysis requires viable tissue, and up to 30% of studies may fail. Microarray analysis is preferred because it has better resolution and does not require living cells; as a result, the yield from microarray analysis is much higher(2). Requesters should specifically request microarray analysis, utilising the non-specific MBS item (73287).

Situations in which microarrays should not be used

There are two important antenatal situations in which microarrays should not be used: preconception screening, and investigation after a high risk non-invasive prenatal testing (NIPT) result.As noted above, a microarray measures the relative amount of genetic material from a specific location on a chromosome; it does not evaluate the shape of that chromosome.Approximately 1:1,000 healthy people has a balanced translocation i.e. part of one chromosome is attached to a different chromosome. The overall amount of genetic material is normal and there is usually no clinical consequence of this rearrangement. A balanced translocation would not be detected by microarray because there is not net gain or loss of chromosomal material.Microscopic analysis is likely to detect the translocation because of the change in shape of the two chromosomes involved.A person with a translocation can produce eggs or sperm that are unbalanced, having an abnormal gain or loss of chromosome material. This can cause infertility, recurrent miscarriages, or the birth of a child with intellectual disability or malformations. The unbalanced abnormality in the child would be detected by microarray, but the balanced precursor in the parent would not.For this reason, cytogenetic investigation of infertility and recurrent miscarriages requires microscopic cytogenetic studies of both partners (MBS item 73289).Approximately 4% of couples with recurrent miscarriages are found to have a balanced translocation in one or both partners.For similar reasons, microarray testing is not recommended for follow-up studies of CVS or amniotic fluid after a high risk result from NIPT. A microarray would identify the trisomy, but may not detect the rare instance of trisomy due to a familial translocation. Prenatal testing for autosomal trisomy requires microscopic cytogenetic studies (MBS item 73287).

The future of microarrays

Rapid developments in DNA sequencing have raised the possibility that microarrays will themselves be displaced as the preferred method of cytogenetic analysis(4). It is already possible to replicate many of the functions of a microarray by advanced sequencing methods. However, the microarray currently has the advantages of precision, reproducibility, and affordability that will ensure its continuing use for at least the next few years. And, as already demonstrated above, there may still be clinical questions that require the older methods. Cytogenetics is changing, but it is not dead.Sonic Genetics offers cytogenetic studies by both microscopic and microarray methods. General Practice Pathology is a new fortnightly column each authored by an Australian expert pathologist on a topic of particular relevance and interest to practising GPs. The authors provide this editorial, free of charge as part of an educational initiative developed and coordinated by Sonic Pathology.References
  1. Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010 May 14;86(5):749–64.
  2. Dugoff L, Norton ME, Kuller JA. The use of chromosomal microarray for prenatal diagnosis. Am J Obstet Gynecol. 2016;215(4):B2–9.
  3. van den Berg MMJ, van Maarle MC, van Wely M, Goddijn M. Genetics of early miscarriage. Biochim Biophys Acta - Mol Basis Dis. 2012;1822(12):1951–9.
  4. Downie L, Donoghue S, Stutterd C. Advances in genomic testing. Aust Fam Physician. 2017;46(4):200–4.
By Prof Graeme Suthers
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Zika Now In Fiji

In what could represent a major blow to tourism in the region, the US Centers for Disease Control have, this week, issued a level 2 warning that mosquitoes in Fiji have been found to be infected with Zika virus and have transmitted the infection to humans.Because of the strong link between Zika virus infection and severe birth defects, the CDC is strongly advising against women who are pregnant or who are even planning on becoming pregnant travelling to the area.And as the virus can also be transmitted through the sex, the advice for pregnant women whose partner has travelled to Fiji is to use condoms or refrain from sex for the duration of the pregnancy.The warning also signals an alert for Australian doctors to consider Zika virus in patients who present with symptoms such as fever, rash and headache following travel to Fiji. However, one of the major problems in curtailing the spread of this virus has been the fact that infected adults may display very few if any symptoms and maybe unaware that have contracted the disease.What’s more an infected male can harbour the Zika virus in his semen for much longer than in other bodily fluids, so the CDC recommends that men travelling to a Zika-prone country, that now includes Fiji, avoid conceiving a child for six months after leaving the area or from the time they develop symptoms if they indeed do develop symptoms. Women clear the virus more quickly and therefore the recommendation from the CDC is that they avoid falling pregnant two months after potential exposure or from when symptoms appear, assuming their partner did not travel.For those people, including pregnant women who can’t avoid travel Fiji or other Zika-prone area, the CDC advises they take precautions to avoid mosquito bites and continue these precautions for three weeks after returning home. These include the use of specific insect repellents and the wearing of long-sleeved clothing.Ref: https://wwwnc.cdc.gov/travel/notices/alert/zika-virus-fiji

By Dr Linda Calabresi
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Why Animal Trial Results Aren’t The Final Word

Throughout the era of modern medicine, animals have been used extensively to develop and test therapies before they are tested in humans. Virtually every medical therapy in use today – including drugs, vaccines, surgical techniques, devices such as pacemakers and joint prostheses, radiation therapy – owes its existence, at some level, to animal experiments.Animals have played a pivotal role in countless life-saving discoveries in the modern era. For example, in crude experiments in the 1800s, dogs were injected with extracts made from the pancreases of other animals, which led to insulin therapy for human diabetes. Much more recently, genetically modified mice were used to develop revolutionary cancer immunotherapy drugs, such as that credited with curing advanced melanoma in AFL footballer Jarryd Roughead.
Read more: How we’re arming the immune system to help fight cancer
In developing and testing drugs for human use, animal trials give us extremely valuable information that is impossible to get from test tube or petri dish experiments alone. They tell us how a drug is absorbed and spread around the body in a living animal and how it affects the targeted, and other, tissues. They also tell us how the body processes and eliminates a drug – for most drugs, this is primarily done by the liver and kidneys.These studies help decide whether to progress the drug to human trials and, if so, what a reasonable starting dose for a human might be. However, because of species differences, something that is effective and safe in an animal might not be so in a human.

What’s the strike rate?

The late Judah Folkman, a cancer researcher at Children’s Hospital in Boston, discovered a compound in the 1990s that eliminated a range of tumours in laboratory mice. Unlike traditional chemotherapies, there were no apparent side effects and the tumours developed no resistance to the treatment. Mass media outlets heralded a miracle cancer cure, but Folkman knew that what happens in the laboratory often fails to translate to the bedside. He famously quipped:
If you have cancer and you are a mouse, we can take good care of you.
The compound, endostatin, went on to human trials and was well tolerated in patients. But its effect on tumour growth was minimal and inconsistent, and results were described as “lukewarm”. Endostatin has since been reformulated and shows some promise in managing certain cancers, especially when combined with other therapies, but it’s not the wonder drug it at first appeared to be.Scientific journal publications on animal studies usually include a disclaimer along the lines of “this effect has only been demonstrated in animals and may not be replicated in humans”. And with very good reason. A 2006 review looked at studies where medical interventions were tested on animals and whether the results were replicated in human trials.It showed that of the most-cited animal studies in prestigious scientific journals, such as Nature and Cell, only 37% were replicated in subsequent human randomised trials and 18% were contradicted in human trials. It is safe to assume that less-cited animal studies in lesser journals would have an even lower strike rate.Another review found the treatment effect (benefit or harm) from six medical interventions carried out in humans and animals was similar for only half the interventions. That is, the results of animal and human trials disagreed half the time.

Costs of failure

The mismatch between animal trials and human trials can cause big problems. Developing a drug to the animal trial phase is already incredibly expensive, but taking it to human clinical trials adds enormous cost, often tens or hundreds of millions of dollars. If a promising drug fails to impress in human trials, it can mean a lot of money, time and effort wasted.But far more problematic is a drug that seems safe in animal trials, but turns out to be unsafe in humans. The consequences can be tragic. For instance, thalidomide (a drug to treat morning sickness) does not cause birth defects when given to pregnant rats and mice, but in humans it caused an international epidemic of birth defects, including severe limb malformations, in the 1950s and 1960s.
Read more: Remind me again, what is thalidomide and how did it cause so much harm?
More recently, a drug designed to treat leukaemia, TGN1412, was tested in monkeys – in many senses the closest laboratory model to humans – and was well tolerated. But when just 1/500th of the safe monkey dose was given to six healthy young men in the first phase of clinical (human) trials in 2006, they immediately developed fever, vomiting and diarrhoea. Within hours, they were in an intensive care unit with multiple organ failure. They only narrowly escaped death.Another drug, fialuridine, developed to treat people with hepatitis B, tested well in mice, rats, dogs, woodchucks and primates. But a subsequent human trial in 1993 caused seven people to develop liver failure. Five died and the other two were saved through liver transplants.

Mice and men differences

So, why do human and animal drug trials sometimes disagree so spectacularly? It boils down to the way the body absorbs and processes the drug and the way the drug affects the body. Often these processes are the same or very similar across species, but occasionally they are different enough that a substance that is benign in one species is deadly in another.Similarly, a cat that ingests even a small amount of paracetamol is a veterinary emergency, as cats lack the liver enzymes required to safely break down paracetamol. Instead, they convert it to a chemical that is toxic to their red blood cells.This will not surprise pet owners, who know a block of chocolate can kill a dog. Dog livers are poor at breaking down the chemicals caffeine and theobromine, found in chocolate, so it doesn’t take much for toxic levels to build up in a dog’s bloodstream.Hindsight has taught us where the human and animal differences lie for thalidomide, TGN1412 and fialuridine, too. Rats and mice not only break down thalidomide much faster than humans, but their embryos also have more antioxidant defences than human embryos.In the case of TGN1412, at least part of the problem was that the drug’s target – a protein on certain immune cells – differs slightly between the monkey and human versions. The drug binds more strongly to the human immune cells and triggers a rapid release of massive amounts of chemicals involved in inflammation.And the reason fialuridine is toxic to humans is because we have a unique transporter molecule deep in our cells that allows the drug to penetrate and disrupt our mitochondria, which act as cells’ internal energy generators. So fialuridine effectively switches off the power supply to human cells, causing cell death. This transporter is not present in any of the five test animal species, so the drug did not affect their mitochondria.Despite the shortcomings of animal models, and the profound ethical questions around subjecting animals to suffering for human benefit – an issue that concerns all researchers despite their commitment to improving human well-being – animal experimentation remains an invaluable tool in developing drugs.The ConversationThe challenges, and indeed the obligations, for medical researchers are to use animals as sparingly as possible, to minimise suffering where experimentation is required and to maximise their predictive value for subsequent human trials. If we can increase the predictive value of animal trials – by being smarter about which animals we use, and when and how we use them – we will use fewer animals, waste less time and money testing drugs that don’t work, and make clinical trials safer for humans.Ri Scarborough, Manager, Cancer Research Program, Monash UniversityThis article was originally published on The Conversation. Read the original article.
By Dr Ri Scarborough
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Flu Season Pretty Bad

This year, the number of laboratory-confirmed influenza (flu) virus infections began rising earlier than usual and hit historic highs in some Australian states. If you have been part of any gathering this winter, this is probably not news.States in the south-east (central and southern Queensland, New South Wales, Victoria, Tasmania and South Australia) are more inflamed by flu than those in the north and west. For example, Queensland has seen more hospital admissions than in the last five years, mostly among an older population, while younger demographics more often test positive without needing hospitalisation.Meanwhile, flu numbers in New Zealand and elsewhere in the Pacific have not matched the same elevated levels. But is Australia really experiencing the biggest flu season on record in 2017, or are we just testing more and using better tools?This is hard to answer for certain because the information we need is not usually reported until later and public databases only show the past five years. We can say for sure that 2017 is on track to be a historically big flu year.
Read more: Have you noticed Australia’s flu seasons seem to be getting worse? Here’s why

Really, a big flu season

Flu can be a nasty illness. Sometimes it’s deadly. Other times it can be mild. But even for cases that fall in the middle you may not be able to work for days, or you’ll have to look after ill children home from school, or visit the very sick who have been hospitalised.Years ago, detection of influenza viruses mostly relied on slow, finicky methods such as testing for virus in artificial cell cultures. But, in Australia today, most laboratories use either sensitive tools to detect viral gene sequences in samples from the patient’s airway, or less sensitive but rapid dipstick methods, where a special strip is placed in a sample to detect viral proteins.These tools have been in use since 2007 in the larger Australian laboratories, so it’s unlikely we are just seeing more positives in 2017. While newer versions of these tests are being rolled out this year, they are unlikely to detect more cases. Equally, it’s unlikely more people with suspected flu decided to change their behaviour in 2017 and get tested, compared to 2016, or the year before.As in all years, there are many people in the community with flu who don’t get tested. The proportion of people with flu who are tested likely remains roughly the same year to year.State-wide flu reports provide reliable, laboratory-confirmed results. By looking at them, we can also be confident that “man flu” and severe common colds aren’t contributing to this specific and large increase in flu. We’re very likely seeing a truly huge flu season.

Why so bad this year?

Flu, caused by infection with an influenza virus, is mostly a disease with an epidemic peak during July and August in non-tropical countries. Flu viruses are broadly grouped into two types: Influenza-A and Influenza-B. Influenza-B viruses have two main sub-types while the Influenza-A viruses are more variable.The Influenza-As you get each year are usually A/H3N2 (the main player so far this season) or A/H1N1, which lingers on from its 2009 “swine flu” pandemic. Multiple flu viruses circulate each year and serial infections with different strains in the same person in a single season are possible.H3N2 has played a big role in the past five flu seasons. When it clearly dominates we tend to have bigger flu seasons and see cases affecting the elderly more than the young.H3N2 is a more changeable beast than the other flu viruses. New variants can even emerge within a season, possibly replacing older variants as the season progresses. This may be happening this winter, driving the bigger-than-normal season, but we won’t know for certain until many more viruses are analysed.Outside winter, flu viruses still spread among us. This year, in particular, we’re being encouraged to get vaccinated even during the peak of flu season. Vaccines are a safe way to decrease the risk that we or loved ones will get a full-blown case of the flu.Yet Australian flu vaccination rates are low. Data are scant but vaccination rates have increased in adults and some at-risk groups, but remain lower than for childhood vaccines.
Read more: Disease risk increasing with unvaccinated Australian adults

The flu vaccine

Each season new flu vaccines are designed based on detailed characterisation of the flu viruses circulating in the previous season. But the viruses that end up dominating the next season may change in the meantime.It is not clear whether that was a factor for this year’s high numbers in Australia this year or precisely what the vaccine uptake has been in 2017. Much of this detail will not be reported until after the epidemic ends. Some testing suggests this year’s vaccine is well matched to the circulating viruses.The flu vaccine is not the most effective of vaccines, but it is safe and the only preventive option we have for now. Of those vaccinated, 10-60% become immune to flu virus.
Read more: Flu vaccine won’t definitely stop you from getting the flu, but it’s more important than you think
Future flu vaccines promise to account for the ever-changing nature of flu virus, reducing the current need for yearly vaccination. Until they are available, though, it remains really important to book an appointment with your vaccine provider and get a quick, safe vaccination, because we are unarguably in the midst of the biggest flu season Australia has seen in years.The ConversationWe have both vaccines and drugs to help us prevent and minimise disease and the extra load on hospitals caused by flu. The young, elderly, those with underlying disease and Indigenous Australian people are most at risk of the worst outcomes and this is reflected by government-funded vaccination for these groups.Ian M. Mackay, Adjunct assistant professor, The University of Queensland and Katherine Arden, Virologist, The University of QueenslandThis article was originally published on The Conversation. Read the original article.
By A/Prof Ian M. Mackay, Dr Katherine Arden
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Rectal Exams Still Important – Sorry

Most GPs of a certain vintage would have heard the old adage “if you don’t put your finger in, you put your foot in.”It refers of course to the digital rectal examination and its importance as part of a thorough physical examination especially when symptoms indicate some potential pathology in that area.However it would be fair to say that most doctors, let alone patients are not particularly enthusiastic about this particular test. Indeed you could almost hear the collective sigh of relief when the authoritative guidelines suggested regular DRE was not useful as a means of screening for prostate cancer.The downside of this change in recommendation and general avoidance behaviour is that one can become deskilled in this examination, potentially missing an opportunity to diagnose a variety of conditions from prostate abnormalities to cancer.In the latest MJA, Dr Christopher Pokorny from the South Western Sydney Medical School at UNSW gives a synopsis of indications for DRE and a run through of the appropriate technique.“About 25% of colorectal cancers occur in the rectum and up to half can be palpated, but accuracy depends on training, experience, examination technique and the length of the examining finger,” Dr Pokorny writes.His list of indications for the procedure include the more obvious symptoms such as PR bleeding or mucus, change in bowel habit and prostatic symptoms but also a history of faecal urgency, difficult defaecation, faecal incontinence and anorectal pain (with the caveat that DRE should be avoided if there is an obvious anal fissure).Placing the patient in the left lateral position for the procedure is recommended with the patient drawing their knees to their chest and assuming that the patient is safe from falling off the examination couch.Assessment is made of the skin around the anus – looking for fissures, fistulae, skin tags, skin diseases such as warts or psoriasis, abscesses and haemorrhoids. The well-lubricated, gloved finger is then gently inserted, rotated in a clockwise direction into the rectum. Dr Pokorny suggests a systematic examination of the rectal mucosa anteriorly, posteriorly and laterally for masses that should be described as soft, hard, irregular or smooth. Prostatic abnormalities in men and ovarian or uterine abnormalities in women may be noted being careful not to confuse a palpable cervix in a woman with a mass.Finally, the doctor needs to check for any blood, including malaena on the glove.Dr Pokorny does concede the value of this examination is limited by the body habitus of the patient, and the length of the examiner’s fingers. Nonetheless, it is unwise to miss this diagnostic opportunity in general practice.“DRE is an often neglected but important part of the physical examination and should be performed whenever symptoms suggest anorectal or prostatic pathology,” he concludes.MJA doi:10.5694/mja17.00373

By Dr Linda Calabresi
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Poo Transplants Beat Antibiotics

Faecal transplantation has been gaining momentum as a mainstream treatment over recent years, but now a systematic review published in the MJA puts it ahead of antibiotics in effectiveness against Clostridium difficile-associated diarrhoea.The literature search examined all the randomised controlled trials on the topic up until February this year, including some recently published studies, and concluded there was moderate quality evidence that faecal microbiota transplantation is more effective in patients with Clostridium difficile-associated diarrhoea than either vancomycin or placebo.The review also found that samples that had been frozen and then thawed prior to transplantation were as effective as fresh samples.“Our systematic review also highlights the fact that frozen/thawed transplants – a more convenient approach that reduces the burden on a donor to supply a sample on the day it is needed – is as effective as fresh [faecal microbiota transplant],” the authors said.However, there was less clarity about the optimal method of administering the transplanted microbiota.“Our analysis indicates that naso-duodenal and colonoscopic application may be more effective than retention enemas, but this conclusion relies on indirect comparisons of subgroups,” they concluded suggesting that further research was needed to determine the best route of administration.There also needs to be more evidence into the most appropriate donor – whether they should be related, unrelated or anonymous, or whether ‘pooling stool from several donors’ would be the best way to go.“Over the past 20 years the worldwide incidence of [Clostridium difficile-associated diarrhoea] has more than doubled, and outbreaks have been associated with greater morbidity and mortality, although to a lesser extent in Australia,” the study authors said.Even though recent guidelines from Europe and North America now recommend these transplants to treat antibiotic-resistant Clostridium difficile-associated diarrhoea, the international authors of the review said these recommendations were based on relatively poor evidence.It is expected this systematic review that includes more scientifically robust clinical trials will inform future guidelines on the topic, particularly in Australia and New Zealand whose guidelines on treating Clostridium difficile-associated diarrhoea currently need updating.Ref: doi: 10.5694/mja17.00295

By Dr Linda Calabresi
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Man flu is real, but women get more autoimmune diseases and allergies

Men and women respond differently to diseases and treatments for biological, social and psychological reasons. In this series on Gender Medicine, experts explore these differences and the importance of approaching treatment and diagnosis through a gender lens.
We know that sex hormones drive characteristic male and female traits such as breast enlargement and hip widening in women, or increased muscle mass and growth of facial hair in men. But now we also recognise they have a major impact on the immune system - our body’s inbuilt mechanism that helps fight and protect us against disease.Research suggests this has an evolutionary basis: survival of the species may mean men are harder hit by viruses, but a woman’s reactive immune system leaves her more susceptible to autoimmune diseases and allergies.

Viruses see men as weaker

Men die significantly more often from infectious diseases than women. For instance, men are 1.5 times more likely to die from tuberculosis, and twice as likely to develop Hodgkin’s lymphoma following Epstein–Barr virus (EBV) infection. Men are also five times more likely to develop cancer after infection with human papillomavirus (HPV), than women.This is because women’s immune systems mount a stronger response against foreign invaders, particularly viruses. While the male hormone testosterone tends to dampen immune responses, the female hormone oestrogen increases the number of immune cells and the intensity of their response. So women are able to recover more quickly from an infection.All this may reflect a sneaky evolutionary trick used by viruses to enable their survival. Women have developed multiple mechanisms to transmit infections; mainly through passing bugs from mother to child during gestation or birth, or through breastfeeding. So women are better vessels for viruses.Meanwhile, viruses have singled men out as the weaker sex. While popular culture has come up with the term “man flu”, suggesting men are over-dramatising flu symptoms, evidence suggests they may in reality be suffering more due to this dampening down of their immune responses.
Read more - Health Check: is man flu real?
However, this increased susceptibility of men to infection may not be an advantage for the long-term (over tens of thousands of years) survival of a disease-causing organism (pathogen), if it induces such severe disease that it results in the death of the host.Pathogens modify themselves so they can be transmitted by women during pregnancy, birth or breast feeding. Because of this, many have adapted to be less aggressive in women allowing wider infection, generally across a population.However, this feature alone is not likely to be sufficient to ensure the ongoing survival of a virus. The fitness of both sexes is necessary to reproduce long-term and thus provide new hosts for invading pathogens. Thus, the hit to the male sex must somehow be balanced by other advantages to their immune system.

Autoimmune diseases

Autoimmune diseases occur when the immune system turns on and attacks the body’s own cells or tissues, initiating a chronic cycle that results in damage or destruction of specific organs. These diseases include type 1 diabetes, lupus, rheumatoid arthritis, multiple sclerosis, and up to 80 different diseases that affect systems such as the intestine, bones, joints and nervous systems.The most striking sex differences in the immune system are seen in autoimmune diseases. Autoimmune disease affects about 8% of the population, but 78% of those affected are women. Women are three times more likely than men to develop these types of disease.
Read more - Explainer: what are autoimmune diseases?
In the case of lupus, the immune system mistakenly attacks the person’s own DNA (the structure that carries a person’s genetic code) causing damage to multiple organs that will lead to weight loss, anemia and eventually heart and kidney failure. Nine out of ten patients with lupus are women and clinical observations suggest that, again, hormones are the culprits.These differences of susceptibility between males and females tend to appear after puberty, and flare-ups increase during pregnancy. On the contrary, menopause is associated with a lower disease severity.Studies have linked oestrogen levels with the exacerbation of lupus. Oestrogens directly act on a particular immune cell (called the plasmacytoid dendritic cell) to promote their capacity to secrete inflammatory signals, which exacerbate lupus symptoms. Although these dendritic cells are generally important for fighting viral infections, in the context of lupus and multiple sclerosis, they cause significant harm.

Hormones and allergies

One in nine Australians (more than 2.5 million in total) suffer from asthma – a disease that causes swelling and narrowing of the airways. This makes it difficult to breathe when we encounter environmental allergens such as pollen.Twice as many women develop asthma compared to men. Interestingly, males are more susceptible to asthma before to the onset of puberty but, after puberty, females are more affected and develop more severe asthma than men. Until now, the reasons for this were not obvious, but hormones were speculated to play a role.In a recent study, we showed that high levels of testosterone in males protect them against the development of allergic asthma. During puberty, the level of testosterone increases.Testosterone acts as a potent inhibitor of a recently discovered immune cell called an innate lymphoid cell (ILC2), which accumulates in the lungs and initiates asthma. ILC2 cells release inflammatory signals that drive the swelling and airway narrowing characteristic of asthma when people are exposed to pollen, dust mites, grass or other common allergens. Testosterone reduces the numbers of ILC2 in the lungs of males, while female hormones provide no protective effect.
Read more: Do kids grow out of childhood asthma?
Immunity and sex are far more intricately linked than we had previously appreciated. More research needs to be done to better understand the triggers involved in the different responses of males and females. But the recent discoveries open the door for tactics to potentially target hormonal pathways or receptors that are preferentially expressed on male or female immune cells.
The ConversationRead the first article in our Gender Medicine series - Medicine’s gender revolution: how women stopped being treated as ‘small men’Gabrielle Belz, Professor, Molecular Immunology, Walter and Eliza Hall Institute and Cyril Seillet, Senior research scientist, Walter and Eliza Hall InstituteThis article was originally published on The Conversation. Read the original article.
By Prof Gabrielle Belz, Dr Cyril Seillet
Clinical Articles iconClinical Articles
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Do Not Order These Tests On Pregnant Women

Hot on the heels of the Choosing Wisely campaign of “do nots” for GPs, the Royal Australasian College of Physicians has released a new list of tests doctors should avoid ordering on pregnant women.The recommendations come from the Society of Obstetric Medicine in Australia and New Zealand (SOMANZ), and include the advice that the D-dimer test should not be used to diagnose venous thromboembolism in pregnant women as it is unreliable.Even though women are five times more likely to develop venous thromboembolism in pregnancy, other investigative tests should be used if a clot is suspected as D-dimer concentrations normally rise in pregnancy regardless of whether thrombosis has occurred, making abnormal results ‘incredibly unreliable’.Another recommendation included in the RACP’s top five low value practices and interventions is to not test for inherited thrombophilia in women who have a history of placenta-mediated complications of pregnancy such as stillbirth, recurrent miscarriages or placental abruption.The rationale behind the recommendation is that while some older, retrospective studies had suggested there might be an association with an inherited clotting disorder and these complications, more recent and more robust evidence has shown there is no link and what’s more, taking low molecular weight heparin is not useful as a preventive measure.The experts also advise not to do repeat tests for proteinuria in women with established  pre-eclampsia. Even though proteinuria is an important diagnostic marker for pre-eclampsia it is has no prognostic value. The level of the proteinuria does not correlate with the severity of the maternal complications, so repeated testing does not help management.MTHFR testing has become popular in certain, mainly allied health circles and is controversial. SOMANZ has made a strong recommendation to not undertake MTHFR polymorphism tests as part of a routine evaluation for thrombophilia in pregnancy.“Patients with the thermolabile variant of the methylenetetrahydrofolate reductase (MTHFR) polymorphism are at higher risk of hyperhomocysteinaemia which has been associated with venous thrombosis. However, these associations appear to hold only in countries lacking grain products nutritionally fortified as a public health measure.”They also say testing may lead to many anxiety-provoking false positives, as up to 15% of the population have homozygous variants, which in most instances appear to have no deleterious effects.The final test on the list is the erythrocyte sedimentation rate. The experts advise do not measure ESR in pregnancy as the levels can vary widely depending on factors such as gestational age and haemoglobin concentrations and therefore the test cannot reliably distinguish between healthy and unhealthy women in pregnancy.The list is the latest publication put out as part of the physician-led Evolve initiative run by the RACP. The aim of the initiative is to help ensure high quality patient care by identifying those practices and interventions that represent poor value to patients in terms of improving their clinical outcome and may even cause harm. According to the media release there are now 17 Evolve lists that have been published across a range of medical specialties, and there are another 15 in development.Ref: https://evolve.edu.au/published-lists/society-of-obstetric-medicine-of-australia-and-new-zealand

By Dr Linda Calabresi
Clinical Articles iconClinical Articles

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