In healthy individuals, the Zika virus causes flu-like symptoms. If a pregnant woman becomes infected, the unborn child can suffer from severe brain abnormalities as a result of mechanisms that have not yet been explained. A study by the Technical University of Munich (TUM) and the Max Planck Institute of Biochemistry (MPI-B) shows that Zika virus proteins bind to cellular proteins that are required for neural development.
A few years ago, Zika virus spread across South America, posing a health issue with global impact. A significant number of South American women who came into contact with the virus for the first time at the start of their pregnancy by a mosquito bite subsequently gave birth to children with severe disabilities. The babies suffered from a condition known as microcephaly; they were born with a brain that was too small. This can lead to intellectual disabilities and other serious neurological disorders.
Scientists succeeded in proving that these deformities are caused by Zika virus infections, but so far they have been unable to explain why. Andreas Pichlmair, Chair for Viral Immunopathology at TUM and his team from the TUM Institute of Virology and MPI-B have examined how Zika virus influences human brain cells. They identified the virus proteins with the potential to affect neuronal development in the developing brain.
“Zika virus is closely related to the Hepatitis C virus and certain tropical diseases such as Dengue and West Nile virus. It is, however, the only virus that causes brain damage in newborns,” explains Pichlmair, who headed the recent study.
The researchers discovered that the virus uses certain cellular proteins to replicate its own genome. These molecules are also important neurological factors in the process of a stem cell developing into a nerve cell. “Our findings suggest that the virus takes these factors away from brain development and uses them to replicate its genome, which prevents the brain from developing properly,” explains the virologist.
When the team headed by Pichlmair removed the factors in the cells, the virus found it much harder to replicate. The researchers were able to demonstrate which virus proteins come in contact with these development factors and cause the brain defects. “Previous studies revealed the virus proteins necessary for the packaging or replication of the viral genome but it was enigmatic to understand how these proteins influence neuronal development. It appears that viral proteins are responsible for causing the serious defects in the unborn – unintentionally we presume,” says Pichlmair.
In their comprehensive proteomics survey, the research team identified cellular proteins that were altered chemically or numerically by the virus or which bound to virus proteins. In this way, they were not only able to illustrate possible reasons for the caused deformities, but also obtained a very clear picture of how the virus reprograms the cell to use it for its own replication.
www.tum.de/nc/en/about-tum/news/press-releases/details/34920/
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Abingdon Health will expand its York headquarters in the UK, following further investment in state-of-the-art lateral flow automation. This will substantially increase in its manufacturing footprint, resulting in Europe’s largest capacity for rapid test manufacturing, according to the company.
Abingdon Health is a technology-enabled lateral flow diagnostics company providing innovative rapid testing solutions to a multi-industry, global client base. The company provides specialist assay development and smartphone reader solutions alongside its lateral flow test manufacturing capacity.
The announcement of the expansion comes weeks after the UK Government announced Abingdon Health as one of the leading members of the UK Rapid Test Consortium.
Michael Hunter, Operations Director of Abingdon Health, commented: “The additional footprint and automation come at a timely moment as demand for rapid tests is growing rapidly, with the market likely to exceed US$10bn globally. Our precision automation and multi-site approach means we can adapt to meet the varying manufacturing needs of our growing global client base.”
Earlier this year, Abingdon Health announced a preliminary round of expansion in York after 90% revenue growth in 2019, thanks to new assay developments and assay manufacturing contract wins, and the introduction of its AppDx Smartphone reader software. In April 2020, growth continued with the acquisition of a new lateral flow manufacturing facility in Doncaster, UK. This latest expansion and investment in equipment comes as 2020 sees continuing high demand for Abingdon Health’s services.
Abingdon Health’s two manufacturing sites in York and Doncaster have the capacity to produce millions of rapid tests per month. This adaptable, dual-site approach provides a peace-of-mind solution that assures customers receive product consistency and a security of supply during routine scheduling and spikes in demand.
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UK-based PCR Biosystems issued a statement 1 April saying they are continuing to scale up operations to ensure the critical enzyme mix for COVID-19 tests remain available to the UK and global healthcare systems as demand for testing rises.
To meet current and upcoming requirements and ensure supply chain security, PCR Biosystems has already significantly increased – and will continue to increase – manufacture of qPCRBIO Probe 1-Step Go and all other critical reagents for rapid and sensitive RT-qPCR, the company said.
The company noted it has capacity to manufacture enough reagent daily for 4 million reactions – which is sufficient for millions of diagnostic tests.
qPCRBIO Probe 1-Step Go is a universal probe kit designed for fast and sensitive probe-based RT-qPCR. It is PCR Biosystems’s recommended product for COVID-19 diagnostic tests, supporting the detection, quantification and typing of the SARS-CoV-2 virus. All that’s required is the addition of specific primers and probes, together with the swab extract and water. qPCRBIO Probe 1-Step Go is compatible with all qPCR instruments and is engineered for use on a wide range of probe technologies including TaqMan®, Scorpions® and molecular beacon probes. In March 2020, PCR Biosystems introduced bulk pack sizes of this key product, to further support customers in high-throughput COVID-19 testing.
Alex Wilson, Co-Founder of PCR Biosystems, explained: “These are unprecedented times, and, as a global PCR company, we are ideally placed to support the scientific and healthcare communities in their response to COVID-19. When the enormity of COVID-19 testing requirements became apparent, we immediately started scaling up production of the critical components. We already have capacity to supply 4 million reactions’ worth of reagent every day – and we have the option to scale up further if needed to ensure we can always meet global demand.”
For more information on PCR Biosystems’s reagents, visit: www.pcrbio.com
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In a new study, researchers at Uppsala University have identified a previously unknown mechanism that regulates release of insulin, a hormone that lowers blood glucose levels, from the β-cells (beta cells) of the pancreas. This mechanism is disrupted in type 2 diabetes. The scientists hope this finding will be used to develop new treatments against the disease.
Globally, more than 400 million people suffer from type 2 diabetes. One of the main problems is inadequate secretion, from the β-cells of the pancreas, of insulin hormone, which lowers blood sugar (blood glucose).
It has been known for some time that im-paired insulin secretion is due to an inability of the insulin-containing secretory granules to attach themselves (‘dock’) to, and then fuse with, the cell membrane. As a result, less insulin reaches the blood and, accordingly, the body becomes less able to reduce blood glucose levels sufficiently.
In the new study, the scientists identify a protein, Sac2, that is found at lower levels in patients with type 2 diabetes. In experiments, the researchers show that lowering the levels of this protein by experimental means leads to reduced insulin secretion from the β-cells. By using advanced microscopy techniques, the researchers were able to show that Sac2 is an important component on the surface of the insulin-containing secretory granules, where it modifies the fat composition of the membrane. In the absence of Sac2, a specific fat molecule accumulates on the surface of the secretory granules. This incapacitates them, so that they cannot dock to the cell membrane, which in turn causes insulin secretion to be reduced.
This study shows, first and foremost, that reduced levels of a single protein gives rise to β-cells that exhibit several defects associated with type 2 diabetes. But it also shows that the fat composition of the insulin-containing secretory granules is of importance for their ability to be released from the cells. The scientists now hope that it will be possible to use these findings to develop new ways of treating type 2 diabetes.
Uppsala Universitywww.uu.se/en/news-media/press-releases/press-release/?id=4814&area=3,8&typ=pm&lang=en
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by Dr Allison B. Chambliss The diagnosis of acute pancreatitis has long relied on elevations in serum amylase or lipase. Recent test utilization efforts have called f or the discontinuation of amylase in acute pancreatitis, favouring the higher specificity and longer elevation of lipase. However, neither biomarker correlates with disease severity, and early recognition of severe cases remains a diagnostic challenge. Introduction to acute pancreatitis Acute pancreatitis (AP) represents one of the most common gastrointestinal-related causes for hospital admissions. AP refers to an inflammatory condition of the pancreas commonly associated with a severe, rapid onset of abdominal pain. Patients may also experience other non-specific symptoms, including fever, tachycardia, nausea and vomiting. AP may be classified as mild, moderate or severe based on the degree of organ failure and systemic complications, a system referred to as the revised Atlanta classification (Table 1) [1].
The most frequent cause of AP is gallstones, which are hardened deposits of bile. Gallstones may account for 40–70% or more of AP cases, depending on the geographic region [2]. Gallstone pancreatitis typically resolves upon spontaneous or endoscopic removal of the stone. Once recovered, gallstone pancreatitis patients typically undergo cholecystectomy, the surgical removal of the gallbladder, to prevent recurrent AP episodes. Alcohol abuse is typically ranked as the second most frequent cause of AP (25–35% of cases), followed by a variety of other rarer causes such as metabolic abnormalities, drugs and toxins, and trauma.
Treatment for most patients involves supportive care, including fluid resuscitation, pain control and monitoring. Although patients with mild disease may recover within a few days without complications, the most severe cases may involve systemic inflammatory response syndrome with the failure of multiple organs, including acute respiratory failure, shock, and/or renal failure. Rapid diagnosis of AP and assessment of risk for disease severity, both of which rely on laboratory testing, are critical to guide patient management. Recurrent episodes of AP may progress to chronic pancreatitis. Increases in disease prevalence The annual incidence of AP is estimated at 20–40 per 100¦000 worldwide [3]. Interestingly, the incidence has increased over the past few decades, particularly in Western countries [4]. One study found an increase of 13.2% in AP-related hospital admissions in 2009–2012 compared to 2002–2005 across the USA [5]. Although these epidemiological trends are not entirely understood, several reasons for the overall increasing incidence of AP have been proposed. One hypothesis is the global epidemic of obesity, which may promote gallstone formation. Increases in alcohol consumption could also play a role in some countries. Other experts suggest that the wider availability and increased frequency of laboratory testing may be major factors. This latter concept is in alignment with the fact that although cases in AP have risen, the mortality rate of the disease has, in fact, declined [5]. Nevertheless, mortality remains high in the severe case category. Biomarkers for AP Serum amylase and lipase are well-established as the primary biomarkers for the diagnosis of AP. Both amylase and lipase are digestive enzymes; amylase hydrolyses complex carbohydrates to simple sugars, and lipase catalyses the hydrolysis of triglycerides. Although lipase is synthesized predominantly by the pancreas, amylase is produced both by the pancreas (P-type) and the salivary glands (S-type) and is found in several other organs and tissues. Both enzymes are released into the circulation at the onset of AP, and elevations of both are typically observed within 3-6|h [6, 7]. Multiple clinical societies and guidelines recommend a serum amylase or lipase test result greater than three times the upper reference limit as a diagnostic criterion for AP, in addition to characteristic symptoms and imaging findings [2, 8]. Both biomarkers are widely measured by automated enzymatic methods and are thus commonly found in routine hospital laboratories, permitting rapid diagnoses. Notably, most routine assays do not distinguish between P-type and S-type amylase. This distinction requires the analysis of amylase isoenzymes, which is typically limited to reference laboratories. Questioning the value of amylase Serum amylase and lipase are well-established as the primary biomarkers for the diagnosis of AP. Both amylase and lipase are digestive enzymes; amylase hydrolyses complex carbohydrates to simple sugars, and lipase catalyses the hydrolysis of triglycerides. Although lipase is synthesized predominantly by the pancreas, amylase is produced both by the pancreas (P-type) and the salivary glands (S-type) and is found in several other organs and tissues. Both enzymes are released into the circulation at the onset of AP, and elevations of both are typically observed within 3-6|h [6, 7]. Multiple clinical societies and guidelines recommend a serum amylase or lipase test result greater than three times the upper reference limit as a diagnostic criterion for AP, in addition to characteristic symptoms and imaging findings [2, 8]. Both biomarkers are widely measured by automated enzymatic methods and are thus commonly found in routine hospital laboratories, permitting rapid diagnoses. Notably, most routine assays do not distinguish between P-type and S-type amylase. This distinction requires the analysis of amylase isoenzymes, which is typically limited to reference laboratories. Questioning the value of amylase In contrast to amylase, lipase is reabsorbed by the tubules of the kidney and is not excreted into the urine. Thus, lipase tends to remain elevated for longer than amylase, which may allow for a longer diagnostic window for AP. This advantage, in addition to lipase’s higher specificity for the pancreas, has led some organizations to recommend lipase over amylase for the diagnosis of AP. The American Board of Internal Medicine Foundation’s Choosing Wisely® campaign, in collaboration with the American Society for Clinical Pathology, has recommended: “Do not test for amylase in cases of suspected acute pancreatitis. Instead, test for lipase” [9].
Despite these recommendations, many hospital laboratories still maintain assays for amylase. We performed a retrospective audit at our institution to determine the ordering patterns of amylase relative to lipase in cases of AP. We found that in a cohort of 438 consecutive patients admitted with AP, lipase was ordered for all patients, while amylase was only ordered for 12% of patients [10]. We observed that most of the amylase orders stemmed from patients with gallstone pancreatitis who were referred for laparoscopic cholecystectomy procedures and who were under the care of the surgical team. We speculated that amylase may have been co-ordered with lipase in this subgroup of patients to check for biomarker normalization. Laparoscopic cholecystectomy is ideally to be performed as early as possible when gallstone AP resolves, and normalization of amylase or lipase may be used to document that resolution. Because amylase is believed to fall more rapidly than lipase after AP, trending amylase over time could possibly allow for a quicker documentation of biomarker normalization. However, our study also showed that there was no significant difference in amylase versus lipase in the time for the biomarker to fall below three times the upper reference limit. These observations led us to further question the added value of amylase relative to lipase alone in the diagnosis and management of AP.
Lipase does have limitations that may preclude it from being the AP biomarker of choice in some cases. Lipase may be elevated in non-pancreatic conditions such as renal insufficiency and cholecystitis (Table 2). Both amylase and lipase may rarely be non-specifically elevated due to complexes with immunoglobulins, termed macroamylasemia and macrolipasemia. Further, amylase may be useful in the workup of other pancreatic diseases and, unlike lipase, can be measured in the urine. Quantitation of amylase in body fluids, such as pancreatic fluid and peritoneal fluid, can aid in the evaluation of pancreatic cysts and pancreatic ascites [11]. For these reasons, many laboratories choose to maintain amylase assays. An unmet need for biomarkers for AP severity Although AP may be easily diagnosed with elevations in amylase or lipase, there is an unmet need for biomarkers or algorithms that can specifically identify severe forms of AP early in the disease course. Twenty to thirty percent of AP patients may develop a moderate or severe form of the disease involving single or multiple organ dysfunction or failure and requiring intensive care. Identifying the severe cases early such that treatment may be tailored to minimize complications remains one of the major challenges of AP. Risk factors such as old age and obesity often correlate with disease severity. However, neither amylase nor lipase levels correlate with disease severity, and no other laboratory tests are consistently accurate to predict severity in patients with AP.
In 2019, the World Society of Emergency Surgery (WSES) published guidelines for the management of severe AP [12]. These guidelines indicate that C-reactive protein (CRP), an acute phase reactant synthesized by the liver and a non-specific indicator of inflammation, may have a role as a prognostic factor for severe AP. However, CRP may not reach peak levels for 48 to 72|h, limiting it as an early severity indicator. Specifically, WSES recommended that a CRP result greater than or equal to 150|mg/L on the third day after AP onset could be used as a prognostic factor for severe disease. Elevated or rising blood urea nitrogen, hematocrit, lactate dehydrogenase, and procalcitonin have also demonstrated predictive value for pancreatic necrosis infections.
Other biomarkers have been investigated to distinguish mild from non-mild forms of AP. Interleukin-6 has shown good discriminatory capability in combination with CRP [13]. Resistin is a more recently discovered peptide hormone that was first described as a contributor to insulin resistance (hence the name). Resistin is secreted by adipocytes and may play a role in obesity, hypertriglyceridemia, and inflammatory cytokine reactions. A prospective observational study found that resistin levels were better than CRP for predicting severe AP on the third day and for predicting the development of necrosis [14]. However, more studies are needed before resistin can be recommended as a prognostic indicator, and clinical resistin testing is not widely available. Thus, there still remains a need for prognostic severity biomarkers that rise early (prior to 48|h) in the course of AP. The authors Allison B. Chambliss PhD, DABCC Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA
E-mail: abchambl@usc.edu
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In symptom-free individuals, the detection of misfolded amyloid-β protein in the blood indicated a considerably higher risk of Alzheimer’s disease – up to 14 years before a clinical diagnosis was made. Amyloid-β folding proved to be superior to other risk markers evaluated, as shown by scientists from the German Cancer Research Center (DKFZ), Ruhr University Bochum (RUB), the Saarland Cancer Registry, and the Network Aging Research at Heidelberg University.
There is currently still no effective treatment for Alzheimer’s disease. For many experts, this is largely due to the fact that the disease cannot be clinically diagnosed until long after the biological onset of disease when characteristic symptoms such as forgetfulness appear. However, the underlying brain damage may already be advanced and irreversible by this stage.
"Everyone is now pinning their hopes on using new treatment approaches during this symptom-free early stage of disease to take preventive steps. In order to conduct studies to test these approaches, we need to identify people who have a particularly high risk of developing Alzheimer’s disease," explained Hermann Brenner from DKFZ. In patients with Alzheimer’s disease, misfolding of the amyloid-β protein may occur 15–20 years before the first clinical symptoms are observed. The misfolded proteins accumulate and form amyloid plaques in the brain. A technique devised by Klaus Gerwert from RUB can determine whether amyloid proteins are misfolded in blood plasma.
In a previous study, Gerwert and Brenner showed that the amyloid-β changes in the blood can be demonstrated many years before the clinical onset of disease. They also showed that demonstration of misfolded amyloid-β in the blood correlates with plaque formation in the brain. The researchers now wanted to investigate whether analysis of amyloid-β can be used to predict the risk of developing Alzheimer’s disease and how the risk marker performs in comparison to other known and suspected risk factors. To do so, they re-examined blood samples collected as part of ESTHER, a cohort study led by Hermann Brenner and conducted in collaboration with the Saarland Cancer Registry. The cohort study was initiated back in the year 2000.
In the current study, the researchers looked at the initial blood samples of 150 ESTHER participants in whom dementia was subsequently diagnosed during the 14-year follow-up period. These samples were compared with those of 620 randomly selected control participants not known to have been diagnosed with dementia who correlated with the dementia participants in terms of age, sex, and level of education.
Participants with Aβ misfolding had a 23-fold increased odds of Alzheimer’s disease diagnosis within 14 years. In patients with other types of dementia, such as those caused by reduced blood supply to the brain, the study did not demonstrate an increased risk, supporting Alzheimer’s disease specificity.
The researchers also included a number of other possible risk predictors in their analysis, including a particular variant of the gene for apolipoprotein E (APOE Ɛ4) and pre-existing diseases (diabetes, high blood pressure, de-pression) or lifestyle factors (bodyweight, level of education). With the exception of the APOE4 status, which showed a 2.4 times higher risk in those people who later went on to develop Alzheimer’s disease, none of the factors studied correlated with the risk of disease.
In predicting the risk of disease, it was largely irrelevant whether 0–8 or 8–14 years had passed between the time the blood sample was obtained and the clinical onset of dementia.
"This work was not about the use of amyloid-β folding as a diagnostic marker. Instead, we wanted to examine whether this marker could be used for risk stratification in the Alzheimer’s disease therapeutic development setting. Amyloid-β misfolding proved to be a far superior risk marker compared to the other potential risk factors," explained lead author Hannah Stocker from DKFZ and the University of Heidelberg’s Network Aging Research.
The German Cancer Research Center (DKFZ)
www.dkfz.de/en/presse/pressemitteilungen/2019/dkfz-pm-19-46-Protein-misfolding-as-a-risk-marker-for-Alzheimers-disease-up-to-14-years-before-the-diagnosis.php
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A team led by Johns Hopkins Kimmel Cancer Center investigators reports that a new laboratory test they developed to identify chemical changes to a group of cancer-related genes can accurately detect which breast tumours are cancerous or benign, and do it in far less time than gold-standard tests on biopsied breast tissue.
Although the findings are preliminary and need further validation in larger groups of people, the investigators say the test has the potential to dramatically reduce the time (minimum by one month, maximum by 15 months) generally needed to make a definitive breast cancer diagnosis in poorer countries. A quick diagnosis has already been definitively proven to boost survival for all cancers by reducing wait times to surgical and other treatments. A report on the test, which exploits the tendency of some cancer-related genes to undergo the attachment of a chemical group, by a process known as methylation, has been published.
“Diagnosis is a huge bottleneck to starting treatment, especially in developing countries that have a small number of pathologists available to review breast cancer biopsies who serve a huge population,” says study leader Saraswati Sukumar, Ph.D., professor of oncology and pathology at the Johns Hopkins Kimmel Cancer Center. “That means a test like ours could be especially useful in places with fewer resources and where mortality rates from breast cancer are much higher compared to the developed world.”
Breast cancer cases are rising around the world, Sukumar notes. Globally, breast cancer incidence is steadily increasing. In 1980, GLOBOCAN reported 641,000 new cases of breast cancer worldwide. In 2018, the estimated incidence of breast cancer worldwide rose to 2.1 million cases (a 3.2% annual rate of increase) with 626,000 deaths due to this cancer.
The reasons for higher death rates in the developing world include social stigmas that prevents many women from seeking timely treatment and a lack of healthcare resources. However, a major factor is time between biopsies and delivery of a diagnosis, which can be as long as 15 months in places with fewer resources compared to a few days or weeks in the United States.
Seeking to shrink the time from biopsy to diagnosis, Sukumar and her colleagues in the Johns Hopkins Kimmel Cancer Center, Johns Hopkins University School of Medicine’s departments of pathology, surgery, and radiology, and the Johns Hopkins Bloomberg School of Public Health and collaborators from Cepheid developed a novel technology platform. Here, a patient’s biopsy sample is loaded into cartridges and inserted in a machine that tests levels of gene methylation—a chemical addition to genes that results in changes in gene activity. This platform returns methylation marker results within five hours.
These results suggest that the test holds promise as a “first pass” to distinguish between malignant and benign breast tumours, Sukumar says. With the 5-hour-long return on results, low skill required to run the test, and relatively low expense, it could offer hope of speeding diagnosis for thousands of women worldwide.
Sukumar cautions that the team’s molecular test cannot replace expert analysis by a pathologist, whose skill will be necessary to review core biopsies of the breast lesion for a definitive diagnosis and optimal therapy recommendations.
John Hopkins University
https://tinyurl.com/yxkg5sjy
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Expert opinions from Dr Heidi Mendoza There are many assessments to make when adding a new test to a lab’s collection. Dr Heidi Mendoza, acting consultant clinical biochemist at Raigmore Hospital, Inverness, UK, shares her experiences and observations of doing exactly that in both ordinary circumstances and during a pandemic, as well as having to contend with the geographic challenges imposed by the nature of life in the Scottish Highlands. Can you provide a little background about yourself and where you work, please?
I am a clinical biochemist based in Raigmore Hospital, which is a small hospital in the Scottish Highlands. In my current role I provide clinical advice and interpretation for biochemistry tests for general practitioner (GP) practices and three hospitals across the Highlands. Working in the Highlands is incredibly rewarding, but also very challenging! It can take between 2 and 6|hours to travel between hospitals and our patients may have to travel by plane or boat to be seen, with journey times of +12|hours depending on where they live. It really puts the laboratories under pressure to get it right for the patient. Repeat testing isn’t as simple or straightforward as it would be in a city and we have to have excellent systems in place for reporting critical results and getting patients into hospital or transferring them between hospitals. Getting the right test, in the right place, with the right turnaround time is really important for our patients and for our clinicians. What are the usual circumstances in which you would think about bringing a new test into the lab’s repertoire?
Any new test is a cost pressure on our National Health Service (NHS) and can only be brought in when it demonstrates clear benefits for patients. We have brought in two new tests in the last 12|months that are good examples of the different ways we can bring in new tests to our laboratory.
The first test is the NT-proB-type natriuretic peptide (NTproBNP) test. NTproBNP is used to investigate patients with suspected heart failure and the results can be used to determine whether a patient needs an echocardiogram (ECHO) or not. If they do need an ECHO the NTproBNP result can be used to split patients into those who need urgent ECHO (2|weeks) or routine ECHO (6|weeks). In theory this is a perfect test to implement as it will benefit patients and is cost-effective with respect to the more expensive ECHO investigation. However, NTproBNP has been implemented in other hospitals without reducing ECHO waiting times or the number of ECHOs performed! To ensure that this didn’t happen in our service, I spent 6|months before implementation of the test liaising with cardiologists and GP representatives from across the Highland region. We changed the ECHO referral pathway to include NTproBNP and created useful guidance for GPs on when to, and importantly when not to, request NTproBNP. We implemented the test just under 1|year ago and have seen a positive effect on ECHO referrals. We will still have to attend a 1|year post-implementation review with the Hospital Board to present our audit data and show that investment in the service by introducing a new test has benefited patients and other areas of the service.
Procalcitonin is the second example. Procalcitonin is a test that can be used in the investigation of sepsis and guide the use of antibiotics. Procalcitonin was not a test available in our hospital before the COVID-19 pandemic. Procalcitonin is not increased in the majority of adult patients with COVID-19; however, an elevated procalcitonin may suggest superimposed bacterial infection and be used to guide treatment of these patients and improve patient outcomes. Early in the COVID-19 pandemic we were approached by our Intensive Care Unit (ITU) and Microbiology consultants who requested that procalcitonin be available for our COVID-19 patients in ITU to guide their antibiotic treatment. We implemented procalcitonin in less than 4|weeks with help from our instrument manufacturer, external quality assessment providers and other Scottish hospitals who provided anonymized patient serum with known values so that we could verify our assay as quickly as possible. We are now in the process of putting together a business case and following the evidence base which will determine whether we continue to offer the procalcitonin test. How would you usually go about adopting a new test?
As highlighted in the two examples above, we must agree a clinical need for a test and then liaise with the users of the service to find out how the test should be implemented into the patient-care pathway. Once we have worked out the clinical utility of the test, then we can carry out the laboratory verification of the test and the laboratory workflow. Verification is very straightforward. For example, the between-batch and within-batch precision, accuracy, linearity on dilution, interferences and sample stability for a test need to be evaluated. The implementation of the test then must be followed by an audit which shows that the test is being used as intended and giving the benefits predicted. If not, the test may need to be withdrawn. The hardest part of the entire process is agreeing how a test is going to be used and fitting it in to the patient-care pathway. In the situation of the COVID-19 pandemic, we have a new disease, caused by a new virus, and new tests that have been created very quickly. How do you start to use a new test in these circumstances – are there any differences in procedure?
There is no difference in the steps that need to be performed we just need to be able to do everything in a much shorter time frame. That is actually much easier than it sounds. In the NHS, the laboratories from different parts of the country are great about helping other laboratories. We regularly share protocols, data and learning. If a new test is released we’ll contact another laboratory and they’ll share their local experience and any problems they have had with the test.
For procalcitonin implementation I contacted the laboratory in Dundee, UK, and they helped us out by lending us kits and reagents, sending us anonymized patient serum with known procalcitonin values, and sharing their data and verification protocols. This allowed us to complete verification incredibly quickly. We will still have to gather the data and evaluate whether the test is providing the benefit that we predicted when we established the clinical need. What are the challenges regarding validation, reference levels, results interpretation and reporting?
Verifying tests is straightforward as we are always evaluating tests in clinical laboratories so are very experienced. Results interpretation can be quite difficult. If we need clinicians to change patient management based on a result then we have to provide them with very clear local guidance on what we want them to do with a result. This might be different from the action they would take in another hospital with different patient pathways, different pressures on patient turnaround times, and different diagnostic facilities. This is where good working relationships with users of the service are key to test implementation. If you just implement a new test without working out where it fits in the patient pathway, it doesn’t matter how great the test is, as it is unlikely to be used well and may not improve patient care. What do you have to think about in terms of logistics?
Many laboratories are understaffed due to a combination of unfilled vacancies and staff on long-term absence. The additional work involved in verifying and implementing a new test does put pressure on staff. However, NHS laboratory staff are highly trained and dedicated. When the staff know how a test is going to be used and the benefit to the local community, they support the implementation and the extra work involved.
Biocontainment and staff safety have been important considerations during the COVID-19 pandemic. We had to adhere to government guidance in the transport, analysis and disposal of samples from patients with suspected COVID-19. This changed laboratory workflows and slowed us down, creating longer turnaround times.
Logistics are a serious consideration for us owing to our geography. Reagent shortages or delays in deliveries have a big impact on small laboratories as they can’t store much surplus reagent stocks because of expiry dates. Unexpected overuse or underuse of a new test can be quite challenging and leave the laboratory short of tests or with expired, wasted kits. There are also several times during the year when the roads are impassable between our central and rural laboratories. We have been down to single numbers of tests remaining several times over the last few years or had failed delivery from manufacturers in winter. There was also a shortage of procalcitonin reagent as there was such a surge in the use of the test during the COVID-19 pandemic. Again, working closely with users of our laboratory services has enabled us to rationalize the use of the test until the global shortage of reagent ended. On a number of occasions we have also shared reagents with other Scottish laboratories to ensure that none of the laboratories were left without reagents. What has been learnt from the current coronavirus situation about diagnostic testing during a pandemic that would help to improve the process in future?
The coronavirus pandemic has shown how robust the infrastructure of the NHS is in Scotland and how adaptable laboratories can be when required. The laboratories really pulled together and worked towards a common goal delivering testing to COVID patients and non-COVID patients during a crisis. The two things that made this possible were: (1) Having a very clear goal – delivery of a service with new testing during a pandemic; and (2) Finances changes which needed to be made to deliver the service got rapid financial approval. How do we take these lessons learned and apply it to the routine delivery of laboratory services? Finance will always be a limiting factor – as it should be! Healthcare is expensive and it is up to us as healthcare professionals to deliver a cost-effective and affordable service. In contrast, having a clear goal, is definitely something that we could do better in the future. In the case of the pandemic, laboratories found different solutions based on local geography, resources and incidence of COVID. The changes made by laboratories in the remote Highlands and Islands were similar, but different than those made by laboratories in major cities. The staff that delivered the service found the best solutions to the goals set by the government – that is the real lesson we need to take away. We need to give very clear goals to services and let local expertise and knowledge drive the changes to solve the problem. The expert Heidi Mendoza BSc MSc PhD RCPath Blood Sciences Department, Raigmore Hospital, Inverness IV2 3UJ, UK E-mail: heidi.mendoza@nhs.net
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:31:372021-01-08 11:07:48Introducing new tests to a laboratory’s repertoire
Cobra Biologics (Cobra), an international contract development and manufacturing organization (CDMO) for biologics and pharmaceuticals, and the Karolinska Institutet (KI), one of the world’s leading medical universities, announced 30 March they have been awarded €3 million emergency funding by Horizon 2020 for research and development, and phase I clinical trial testing of a DNA vaccine against COVID-19, as part of the OPENCORONA consortium to support global efforts tackling the pandemic. Partners in the consortium also include Karolinska University Hospital, Public Health Authority (FoHM), IGEA, Adlego AB and Giessen University.
The project is called OPENCORONA and the application, ‘Rapid therapy development through Open Coronavirus Vaccine Platform’, was one of the first two to be successfully selected by the European Commission, with 17 applications chosen out of 91, receiving €47.5 million in total. The aim of the project is to manufacture a DNA vaccine, which will be delivered to patient muscle to generate a viral antigen on which the immune system then reacts. The ‘open’ project will utilise Cobra’s 50L DNA suite in Sweden to produce the plasmid DNA. The plasmid production will support the vaccine development process in accordance with GMP and with a new kind of ‘open’-ness that will help to speed the fight against COVID-19 by making relevant data and research results available to the wider scientific community.
KI notes that “genetic analysis shows that the SARS-CoV-2 envelope and receptor binding domain only has a 75% homology with other human coronaviruses. Thus, existing immunotherapies and vaccine candidates against other coronaviruses, such as SARS, will not be useful against SARS-CoV-2. We will use the DNA vaccine platform as this is currently the most rapid and robust vaccine platform. We have generated several chimeric SARS-CoV-2 genes and will select for the most potent DNA vaccine/immunotherapy candidate delivered by in vivo electroporation that protects against SARS-CoV-2 infection and/or disease in animal models and take this to phase I clinical testing.”
To date, no approved human COVID-19 immunotherapy or vaccine exists, and in response to the outbreak, speed in therapy and vaccine R&D is critical. Harnessing each partner’s expertise and experience in reliable development manufacturing, the OPENCORONA consortium is using the DNA vaccine platform as it is currently one of the most rapid and robust vaccine platforms available. First trials in humans will begin in 2021, and will take place at the Karolinska University Hospital.
Commenting on the funding, Matti Sällberg, Head of Department of Laboratory Medicine, Karolinska Institutet, commented: “The need to find an effective vaccine is urgent and we are working as quickly as possible to find one. With this funding from the EU we will have secured a significant part of the financing going forward, which means that we can focus entirely on the research. It is a relief to know that we are now financed all the way to studies in humans.”
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:31:372021-01-08 11:07:55Cobra Biologics and the Karolinska Institutet collaborate to develop COVID-19 vaccine
Horiba has recently announced the publication of scientific studies which demonstrate the excellent performance of its new HELO high throughput fully automated hematology platform on body fluid and pathological samples. Horiba’s Yumizen® H2500 and H1500 automated hematology analysers within the HELO platform deliver enhanced precision for complete blood counts and white blood cell (WBC) differential testing, with body fluid analysis included as standard. This improves diagnosis, minimizes unnecessary manual microscopy slide reviewing and enhances laboratory workflow, as highlighted by two recent scientific evaluation studies. The first study was undertaken by Nantes University Hospital (CHU de Nantes) focusing on the need for automated analysis of biological fluids for robust and reliable results reporting. Hematological analysis of body fluids (BF) can provide clinicians with valuable diagnostic information as it can indicate a number of serious medical conditions. Manual microscopy has traditionally been used to determine total and differentiated WBC in BFs, however, results can be affected by inter-operator variability and take time to undertake. By using an automated method of analysis of WBC in a body fluid smear, this can improve turnaround times and accuracy. To ensure the robustness and reliability of automated BF analysis in routine laboratory workflows, the evaluation study was undertaken on the performance of the automated body fluid analysis cycle on the Yumizen H2500. The study included 98 samples from cerebro-spinal, pleural, ascitic, pericardic and bronchoalveolar liquid (BAL) fluids which were used for comparative leukocyte and erythrocyte counts, as well as differential. This confirmed the good analytical performance of Yumizen analyser in comparison with conventional microscopic count, as well as a reference analyser. The second study explored the flagging efficiency of the new analyser. Pathological samples, coming from patients with altered hematopoiesis, often trigger a WBC-Diff flag; this is due to poor cell separation and requires a manual slide review (MSR) by microscopy to confirm the WBC differential. Laboratory workload would be optimized if MSR could be reduced without compromising patient care. Therefore, the study undertaken by the Institut Bergonié Comprehensive Cancer Centre compared the flagging performance in the WBC differential of the Yumizen H1500/H2500 to a routine analyser. This included patients with pathology or treatment affecting hematopoiesis, such as those undergoing chemotherapy or with onco-hematologic disorders. The study on 228 pathological samples (100 from patients on chemotherapy for solid tumours and 128 from patients with malignant blood disease) demonstrated an improvement in the WBC-diff analysis and reliability of the Yumizen H1500/2500 analyser compared to a routine analyser. It delivered better precision and specificity, due to improved cell separation, and a significant decrease (-21%) in unnecessary morphology reviewing by microscopy, thus saving significant time in the laboratory. Commenting on the successful outcome of the studies, Mandy Campbell, Horiba Medical said, “These evaluation studies undertaken by recognized authorities in hematological analysis, demonstrate the excellent performance of our new Yumizen H1500/H2500 automated hematology analysers with both body fluid and pathological samples. Body fluid analysis is available as standard on these analysers which have been shown to enhance diagnoses and lower film review rates to improve laboratory workflow.”
www.horiba.com/medical
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