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Dr Linda Calabresi

Vaccination in immunosuppressed adult patients has many facets and can be challenging for GPs who don’t deal with these cases regularly. But there are a few key considerations that can help guide clinicians, says Associate Professor Michael Woodward, Melbourne-based geriatrician, writer, researcher and passionate advocate for health promotion. Firstly, not all immunosuppression is equal. It is important to ascertain the degree of immunosuppression, as some people may be being unnecessarily denied vaccines because they are taking medication that can suppress the immune system but only at higher doses or in different formulations. “For instance, someone who is on inhaled corticosteroids for their asthma or on low dose (less than 20mg) prednisolone daily for just a few weeks is not significantly immunosuppressed and can be vaccinated in the same way as other people,” said Professor Woodward in an interview following his presentation at Healthed’s recent Annual Women's and Children’s Health Update in Perth. However, those on higher doses of steroids or on steroids more long-term, as well as those people who have conditions associated with immunosuppression such as haematological malignancy do need special consideration when it comes to vaccination. Most importantly, live vaccines are not to be given to this group. This includes the new herpes zoster vaccine (Zostavax), which absolutely contraindicated in severely immunocompromised patients. The consequences of inadvertently administering this vaccine to an immunosuppressed patient hit the headlines some months ago, highlighting the importance of this guideline. The other question often asked is whether patients who are known to be immunosuppressed, and therefore at greater risk of significant infections actually need more or stronger doses of the vaccines they are able to have. In some cases that is a very real and worthwhile consideration if you want to achieve the objective of immunoprotection, Professor Woodward said. For example, you might consider giving an immunosuppressed patient the pneumococcal vaccine (Prevenar 13) as opposed to the polysaccharide pneumococcal vaccine (Pneumovax 23). “The conjugate vaccine is generally slightly more likely to produce an immune response [than the polysaccharide vaccine],” he said. The other scenario where GPs might need to be considering vaccination in association with immunosuppression, is in patients who are scheduled for an elective splenectomy. The lack of a spleen is known to be associated with a reduction of the body’s ability to respond to a vaccine, so it is currently recommended that people who are about to undergo a splenectomy have the influenza, pneumococcal and the newer zoster vaccine. In addition, they should be vaccinated against H. influenza B and receive the two meningococcal vaccines currently available. All these are detailed as part of the pre-splenectomy recommendations on the spleen.org.au website, with the exception of the zoster vaccine, as the guidelines have yet to be updated. However, Professor Woodward says most health professionals in this area are advocating the inclusion of the zoster vaccine. Some of these vaccinations may also be given shortly after the removal of the spleen in cases where the splenectomy has been urgent, but this is generally not the remit of the GP. In general, the question of vaccination in the immunosuppressed patient can be complicated. It is a highly specialised area and Professor Woodward suggested, if in doubt GPs might want to seek input from a specialist in this area such as an immunologist or a rheumatologist.

Sullivan Nicolaides Pathology

Prenatal screening for chromosome disorders by maternal serum screening, ultrasound and non-invasive prenatal tests, such as Harmony®, is an established part of reproductive care in Australia. The overall risk of chromosome disorders rises markedly with maternal age, as shown in Figure 1. (There are two exceptions: Monosomy X, also known as Turner syndrome, and microdeletions, such as 22q11.2, occur independently of maternal age). This does not mean that chromosome screening should be restricted to older mothers. Younger mothers have more babies than older mothers, and the overall outcome is that the majority of pregnancies with a serious chromosome disorder occur in mothers under 35 years of age. For this reason, screening for chromosome disorders in pregnancy should be offered to mothers of all ages. The great majority of these chromosome disorders are new abnormalities that have happened for the first time in this pregnancy. They are not inherited disorders, and genetic testing of the parents provides no information about the risk of such an abnormality. This provides another reason for offering screening for chromosome disorders to all mothers, irrespective of family history.  

The frequency of single-gene disorders at birth

Chromosome disorders are not the only type of genetic condition which can affect the developing foetus. Many serious childhood disorders are due to recessive mutations that have been inherited from parents, with the parents being unaffected by these mutations. A parent who is a carrier of a recessive mutation, that is, having one normal and one abnormal copy of a gene, will not be affected by the abnormal gene. Everyone is a carrier for one or more disorders; this is of no immediate consequence and there usually is no family history of the disorder. The situation changes if both parents are carriers of mutations in the same gene located on one of the autosomes (chromosomes 1-22). The chance of their child inheriting the abnormal gene from each parent, and so developing an autosomal recessive disorder, is 25%. The situation is a little different for a woman with a recessive mutation on an X-chromosome: each of her sons is at 50% risk of inheriting the abnormal gene and being affected, and half of her daughters will be carriers. Overall, the risk of a woman who is an X-linked carrier having an affected child is approximately 25%. There are hundreds of inherited autosomal and X-linked recessive disorders that present in infancy and early childhood. These disorders are individually rare but, together, they are more common than the chromosome disorders for which prenatal screening is widely available and accepted. Further, the risk of these recessive disorders does not vary with maternal age (Figure 1). For mothers under 35 years of age, the risk of having a child with a serious childhood-onset recessive disorder is greater than the risk of having a child with a chromosome disorder.  

Screening potential parents for recessive disorders

These disorders are inherited but there is usually no family history to provide a clue. Until recently, the only way of identifying a carrier of a rare recessive disorder was to diagnose the disorder in their affected child. This has now changed. It is possible to screen a couple for mutations in autosomal genes, and a woman for mutations in X-linked genes, to determine whether they are at 25% risk of having an affected child. This screening test is called ’reproductive carrier screening’. From both a technical and clinical perspective, the challenge lies in choosing which genes to analyse. A number of providers, including Sonic Genetics, offer reproductive carrier screening for mutations responsible for three common disorders: cystic fibrosis and spinal muscular atrophy (both autosomal recessive) and Fragile X syndrome (X-linked recessive). Approximately 6% of people are carriers of one or more of these conditions, and 0.6% (one in 160) couples are at 25% risk of having an affected child. Those couples who are identified as carriers can consider a variety of options, including IVF with a donor gamete, pre-implantation genetic diagnosis, prenatal diagnosis by CVS, or they may make an informed decision to accept the risk. RANZCOG recommends that couples be offered such screening. The cost of this three-gene panel is approximately $400* per person. There is no Medicare rebate for carrier screening; there are exceptions (and restrictions) for people with a documented family history of cystic fibrosis or Fragile X syndrome.  

Expanded reproductive screening

If we were to screen more genes, we would identify more carriers. Sonic Genetics offers a screen of over 300 genes (autosomal and X-linked) which cause serious recessive childhood disorders. We estimate that approximately 70% of Australians are carriers for one or more conditions included in this screen and 3% (one in 30) couples are at 25% risk of having an affected child. This amounts to five times more information than is provided by the three-gene panel. This screen, the Beacon Expanded Carrier Screen, currently costs $995* per person or $1,750* for couples tested together. It is tempting to think that ‘more genes tested = more information for a couple’. This is not the case because the information provided by a carrier screen is also determined by the carrier frequency, mode of inheritance and detection rate of the assay for each gene. Some currently available screens of more than 100 genes provide less information than the three-gene screen described earlier.  

Implementing reproductive screening

Before offering reproductive carrier screening to your patients, it is important to consider some of the nuances, particularly in relation to the Fragile X syndrome (some carriers will develop premature ovarian failure or a tremor/ataxia syndrome in later life) and when there is a family history of a recessive disorder (seek expert advice; do not rely on screening). It is also important to recognise that some couples will not want this carrier information – and others will demand it. Each person needs to be free to make their own decision about what information they wish to have. We provide information about the three-gene and Beacon screens for both requestors and patients on our website. Sonic Genetics also offers genetic counselling free-of-charge for couples who are identified by either of these reproductive carrier screens as being at high risk of having an affected child (see www.sonicgenetics.com.au/rcs/gc).  

Conclusion

It is accepted practice that every woman is offered screening for chromosome disorders in pregnancy, irrespective of age and family history. In a similar vein, every couple should be offered reproductive carrier screening for recessive disorders, irrespective of age and family history. For women under 35 years, the risk of their child having a recessive disorder is greater than the risk of a chromosome disorder. Offering reproductive carrier screening simply represents good medical practice.  

References

RANZCOG. Prenatal screening and diagnostic testing for fetal chromosomal and genetic conditions. 2018 Aug. 35 p. Available from: https://www.ranzcog.edu.au/RANZCOG_SITE/media/RANZCOG-MEDIA/Women%27s%20Health/Statement%20and%20guidelines/Clinical-Obstetrics/Prenatal-screening.pdf?ext=.pdf Archibald AD, Smith MJ, Burgess T, Scarff KL, Elliott J, Hunt CE, et al. Reproductive genetic carrier screening for cystic fibrosis, fragile X syndrome, and spinal muscular atrophy in Australia: outcomes of 12,000 tests. Genet Med. 2018; 20(5): 513-523 Available from https://www.ncbi.nlm.nih.gov/pubmed/29261177 doi:10.1038/gim.2017.134. Sonic Genetics [Internet]. c2015. Reproductive Carrier Screening; 2018. Available from: www.sonicgenetics.com.au/rcs   General Practice Pathology is a new regular 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.
Dr Linda Calabresi

GPs can make a significant difference in curbing the rising rates of liver cancer deaths in Australia, experts say. According to an analysis of over 270 cases of newly diagnosed cases of hepatocellular cancer presenting at seven Melbourne tertiary hospitals over one year, researchers say survival rates could be improved with earlier diagnosis of cirrhosis and better adherence to recommended screening  schedules among those known to be at high risk. “[T]he number of liver cancer-related deaths has been the most rapid for any cancer type in Australia over the past 40 years,” the study authors said in the MJA. And of all the types of liver cancer, hepatocellular carcinoma is by far the most common, accounting for 82%. Even though treatments are available, both curative and palliative survival remains very poor with the Australian 12-month survival rate estimated to be only 62%. In this particular study, conducted over 2012/2013 the mean survival was only 18 months. As one would expect, the patients who did better, who generally survived the longest were those whose tumours were detected at an earlier stage. These were usually the patients who were known to be at high risk of developing liver cancer and were participating in a surveillance program. But this was only 40% of the 272 cases, even though 89% would have qualified for surveillance based on their risk factors. Why was this? Well firstly, many of these people did not know they were at risk. And that’s where GPs fit in. In the study the most common risk factors for liver cancer were found to be hepatitis C infection (41%), alcohol-related liver disease (39%), hepatitis B infection (22%) and non-alcoholic fatty liver disease (14%). Many had more than one risk factor. Most telling was the finding that, even though the vast majority of patients (83%) had cirrhosis when they were diagnosed with hepatocellular carcinoma, for one third of them that was the first they knew of it. The study authors suggest clinicians need to be alert for risk factors for chronic liver disease such as excess alcohol use, chronic HCV and HBV infections and even non-alcoholic liver disease in certain groups. In these people, checking for cirrhosis is likely to be worthwhile. “An aspartate transaminase to platelet ratio index (APRI) value greater than 1.0 predicts cirrhosis with 76% sensitivity and 72% specificity, and the test is simple to undertake,” the researchers said. The other major barrier to the earlier detection of liver cancer identified in the study was the poor adherence to surveillance among those people identified as being at high risk. Researchers found patients with alcohol-related liver disease or decompensated liver disease were the least likely to get regular monitoring. A surveillance program for this particular cancer involves a 6-monthly liver ultrasound and serum alpha-fetoprotein assessment. The study authors are advocating a national hepatocellular cancer surveillance program for those who are at high risk of developing the disease, which would include all patients with cirrhosis, Asian men over 40, women over 50, Africans over 20 years of age, and patients with a family history of [hepatocellular carcinoma] without cirrhosis but with chronic HBV infections. A national program to screen for hepatocellular carcinoma amongst this particular group would be worthwhile, the researchers said, as the incidence of the cancer is high, the screening is non-invasive and inexpensive and, perhaps most importantly early detection has been shown to improve survival. However, until such a national program is developed, researchers are encouraging GPs to ensure that their at-risk patients are enrolled in a surveillance program in order to hopefully improve their health outcomes.   Reference: Hong TP, Gow PJ, Fink M, Dev A, Roberts SK, Nicoll A, et al. Surveillance improves survival of patients with hepatocellular carcinoma: a prospective population-based study. Med J Aust [Internet]. 2018 Sep 24; 209(8): 1-7. Available from: https://www.mja.com.au/journal/2018/209/8/surveillance-improves-survival-patients-hepatocellular-carcinoma-prospective doi: 10.5694/mja18.00373

Kevin Davies, Jessica Eccles & Neil Harrison

Fibromyalgia is something of a mystery. It can’t be detected with scans or blood tests, yet it causes lifelong pain for millions of people. The disease mainly affects women (about 75-90% of cases), causing pain all over the body. Because not all healthcare professionals are adept at identifying and diagnosing fibromyalgia, reported rates of the condition vary greatly from country to country. In China, it affects only 0.8% of people, in France around 1.5%, in Canada 3.3%, and in Turkey 8.8%. Estimates in the US range from 2.2% to 6.4%, and in Russia, about 2% of the population is affected. People with the condition are often diagnosed if they have longstanding muscle pain, bone or joint pain and fatigue. Fibromyalgia can also cause insomnia, “brain fog”, some symptoms of depression or anxiety, as well as a range of other complaints, including irritable bowel syndrome and headache. Many patients are also hypermobile (“double-jointed”), and there is some overlap with chronic fatigue syndrome (also known as ME). Guidelines from the American College of Rheumatology make it clear that the diagnosis should be made using defined criteria based on the “widespread pain index” (which scores the number of painful regions out of 19) coupled with a symptom severity scale. The diagnosis also takes fatigue, generalised pain, unrefreshing sleep and cognitive symptoms into account. It doesn’t matter if the patient has another rheumatic disease, they can still be diagnosed with fibromyalgia. The scoring system, recommended by the American College of Rheumatology, is often used in clinical trials, but in the clinic, most doctors rely on detecting tender points in specific places and on excluding other medical conditions, including rheumatic conditions. Unlike say, rheumatoid arthritis or lupus, the tests do not show clear evidence of inflammation or autoimmunity (when the body’s immune system attacks itself) and scans are normal. The lack of inflammation or structural abnormality in muscles or joints – aside from making diagnosis difficult – is the main reason there are no widely accepted or effective treatments. In rheumatic diseases, where we understand the mechanisms that underlie the condition, we have the most effective treatments. In rheumatoid arthritis, for example, we know that much of the inflammation is caused by a cell-signalling protein (cytokine) called tumour necrosis factor and that blocking the activity of this protein switches off the disease in most patients. A number of possible mechanisms have been proposed in fibromyalgia, including abnormal muscle metabolism, reduced levels of steroid hormones such as cortisol, or abnormal small nerve fibres. But these abnormalities aren’t found in all patients with the condition. As such, they can’t be used as part of a diagnostic test, nor can they help develop treatments. Some experts have suggested that fibromyalgia may be related to abnormalities in the autonomic nervous system – the part of the nervous system that controls bodily functions, such as heart rate and blood pressure – and how the brain responds to pain signals and reacts to external stressors (such as infections). But there is currently no hard evidence to back up this theory. Looking for clues To fill in some of the gaps in our knowledge about this devastating condition, our research team at Brighton and Sussex Medical School is investigating the potential role of the autonomic nervous system and inflammation in fibromyalgia and chronic fatigue syndrome. For our study, we have two groups of patients: one with pain as the main symptom and the other with fatigue as the main symptom. We also have matched controls – people without the disease, but otherwise similar characteristics – to make meaningful comparisons. The study is in two parts. First, we will test the patients’ autonomic nervous system using a tilt-table. This involves tilting the person head downwards to see how well their body adapts to this change in posture by changing heart rate and blood pressure (both of which are monitored during the test).Second, we will stimulate patients’ immune systems with a typhoid vaccine (the normal type used in travellers) and perform magnetic resonance brain scans to look for changes in blood flow and also measure the levels of “inflammatory mediators” (the chemicals the body produces in response to stimuli of this type), to see whether these are higher in the fibromyalgia patients. Our study should, for the first time, help us to address the question of whether there really is an abnormal brain response to inflammation or infection in these patient groups and enable us to explore the relationship between the abnormal functioning of the autonomic nervous system and fibromyalgia and chronic fatigue syndrome. Fibromyalgia rarely goes away and treatment options are limited. Only by developing a proper understanding of the disease processes underlying this condition will doctors be able to make a clear, positive diagnosis, and most importantly, offer effective therapy.   Disclosure Statement Kevin Davies receives funding from AR-UK. Jessica Eccles receives funding from Academy of Medical Sciences, National Institute of Health Research, MQ Neil Harrison receives funding from the Wellcome Trust, Medical Research Council (MRC), Arthritis Research UK, and Janssen Pharmaceuticals.

Dr Linda Calabresi

The value of omega-3 fatty acids has come under fire lately. But now a new systematic review suggests they might have benefits beyond the previous therapeutic targets of depression, cardiac health, eye health and arthritis. Researchers have found that omega-3 polyunsaturated fatty acids (PUFA) might reduce the symptoms of clinical anxiety, particularly among those people who had a specific clinical condition be it medical (such as Parkinson disease) or psychological (premenstrual syndrome). “This systematic review…provides the first meta-analytic evidence, to our knowledge, that omega-3 PUFA treatment may be associated with anxiety reduction, which might not only be due to a potential placebo effect, but also from some associations of treatment with reduced anxiety symptoms,” the review authors said in JAMA. The finding is likely to be welcome news for patients with this condition. Be it the potential side-effects of medications or the cost and accessibility of psychological therapy, patients with anxiety, especially those with comorbid medical conditions are keen for alternative or at least supplementary safe, evidence-based treatments for their symptoms. Previous research, in both human and animal studies had found that a lack of omega-3 PUFAs could induce various behavioural and neuropsychiatric disorders. What had not been shown was whether taking this supplement was effective in reducing the specific anxiety symptoms. The review involved an extensive literature search through a wide range of databases including PubMed and Cochrane looking for trials that had assessed the anxiolytic effects of these fatty acids in humans. In the end they found 19 trials that matched their eligibility criteria, which allowed researchers to analyse the effect of supplementation in just over 1200 participants and compare it with about 1000 matched controls who didn’t take the fatty acids. Overall, they found ‘there was a significantly better association of treatment with reduced anxiety symptoms in patients receiving omega-3 PUFA treatment than in those not receiving it.’ Subgroup analysis also showed that those taking at least 2000mg or more of the omega-3 PUFA treatment were more likely to have reduced anxiety. And somewhat surprisingly, those patients receiving supplements containing less than 60% EPA did better than those taking formulations with a greater concentration of EPA. The studies in the review included very different cohorts, and because of this and the limited number of studies included, the authors understandably say the results need to be interpreted with caution. However, while bigger, better studies are still needed to prove the benefit of omega-3 PUFAs in patients with clinical anxiety, this research certainly does suggest that higher dose formulations of less than 60% concentration of EPA might have a role as at least adjunctive treatment to standard therapy.   Reference: Su KP, Tseng PT, Lin PY, Okubo R, Chen TY, Chen YW, et al. Association of Use of Omega-3 Polyunsaturated Fatty Acids With Changes in Severity of Anxiety Symptoms; A Systematic Review and Meta-analysis. JAMA Network Open [Internet]. 2018 Sep; 1(5): e182327. Available from: https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2701735 doi:10.1001/jamanetworkopen.2018.2327.

Megan Lee & Joanne Bradbury

We all know eating “healthy” food is good for our physical health and can decrease our risk of developing diabetes, cancer, obesity and heart disease. What is not as well known is that eating healthy food is also good for our mental health and can decrease our risk of depression and anxiety. Mental health disorders are increasing at an alarming rate and therapies and medications cost $US2.5 trillion dollars a year globally. There is now evidence dietary changes can decrease the development of mental health issues and alleviate this growing burden. Australia’s clinical guidelines recommend addressing diet when treating depression. Recently there have been major advances addressing the influence certain foods have on psychological well-being. Increasing these nutrients could not only increase personal well-being but could also decrease the cost of mental health issues all around the world. 1. Complex carbohydrates One way to increase psychological well-being is by fuelling brain cells correctly through the carbohydrates in our food. Complex carbohydrates are sugars made up of large molecules contained within fibre and starch. They are found in fruit, vegetables, and wholegrains and are beneficial for brain health as they release glucose slowly into our system. This helps stabilise our mood. Simple carbohydrates found in sugary snacks and drinks create sugar highs and lows that rapidly increase and decrease feelings of happiness and produce a negative effect on our psychological well-being. We often use these types of sugary foods to comfort us when we’re feeling down. But this can create an addiction-like response in the brain, similar to illicit drugs that increase mood for the short term but have negative long-term effects. Increasing intake of complex carbohydrates and decreasing sugary drinks and snacks could be the first step in increased happiness and well-being. 2. Antioxidants Oxidation is a normal process our cells carry out to function. Oxidation produces energy for our body and brain. Unfortunately, this process also creates oxidative stress and more of this happens in the brain than any other part of the body. Chemicals that promote happiness in the brain such as dopamine and serotonin are reduced due to oxidation and this can contribute to a decrease in mental health. Antioxidants found in brightly coloured foods such as fruit and vegetables act as a defence against oxidative stress and inflammation in the brain and body. Antioxidants also repair oxidative damage and scavenge free radicals that cause cell damage in the brain. Eating more antioxidant-rich foods can increase the feel-good chemicals in our brain and heighten mood. Antioxidants can help restore the happy chemicals in the brain. www.shutterstock.com.au 3. Omega 3 Omega 3 are polyunsaturated fatty acids that are involved in the process of converting food into energy. They are important for the health of the brain and the communication of its feel-good chemicals dopamine, serotonin and norepinephrine. Omega 3 fatty acids are commonly found in oily fish, nuts, seeds, leafy vegetables, eggs, and in grass fed meats. Omega 3 has been found to increase brain functioning, can slow down the progression of dementia and may improve symptoms of depression. Omega 3 are essential nutrients that are not readily produced by the body and can only be found in the foods we eat, so it’s imperative we include more foods high in omega 3 in our everyday diet. 4. B vitamins B vitamins play a large role in the production of our brain’s happiness chemicals serotonin and dopamine and can be found in green vegetables, beans, bananas, and beetroot. High amounts of vitamins B6, B12, and folate in the diet have been known to protect against depression and too low amounts to increase the severity of symptoms. Vitamin B deficiency can result in a reduced production of happiness chemicals in our brain and can lead to the onset of low mood that could lead to mental health issues over a long period. Increasing B vitamins in our diet could increase the production of the feel good chemicals in our brain which promote happiness and well-being. 5. Prebiotics and probiotics The trillions of good and bad bacteria living in our tummies also influence our mood, behaviour and brain health. Chemical messengers produced in our stomach influence our emotions, appetite and our reactions to stressful situations. Prebiotics and probiotics found in yoghurt, cheese and fermented foods such as kombucha, sauerkraut and kimchi work on the same pathways in the brain as antidepressant medications and studies have found they might have similar effects. Prebiotics and Probiotics have been found to suppress immune reactions in the body, reduce inflammation in the brain, decrease depressed and anxious states and elevate happy emotions. Incorporating these foods into our diet will not only increase our physical health but will have beneficial effects on our mental health, including reducing our risk of disorders such as depression and anxiety.   Disclosure Statement Megan Lee receives funding from Southern Cross University and Santos Organics Joanne Bradbury receives funding from the Australian Traditional-Medicinal Society (ATMS), Santos Organics, and Metagenics to support academic research

Dr Linda Calabresi

Adolescent boys who struggle to understand how basic machines work and young girls who have difficulty remembering words are at increased risk of developing dementia when they’re older, new research has found. According to the longitudinal study published in The Journal of the American Medical Association, lower mechanical reasoning in adolescence in boys was associated with a 17% higher risk of having dementia when they were 70. With girls it was a lower memory for words in adolescence that increased the odds of developing the degenerative disease. It has been known for some time that the smarter you are throughout life, even as a child the less likely it is that you will develop dementia. Not a guarantee of protection – just a general trend. It has to do with cognitive reserve, the US researchers explain. “Based on the cognitive reserve hypothesis, high levels of cognitive functioning and reserve accumulated throughout the life course may protect against brain pathology and clinical manifestations of dementia,” they wrote. This theory has been supported by a number of studies such as the Scottish Mental Health Survey that showed that lower mental ability at age 11 increased the risk of dementia down the track. But what had been less well-defined was whether there were any particular aspects of intelligence in young people that were better predictors (or protectors) of dementia than others. This study goes some way to addressing this. Researchers were able to link sociobehavioural data collected from high school children back in 1960 with Medicare claims data over 50 years later that identified those people who had been diagnosed with Alzheimer's disease and related disorders. Interestingly, poor adolescent performance in other areas of intelligence such as mathematics and visualisation were also associated with dementia but not nearly to the extent of mechanical reasoning and word memory. So why is this so? The study authors say there are a few possible explanations. Maybe the poor performance in adolescence reflected poor brain development earlier in life, a risk factor for dementia. Or maybe these adolescents are more susceptible to neuropathology as they get older? Or maybe they are the adolescents who adopt poor health behaviours such as smoking and little exercise? “Regardless of mechanism, our findings emphasise that early-life risk stretches across the life course,” they said. And what can be done about it? That’s the million-dollar question. The researchers say the hope is if we know the at-risk group we can get aggressive with preventive management early. “Efforts to promote cognitive reserve-building experiences and positive health behaviours throughout the life course may prevent or delay clinical symptoms of Alzheimer's disease and related disorder.” An accompanying editorial takes this concept a little further. Dr Tom Russ, a Scottish psychiatrist says interventional research has identified a number of factors that can potentially influence cognitive reserve. These include modifiable health factors, education, social support, positive affect, stimulating activities and/or novel experiences, and cognitive training. As Dr Russ says, you can’t necessarily change all of these risk factors, and even the ones you can change may become less modifiable later in life. But as this study demonstrates, you may be able to work on a person’s cognitive reserve at different stages throughout their life to ultimately lower their risk of dementia.   Reference
  1. Huang AR, Strombotne KL, Horner EM, Lapham SJ, Adolescent Cognitive Aptitudes and Later-in-Life Alzheimer Disease and Related Disorders. JAMA Network Open [Internet]. 2018 Sep; 1(5): e181726. Available from: https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2701735 doi:10.1001/jamanetworkopen.2018.1726.
  2. Russ TC, Intelligence, Cognitive Reserve, and Dementia: Time for Intervention? JAMA Network Open [Internet]. 2018 Sep; 1(5): e181724. Available from: https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2701735 doi:10.1001/jamanetworkopen.2018.1724.

Dr James Harraway

Non-Invasive Prenatal Testing (NIPT), the cell-free DNA-based blood test that screens for fetal chromosomal abnormalities, is fast becoming a routine part of obstetric care. NIPT at a glance During pregnancy, maternal plasma contains fragments of DNA from the mother and from the placenta (fetal DNA). The proportion of DNA fragments from particular chromosomes is usually very stable throughout pregnancy. If there is an excess of fetal fragments from one chromosome, the proportion of fragments from that chromosome will be changed. Inconclusive tests A key reason that NIPTs should precisely measures the amount of fetal DNA in the sample – the fetal fraction – is if there is insufficient fetal DNA, the result may merely reflect the genetic status of the mother. NIPT assays should report a result only if there is sufficient fetal DNA to be confident of accuracy. Rarely, a test for trisomy 21,18 and 13 cannot be reported. This occurs in 3% of women tested by Sonic Genetics and is usually because there is insufficient fetal DNA compared with maternal DNA in the mother’s plasma. This low fetal fraction can be due to a relative excess of maternal DNA and this can vary over time. It is more common in women with increased body weight, and more likely in the presence of infection and inflammation, or after exercise. It also occurs if the mother or fetus has some subtle benign variations in chromosome structure (copy number variants) that make estimating the proportion of fragments from a chromosome unreliable. In some instances, the DNA in the sample has degraded during collection and shipping to the laboratory, and the quality is insufficient for a reliable result. These factors interfere with quality control of the test. Two thirds of women will get a result on re-testing. However, if the second test is inconclusive, it should not be repeated. This occurs in 1% of pregnant women screened. It is also not worth using another form of non-invasive prenatal test. Other tests do not estimate the fetal fraction accurately and may provide false reassurance. A decision about other test modalities (combined first trimester screen, second trimester serum screen, detailed ultrasonography or invasive genetic testing such as CVS/amniocentesis) should be based on assessment of all identified risk factors and may require specialist consultation. More rarely (in 0.5 –1% of women) the test reports a result for trisomy 21, 18 and 13 but not for fetal gender and sex chromosome abnormalities. It is unlikely that a repeat test will provide a result. A decision about using fetal ultrasound or invasive genetic testing to document fetal gender should be based on assessment of need and any identified risk factors.   General Practice Pathology is a new regular 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.

Dr Linda Calabresi

GPs may have to correct some patients’ misunderstanding following reports in the general media suggesting that testing for high risk cancer genes was now available to everyone free of charge. Writing in the latest issue of the MJA, Australian genetics experts say that testing for specific high- risk genetic mutations, especially BRCA1 and BRCA2 has been available to appropriate patients free of charge (but not Medicare-rebated) by genetic specialists in public clinics for over 20 years. What’s new is that these tests now attract a Medicare rebate and you don’t have to be a genetic specialist to order them, but they are still only available to selected patients. “Testing is appropriate when there is at least a 10% chance of identifying a gene mutation responsible for the personal or family history of cancer,” the authors of the article wrote. There are a number of algorithms available to help clinicians calculate whether the likelihood of having one of these cancer-causing genetic mutations is at least 10%. Usually testing is initially considered for patients who have been diagnosed with either breast or ovarian cancer, and because of their young age and/or their strong family history are considered at high possibility of having a genetic mutation that explains their condition. The new item numbers (73295,73296 and 73297) cover testing for heritable germline mutations in seven genes including BRCA1 and BRCA2. If such a mutation is found, then at risk adult relatives will be justified in also accessing testing. However, as the article authors point out there are limitations with this type of genetic testing. Firstly most breast and ovarian cancers occur in people without an identifiable underlying genetic variant. “Only 5% of female breast cancers, 15% of invasive epithelial ovarian cancers and up to 14% of male breast cancers are related to BRCA1 or BRCA2 mutations, thus, most patients with breast cancer do not need, nor will they benefit from, a genetic test,” they said. That’s not to say the absence of BRCA1 or BRCA2, or one of the other rarer high-risk mutations currently tested for, excludes the possibility that the patient has inherited a predisposition to the cancer. Families that appear to have a high prevalence of these types of cancer may indeed have an inherited genetic mutation, it is just that because of limitations of technology and knowledge it is yet to be isolated. What’s more, the sensitivity of the current testing methods, means that a number of incidental genetic mutations may be noted, but the significance of these is as yet unknown. It is critical that when testing is requested for a relative of an affected patient, the laboratory is informed of the exact genetic variation found in the original affected patient, to ensure pathologists distinguish between the disease-causing mutation and variants of undetermined significance. The authors also suggest confining testing to only the most likely variant/s rather than requesting testing for mutations in multiple genes. “[T]he testing of multiple genes may uncover unclassified variants, variants outside the usual clinical context, variants unrelated to the current cancer, or unexpected important variants for which the patient has not been well prepared,” they said. They also suggest education and counselling be given to patients considering this genetic testing, and written consent obtained. The new Medicare item numbers represent a major step forward in terms of genetic and genomic testing becoming mainstream, but, as the current incorrect media headlines demonstrate, this transition is going to require information and education. Clinicians who order these tests are likely to benefit from establishing close ties with genetic services and specialists to ensure best and appropriate practice in this ever-expanding area of medicine. Ref: Med J Aust 2018; 209 (5): 193-196. || doi: 10.5694/mja17.01124

Healthed

There’s no way you’d want to go to work when you’ve got the telltale signs of gastro: nausea, abdominal cramps, vomiting and diarrhoea. But what about when you’re feeling a bit better? When is it safe to be around colleagues, or send your kids to school or daycare? The health department recommends staying home from work or school for a minimum of 24 hours after you last vomited or had diarrhoea. But the question of how long someone is contagious after recovering from gastro is a very different question.   What causes gastro? To better understand how long you can be contagious with gastro, we need to look at the various causes. Viruses are the most common causes of gastro. Rotavirus is the leading cause in infants and young children, whereas norovirus is the leading cause of gastro in adults. There are around 1.8 million cases of norovirus infection in Australia each year. This accounts for almost 40% of the total cases of gastro. Bacterial gastroenteritis is also common and accounts for around 1.6 million cases a year. Of those cases, 1.1 million come from E. coli infections. Other bacteria that commonly cause gastro include salmonella, shigella and campylobacter. These bacteria are often found in raw or undercooked meat, seafood, and unpasteurised milk. Parasites such as giardia lamblia, entamoeba histolytica and cryptosporidium account for around 700,000 cases of gastro per year. Most of the time people recover from parasitic gastroenteritis without incident, but it can cause problems for people with weaker immune systems. Read more: Health Check: I feel a bit sick, should I stay home or go to work?   Identifying the bug Most cases of diarrhoea are mild, and resolve themselves with no need for medical attention. But some warrant further investigation, particularly among returned travellers, people who have had diarrhoea for four or five days (or more than one day with a fever), patients with bloody stools, those who have recently used antibiotics, and patients whose immune systems are compromised. The most common test is the stool culture which is used to identify microbes grown from loose or unformed stools. The bacterial yield of stool cultures is generally low. But if it does come back with a positive result, it can be potentially important for the patient. Some organisms that are isolated in stool cultures are notifiable to public health authorities. This is because of their potential to cause serious harm in vulnerable groups such as the elderly, young children, pregnant women and those with weakened immune systems. The health department must be notified of gastro cases caused by campylobacter, cryptosporidium, listeria, salmonella, shigella and certain types of E.coli infection. This can help pinpoint outbreaks when they arise and allow for appropriate control measures.   You might feel better but your poo isn’t Gastro bugs are spread via the the faecal-oral route, which means faeces needs to come into contact with the mouth for transmission to occur. Sometimes this can happen if contaminated faecal material gets into drinking water, or during food preparation. But more commonly, tiny particles of poo might remain on the hands after going to the toilet. Using toilet paper to wipe when you go to the toilet doesn’t completely prevent the contamination of hands, and even more so when the person has diarrhoea. The particles then make their way to another person’s mouth during food preparation or touching a variety of contaminated surfaces and then putting your fingers in your mouth. After completely recovering from the symptoms of gastro, infectious organisms can still be shed into stools. Faecal shedding of campylobacter, the E. coli O157 strain, salmonella, shigella, cryptosporidium, entamoeba, and giardia can last for many days to weeks. In fact, some people who have recovered from salmonella have shed the bacteria into their stools 102 days later. Parasites can remain alive in the bowel for a long period of time after diarrhoea finishes. Infectious cryptosporidium oocysts can be shed into stools for up to 50 days. Giardia oocysts can take even longer to be excreted.   So, how long should you stay away? Much of the current advice on when people can return to work, school or child care after gastro is based on the most common viral gastroenteritis, norovirus, even though few patients will discover the cause of their bug. For norovirus, the highest rate of viral shedding into stools occurs 24 to 48 hours after all symptoms have stopped. The viral shedding rate then starts to quickly decrease. So people can return to work 48 hours after symptoms have stopped. Yes, viral shedding into stools can occur for longer than 48 hours. But because norovirus infection is so common and recovery is rapid, it’s not considered practical to demand patients’ stools be clear of the virus before returning to work. While 24 hours may be appropriate for many people, a specific 48-hour exclusion rule is considered necessary for those in a higher-risk category for spreading gastro to others. These include food handlers, health care workers and children under the age of five at child care or play group. If you have a positive stool culture for a notifiable organism, that may change the situation. Food handlers, childcare workers and health-care workers affected by verotoxin E.coli, for example, are not permitted to work until symptoms have stopped and two consecutive faecal specimens taken at least 24 hours apart have tested negative for verotoxin E. coli. This may lead to a lengthy exclusion period from work, possibly several days.   How to stop the spread Diligently washing your hands often with soap and water is the most effective way to stop the spread of these gastro bugs to others. Consider this: when 10,000 giardia cysts were placed in the palm of a hand, handwashing with soap eliminated 99% of them. To prevent others from becoming sick, disinfect contaminated surfaces thoroughly immediately after someone vomits or has diarrhoea. While wearing disposable gloves, wash surfaces with hot water and a neutral detergent, then use household bleach containing 0.1% hypochlorite solution as a disinfectant.

Dr Linda Calabresi

Why are Australians having rehabilitation as an inpatient after their total knee replacements rather than as an outpatient at a rate higher than any other country in the world? And why are our rates of inpatient rehabilitation as opposed to community or home-based rehab increasing? That’s what researchers were investigating in a study just published in the MJA. Could it be inpatient rehab was associated with better health outcomes for the patient than the other options? Or were patients too complex, lived too far away or needed greater supervision to allow them to have their rehab off-site? As it turns out, the reason inpatient rehabilitation rates are increasing has much more to do with private hospitals being able to access funding than any patient factors. According to the study authors, more than 50,000 total knee replacement operations were performed in Australia in 2016, about 70% of which took place in a private hospital. In that year, 2016, 45% of patients underwent inpatient rehabilitation following surgery. This represents a substantial increase from the 31% who had the same inpatient service back in 2009. This bucks an international trend. “Inpatient rehabilitation rates in the United States decreased from a peak of 35% in 2003 to 11% in 2009, with a mean rate during 2009-2014 of 15%,” the researchers said. Randomised controlled trials have failed to show the functional improvements achieved through inpatient rehabilitation are superior to those achieved with home- or community-based rehabilitation. However, the cost was significantly more. A recent analysis including almost 260 privately insured patients at 12 Australian hospitals put the cost differential at an average of $9500. And even though the mean age for patients undergoing inpatient rehab was slightly higher than for those who did not (71.0 vs 67.3 years), and they were more likely to have comorbidities and live alone, the study authors said the differences didn’t explain the wide variation in admission rates from hospital to hospital. “Patients in hospitals with high rates of inpatient rehabilitation were similar to those in hospitals with low rates, eliminating patient complexity as the reason,” they said. It seems the greatest determinant of whether a person had inpatient rehabilitation was the hospital in which the total knee replacement took place. “This factor was substantially more important than the clinical profile of the patient,” the study authors said. They suggested some private hospitals were encouraging inpatient rehabilitation because they were able to access funding on a per day basis for the rehab, in addition to the payment received for the knee surgery. The study authors concede it is an attractive business model, but while these hospitals may be offering excellent rehab in terms of services and facilities, it all comes at a cost ‘that, for many patients, is not justified by better outcomes.’ They suggest the proportion of patients receiving inpatient rehabilitation after a total knee replacement could be reduced, improving health care efficiency without harming health outcomes. “Reducing low value care will require system-level changes to guidelines and incentives for hospitals, as hospital-related factors are the major driver of variation in inpatient rehabilitation practices,” they concluded.   Reference: Schilling C, Keating C, Barker A, Wilson SF, Petrie D,  Predictors of inpatient rehabilitation after total knee replacement: an analysis of private hospital claims data. Med J Aust. 2018 August 27. 209(5): 222-7. Available from: https://www.mja.com.au/journal/2018/209/5/predictors-inpatient-rehabilitation-after-total-knee-replacement-analysis doi:10.5694/mja17.01231  

Dr Jenny Robson

Mycoplasma genitalium (M. genitalium), is thought to affect up to 400,000 Australians. It causes urethritis in men, and in women it can lead to pelvic inflammatory disease, cervicitis and preterm labour. It is also a recognised cause of anorectal proctitis along with other infections including Chlamydia trachomatis (including the LGV strains), gonorrhoea, syphilis, HSV and shigellosis. Asymptomatic infection is also common. Who to test Only test those with symptoms and their contacts. Screening asymptomatic people for M. genitalium is not currently recommended. Diagnosis Females: PCR on endocervical or vaginal swab, first pass urine (FPU), ThinPrep -collected by cervical brush/swab. Males: PCR on urethral swab (in preference to FPU), anorectal swabs. Throat swabs are not recommended as pharyngeal infection is uncommon. Transport: Ambient temperature; if there is any delay from collection to transport to the laboratory, the sample must be refrigerated Current treatment recommendations Preliminary data from the patient populations suggests resistance rates to macrolides may be as high as 64 per cent. The highest rates are likely to be in the men who have sex with men (MSM) population. Although information regarding fluoroquinolone resistance (moxifloxacin) is not available with this test, some studies suggest resistance to fluoroquinolones is present in 10–15% of infections. Doxycycline alone is ineffective in two-thirds of infections but will lower bacterial load in most cases, increasing the likelihood of cure with a subsequent antibiotic. Pretreating M. genitalium infections with doxycycline for one week and then treating susceptible infections with azithromycin and macrolide-resistant infections with a fluoroquinolone eradicates >90% of infections. Current treatment regimens Macrolide sensitive Doxycycline 100mg bd for seven days followed by azithromycin 1g stat then 500mg daily for three days (total 2.5g) OR Doxycycline 100mg bd for seven days followed by azithromycin 1g single dose. It is not known to what extent the improved outcomes resulting from the use of doxycycline followed by 2.5g azithromycin are due to this dose of azithromycin, rather than simply the pre-treatment with doxycycline. The higher dose of azithromycin requires a private prescription. Macrolide resistant Doxycycline 100mg bd for seven days followed by moxifloxacin 400mg daily for seven days. A longer course of moxifloxacin may be required in women with pelvic inflammatory disease. Moxifloxacin requires a private prescription, cannot be used in pregnancy and is expensive. It is associated with diarrhoea, occasional tendinopathy and rare neurological and cardiac events. Treatment failures following appropriate fluoroquinolone treatment may require specialist advice. Additional actions Advise no sex without condoms until tested for cure (14 days after completion of treatment). Advise no sex with untested previous sexual partners. Test of cure Test of cure by PCR should be done at least two weeks after treatment is completed i.e. four weeks after commencing therapy. Contact tracing In heterosexuals, the risk of PID and reproductive complications suggests a greater need to trace, test and treat infected contacts. The time period for contact tracing is unknown. Asymptomatic infection and macrolide resistance are more common in MSM and there is only limited evidence that this is harmful. As moxifloxacin will probably be required for treatment, contact tracing may be best confined to continuing partners of a symptomatic person.   References: Australian STI Management Guidelines for Use in Primary Care http://www.sti.guidelines.org.au/sexually-transmissible-infections/mycoplasma-genitalium#management Australian Contact Tracing Manual contacttracing.ashm.org.au/conditions/when-contact-tracing-is-recommended/mycoplasma-genitalium   General Practice Pathology is a new regular 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.