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Schizophrenia directly linked to diabetes

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Investigators at the Institute of Psychiatry, Psychology and Neuroscience, King’s College London, United Kingdom, found that fasting plasma glucose levels were increased in patients with first-episode psychosis (FEP). In addition, at illness onset, glucose tolerance was reduced, fasting plasma insulin levels were increased, and insulin resistance was increased, even when factors such as antipsychotic use, diet, and exercise, which are known to influence diabetes risk, were taken out of the equation.

“This is a wake-up call that we need to consider diabetes prevention right from the onset of schizophrenia,” study investigator Toby Pillinger, MRCP. The study was published online January 11 in JAMA Psychiatry.

Premature Death

Research shows that schizophrenia patients die 15 to 30 years earlier than the general population and that most of this premature mortality is due to causes unrelated to the central nervous system. It is estimated that rates of type 2 diabetes are up to threefold higher in schizophrenia patients compared to the general population, the researchers note.

It is unclear whether schizophrenia confers an inherent risk for glucose dysregulation in the absence of the effects of chronic illness and long-term treatment.

In a systematic review and meta-analysis of 16 case-control studies, the investigators examined whether glucose homeostasis was imparied in patients with FEP in comparision with control persons. The overall sample included 731 patients and 614 healthy control persons. FEP patients were physically healthy and had no illnesses that would affect glucose homeostasis.

After an oral glucose tolerance test, fasting plasma glucose levels were significantly elevated in patients with FEP (Hedges g = 0.20; 95% confidence interval [CI], 0.02 – 0.38; P = .03), as were plasma glucose levels (Hedges g = 0.61; 95% CI, 0.16 – 1.05; P = .007), in comparison with control persons, the researchers report.

The same was true for fasting plasma insulin levels (Hedges g = 0.41; 95% CI, 0.09 – 0.72; P = .01) and insulin resistance, as determined by homeostatic model assessment of insulin resistance (Hedges g = 0.35; 95% CI, 0.14 to 0.55; P = .001).

“With the exception of fasting glucose levels, these alterations were also seen when analyses were restricted to antipsychotic-naive and BMI-matched samples. When analysis was restricted to diet and exercise-matched samples, significance was maintained for raised fasting glucose levels in patients. All results remained significant when analyses were restricted to samples matched for race/ethnicity,” the authors write.

No significant differences between patients with FEP and control persons were seen in HbA1c levels (Hedges g = −0.08; CI, −0.34 to 0.18; P = .55), although this result should be interpreted with caution, owing to the small sample size used in this analysis.

Major clinical implications

“The results of our meta-analysis extend recent studies showing high rates of diabetes in patients with chronic schizophrenia by demonstrating that altered glucose homeostasis is present from illness onset,” the investigators note.

“The mortality gap between those with schizophrenia and the general population is large, and moreover, it continues to grow. In that context, the findings of our study have major clinical implications,” said Dr Pillinger.

“We would argue that a more holistic approach to the treatment of schizophrenia, combining both physical and mental health care, is required. Given that some antipsychotic drugs may worsen diabetic risk, there is a particular responsibility on the clinician to select an appropriate antipsychotic at an appropriate dose so as to limit this risk.

“There is also a need for clinicians to provide patient education regarding diet and exercise, ensure regular screening for diabetes, and offer prompt management to those who go on to develop diabetes,” he added.

In addition, “longitudinal studies examining the relative effectiveness of early interventions targeting a reduction in diabetic risk (both lifestyle based and pharmacological) in individuals with schizophrenia who exhibit evidence of early glucose dysfunction would be of value,” he said.

Reached for comment, Benjamin Ian Perry, MBBS, of Coventry and Warwickshire Partnership NHS Trust, United Kingdom, noted that the composition of this “interesting meta-analysis” is slightly different from one that his team conducted, which was published last year in Lancet Psychiatry and was reported by Medscape Medical News at the time.

“However, the results remain consistent with our findings across most measures of dysglycemia. This gives further weight to the conclusions of both meta-analyses,” said Dr Perry.

“There is now clear impetus for those looking after patients with psychosis, especially those younger patients in their first episode, to take utmost care in ensuring appropriate screening for physical comorbidity, particularly prediabetes. Care should also be taken in selecting a medication that doesn’t exacerbate or accelerate the risk of diabetes in such patients,” Dr Perry said.

The study had no commercial funding. Dr Pillinger and Dr Perry have disclosed no relevant financial relationships. One author has relationships with AstraZeneca, Autifony, BMS, Eli Lilly, Heptares, Janssen, Lundbeck, Lyden-Delta, Otsuka, Servier, Sunovion, Rand, and Roche.

Source: MedScape

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El Microscopio – Program 27

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  • Dr. Larissa Furtado (Brazil). Interview about Next Generation Sequencing (NGS).
  • Dr. Vera Tesic (USA). Interview about NGS for microbiological diagnostics.
  • Dr. Karl Bacos (Sweden). Interview about a new method that measures the risk of type 2 diabetes in blood.
  • Agenda.
  • News and events about clinical chemistry.

 

Interview: Dr. Larissa Furtado (Brazil)

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Dr. Furtado is an assistant professor of pathology at the University of Utah School of Medicine. She received her MD at UniFOA in Brazil and completed a medical genetics residency at the University of São Paulo. Dr. Furtado completed her residency in anatomic and clinical pathology at the University of Utah and ARUP Laboratories, where she was chief resident, and her molecular genetic pathology fellowship at the University of Michigan.

Prior to joining ARUP as a medical director, Dr. Furtado worked as an assistant professor of pathology at the University of Chicago and was co-director of the University of Chicago Clinical Genomics and Molecular Diagnostics Laboratories. She is board certified by the American Board of Pathology in anatomic and clinical pathology, with subspecialty certification in molecular genetic pathology. Dr. Furtado’s research interests include genomic diagnostics in solid tumors and molecular diagnostic methods in oncology.

Interview about Next Generation Sequencing (NGS).

Interview: Dr. Vera Tesic (USA)

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Dr. Vera Tesic is a pathologist in Chicago, Illinois and is affiliated with University of Chicago Medical Center. She received her medical degree from University of Belgrade, Faculty of Medicine and has been in practice for more than 20 years.

Interview about NGS for microbiological diagnostics.

 

The 2016 revision to the WHO classification of myeloid neoplasms and acute leukemia

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In collaboration with the Society for Hematopathology and the European Association for Haematopathology, the World Health Organization (WHO) published the third and fourth editions of the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, in 2001 and 2008, respectively, as part of a series of WHO Classification of Tumours “blue book” monographs. In the spring of 2014, a clinical advisory committee (CAC) composed of ∼100 pathologists, hematologists, oncologists, and geneticists from around the world convened to propose revisions to the fourth edition of the classification. The revision of the fourth edition follows the philosophy of the third and fourth editions to incorporate clinical features, morphology, immunophenotyping, cytogenetics, and molecular genetics to define disease entities of clinical significance. The fourth edition of the classification of hematopoietic and lymphoid tissues was the second volume of the WHO “blue book” tumor series, and the series publication is still in progress. A fifth edition series cannot begin until the fourth edition series is completed; but after 8 years of information and experience that have emerged from scientific and clinical studies, a revision of these criteria for hematopoietic and lymphoid neoplasms was felt to be necessary and timely. In relation to myeloid neoplasms and acute leukemia, this revision has been influenced by several factors including the following:

  1. The discovery of recently identified molecular features has yielded new perspectives regarding diagnostic and prognostic markers that provide novel insights for the understanding of the pathobiology of these disorders.

  2. Improved characterization and standardization of morphological features aiding in the differentiation of disease groups, particularly of the BCR-ABL1−myeloproliferative neoplasms (MPNs), has increased the reliability and reproducibility of diagnoses.

  3. A number of clinical-pathological studies have now validated the WHO postulate of an integrated approach that includes hematologic, morphologic, cytogenetic, and molecular genetic findings.

For these reasons, the fourth edition is being updated, but this 2016 classification is not a major overhaul of the disease categories. Rather, it is intended to incorporate new knowledge of these disorders obtained since the 2008 publication and is a revision of that classification. The purpose of this report is to summarize the major changes in the revised WHO classification of myeloid neoplasms and acute leukemia and to provide the rationale for those changes.

Download full text from here.

Iron deficiency testing deficient in ulcerative colitis

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The findings underscore the need for physician education about the need to diagnose and treat IDA in its early stages.

Treatment guidelines issued in 2007 called for UC patients to be screened regularly for anemia and ID with hemoglobin (Hb), C-reactive protein (CRP), ferritin, and transferrin saturation (TSAT) testing. Uptake of this guideline, however, is “low,” according to the authors. Prior studies in Europe and at a single U.S. center showed that testing and treatment for ID in patients with UC was low, despite a high prevalence of IDA in this population. The authors sought to identify factors associated with testing and treatment frequency and thereby pinpoint quality improvement targets.

The investigators accessed data from the Veterans Affairs (VA) pharmacy benefits management and corporate data warehouse databases to identify veterans newly diagnosed with UC during an 11-year period. They defined anemia as Hb <13 g/dL in men and <12 g/dL in women. The criteria for ID was ferritin <30 µg/L and/or TSAT <16%, or ferritin <100 µg/L and active disease, according to CRP levels, endoscopy reports, and use of prednisone.

Overall, 70% of patients developed anemia during a median of 8 years’ follow-up. Of these patients, just 68.6% had an iron study evaluation. Less than half of patients with mild anemia (46%) were tested for ID, in comparison to 91% with severe anemia. The authors also found that patients who reside in the Midwest and South were less likely than those in the Northeast and West to undergo testing.

Although the investigators cautioned that their study involved only VA patients, more likely to be middle-aged and elderly white men, they added that this population is similar socioeconomically to the general U.S. population. They suggested that their findings highlight physician attitudes that “anemia is an inevitable concomitant symptom of inflammatory bowel disease,” and that many delay testing and treatment for the disease until patients have symptoms of anemia. The authors also opined that physicians underappreciate the “profound impact of anemia” on patients’ quality of life, and recommended that testing for ID in patients with anemia should become a quality process indicator for UC.

Early Procalcitonin Testing Associated With Favorable Sepsis-Related Outcomes

A retrospective study of administrative data from more than 130,000 patients has found that procalcitonin (PCT) testing on the day of intensive care unit (ICU) admission in patients with suspected or documented sepsis and related conditions was associated with significantly lower hospital and ICU length of stay (LOS) and decreased total cost (Chest 2016; doi/10.1016/j.chest.2016.06.046). While cautioning that the mechanisms behind these outcomes are “not immediately evident,” the authors suggested that “it is likely that PCT is being used both to help rule-out and rule-in sepsis on ICU admission.”

The researchers conducted the study because although PCT has been a diagnostic criterion for sepsis since 2012, and other research has shown PCT has good specificity for causes of suspected infection, PCT testing has not been “uniformly adopted, in part because of cost considerations.”

The authors accessed data during a 3-year period from 550 hospitals in the Premier Healthcare Database. They examined records on 33,569 patients who were at least 18 years old with an admitting or discharge diagnosis code consistent with suspected or documented sepsis, septicemia, systemic inflammatory response syndrome, or shock, and on 98,543 propensity-matched patients who did not have PCT testing.

In comparing outcomes between the PCT versus non-PCT patients using multivariable regression analysis, PCT testing was associated with >1 day shorter hospital LOS, 0.2 day shorter ICU LOS, 0.72 days shorter antibiotic exposure, and nearly $3,000 less in hospital costs. In contrast to these trends, laboratory costs in patients with PCT testing was $81 higher than in those without PCT testing, perhaps reflecting the additional cost of PCT testing, according to the authors.

Rapid Point-of-Care Assay for Acetaminophen-Related Liver Injury Compares Favorably to Reference Method

A proof-of-concept study showed that a competitive point-of-care (POC) immunoassay is highly concordant with the reference standard high pressure liquid chromatography with electrochemical detection (HPLC-EC) for detecting acetaminophen-associated acute liver injury (ALI) (Clin Gastroenterol Hepatol 2016; doi:10.1016/j.cgh.2016.09.007). This POC test might help guide clinical management of patients with acetaminophen-related ALI.

The authors sought to develop a rapid, reliable POC assay to detect acetaminophen protein adducts as a way to address challenges in the diagnostic work-up of acetaminophen toxicity. Clinicians use the Rumack Nomogram to identify acetaminophen-related ALI and acute liver failure, but it is applicable for only the first 18–24 hours after overdose, due to the short elimination half-life of acetaminophen in the peripheral circulation and inaccurate patient reporting of acetaminophen exposure. HPLC-EC accurately detects acetaminophen-protein adducts formed after toxic intake of the drug, but it requires complex equipment and trained laboratory personnel. Prior studies have shown the median elimination half-life of acetaminophen protein-adducts to be 42 hours, versus 5.4 hours for the parent drug.

The authors developed a competitive, lateral flow immunochromatographic assay that detects acetaminophen protein-adducts in patient serum and returns results as test-band amplitude. The proof-of-concept study compared the accuracy of this POC test with HPLC-EC in 19 healthy individuals with no liver injury, 29 patients without acetaminophen-related ALI, and 33 with acetaminophen-related ALI.

The POC test took a median of 27 minutes to return results, and effectively distinguished the three groups of patients, including between acetaminophen-related ALI and non-acetaminophen-related ALI, with medium test band amplitude of 584 versus 3,678, respectively. The POC test yielded a 100% sensitivity, 86.2% specificity, 89.2% positive-predictive value, and 100% negative-predictive value for identifying patients with acetaminophen-associated ALI.

Five Genes Added to Recommended Secondary Findings List

The American College of Medical Genetics and Genomics (ACMG) has updated its list of genes to be reported as secondary findings during whole exome or whole genome sequencing (Genet Med 2016; doi:10.1038/gim.2016.190). The list of 59 medically actionable genes recommended for return in clinical genomic sequencing includes five of six genes that had been submitted for consideration to ACMG’s Secondary Findings Maintenance Working Group. The working group also removed one gene, MYLK, associated with familial thoracic aortic aneurysm and dissection (FTAAD), on the grounds that known pathogenic variants of this gene are rare and that an effective confirmatory test, screening modality, or intervention to prevent or reduce FTAAD-related morbidity or mortality does not exist.

The revised list reflects the first test of the working group’s process, announced in March 2015, for accepting and evaluating genes nominated for the secondary findings list. Some of the criteria for considering a gene include the clinical features associated with the gene, the likelihood of physicians making an early clinical diagnosis in patients with the gene, clinical genetic testing options for the gene, and medical actionability involving the gene. The latter criterion had included the severity of disease, likelihood of death or disease, efficacy of specific interventions, and the overall depth of knowledge about the gene and associated conditions. To these considerations, the working group added the acceptability of the proposed intervention based on its risks and benefits.

Source: AACC

Latest issue of the eJIFCC 2016 Vol 27 no. 4

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  1. Foreword of the editor. Gábor L. Kovács
  2. Recent advances in the clinical application of mass spectrometry. Guest editor: Ronda F. Greaves
  3. Mass spectrometry applications for toxicology. Michael M. Mbughuni, Paul J. Jannetto, Loralie J. Langman
  4. Mass spectrometry analysis of dried blood spots across the total testing pocess. Rosita Zakaria, Katrina J. Allen, Jennifer J. Koplin, Peter Roche, Ronda F. Greaves
  5. Serum insulin-like growth factor I quantitation by mass spectrometry: insights for protein quantitation. Richard Kin Ting Kam, Chung Shun Ho, Michael Ho Ming Chan
  6. Progress in metabolomics standardisation and its significance in future clinical laboratory medicine. Daniel A. Dias, Therese Koal
  7. National External Quality Assurance Program Pakistan – a milestone in proficiency testing. Muhammad Usman Munir, Aamir Ijaz
  8. Letter to the editor – Successful ISO 15189 accreditation in Bethzatha Advanced Medical Laboratory in Ethiopia. Nardos Abebe
  9. Book review – “Cardiovascular Disease and Laboratory Medicine”. Joseph B. Lopez
  10. Book review – “Critial Care and Laboratory Medicine”. Joseph B. Lopez

Click here to download a PDF of the full issue

Routine blood test predicts how long cancer patients will survive

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“Cancer patients in palliative care want honest and accurate prognostic information but this information needs to be shared sensitively and in a way that respects their desire to maintain hope,” said lead author Dr Yu Uneno, an oncologist at Kyoto University, Japan.

“Patients with advanced cancer and their families have to make decisions about treatment, where to spend the end-of-life, and when to discontinue palliative chemotherapy,” added Dr Uneno. “Continuing ineffective therapy increases life-threatening adverse events, reduces quality of life, delays hospice referral, and deprives patients of the chance to die in their preferred place. Accurately predicting prognosis improves end-of-life care for cancer patients and their caregivers.”

Survival evaluations can determine whether or not pharmacological treatment should be given. Cytotoxic chemotherapy would rarely be prescribed in a patient unlikely to survive beyond several weeks because of unpleasant side effects. The sedative midazolam is used for symptom relief in palliative care settings, but tolerance can develop if administered for two weeks or longer. Chronic midazolam treatment could therefore be recommended only for patients likely to die within a few weeks, and be contraindicated when predicted survival was longer than a month.

Previous models for predicting prognosis used subjective conditions such as dyspnoea and delirium which may be scored differently by clinicians. These conditions were assessed once (at the start of treatment, for example), limiting the use of the models to that time point.

The current Six Adaptable Prognostic (SAP) models use three laboratory measurements (albumin, neutrophil, lactate dehydrogenase) which are routinely monitored in daily clinical practice with a blood test. The models can be used at any time point after the initiation of treatment – an important feature since a patient’s condition can change. The six models were developed in approximately 5,000 cancer patients receiving chemotherapy at Kyoto University Hospital in Japan. They predicted death within 1-6 months for patients with cancer receiving chemotherapy, allowing physicians to re-estimate prognosis at any time point after the initiation of chemotherapy.

The current study tested the predictive value of the models in cancer patients receiving palliative care. It was designed as a sub-analysis of the Japan-prognostic assessment tools validation (J-ProVal) study, which compared the ability of four models to predict survival of advanced cancer patients in the real world.

This sub-analysis included 1,015 patients, of whom 385 were based with palliative care teams in hospital, 464 were in palliative care units, and 166 were receiving palliative care services at home. The investigators performed receiver operating characteristic (ROC) analysis to calculate the ability of the SAP models to predict death in cancer patients in the palliative care setting. The area under the curve (AUC) for predicting death within 1-3 months ranged from 0.75 to 0.80.

Dr Uneno said: “We found that the SAP models had a good ability to predict that a patient would die in one to three months. The prediction was accurate in 75-80% of cases. The SAP models could be a promising decision aid for healthcare professionals and patients. Accurate prediction of survival allows patients adequate time to prepare for their impending death5 and is vital for planning effective palliative care.”

Commenting on the findings, Dr Grace Yang, consultant, Division of Palliative Medicine, National Cancer Centre Singapore, said: “The rapidly increasing armamentarium of anti-cancer therapy means that cancer patients can receive multiple lines of chemotherapy, immunotherapy or targeted therapy. Cancer patients may have aggressive treatment until the very last days of life, not without physical symptoms and great financial cost. Information about a cancer patient’s prognosis will help weigh the benefits and burdens of further cancer-directed treatment.”

“Knowing the patient’s prognosis will facilitate decision making regarding trade-offs, not only for anti-cancer therapy, but for treatments directed at relieving symptoms. For example, in deciding between pain-relieving treatments with different time horizons for onset and duration of effect, with different side effects/ risk profiles and different financial costs. As we get closer to knowing how long a cancer patient has to live, further studies exploring the ethical and psychological implications will also be worthwhile.”

Source: Science Blog

Algorithms compete to predict recipe for cancer vaccine

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Could predictive algorithms be the key to creating a successful cancer vaccine? Two US nonprofit organizations plan to find out by pitting a range of computer programs against each other to see which can best predict a candidate for a personalized vaccine from a patient’s tumour DNA.

The Parker Institute for Cancer Immunotherapy in San Francisco, California, and the Cancer Research Institute of New York City announced the algorithmic battle on 1 December. It is part of a multimillion-dollar joint project to solve a major puzzle in the nascent field of cancer immunotherapy: which of a patient’s sometimes hundreds of cancer mutations could serve as a call-to-arms for their immune system to attack their tumours.

If the effort succeeds, it could spur the development of personalized cancer vaccines that use fragments of these mutated proteins to fire up the body’s natural immune responses to them. Because these mutations are found in cancer cells and not healthy ones, the hope is that this would provide a non-toxic way to battle tumours.

The idea is gaining traction. In 2014, news that vaccines containing such mutated proteins had vanquished tumours in mice set off a mad dash to find out whether the approach would work in people. A generation of biotechnology companies has been founded around the concept, and clinical trials run by academic labs are under way.

Still, a challenge remains. To be a good candidate for a vaccine, a mutated cancer protein must be visible to T cells, the soldiers of the immune system. And for that to happen, tumour cells must chew up the protein into fragments. Those fragments then must bind to specialized proteins, which are shipped to the cell’s surface to be displayed to passing T cells.

The trick that vaccine researchers must master is using a tumour’s DNA to predict which mutations to home in on. “We can do the sequencing and find out the mutations, but it’s very hard to know which of these tens or hundreds or thousands of mutations are actually going to protect people from the growth of their cancers,” says Pramod Srivastava, an immunologist at the University of Connecticut School of Medicine in Farmington.

One approach is to use algorithms to predict which bits of a mutated protein might be seen by a T cell. These work by analysing where the proteins could be cleaved, for example, and which of the resulting fragments will bind tightly to the molecules that put them on display.

But each laboratory has a different “secret sauce”, says Robert Schreiber, a cancer immunologist at Washington University in St. Louis, Missouri. And most are not very predictive: Robert Petit, chief scientific officer of biotechnology company Advaxis in Princeton, New Jersey, estimates that the algorithms are typically less than 40% accurate.

To solve the problem, the Parker Institute and the Cancer Research Institute launched their challenge. They have arranged for 30 laboratories that already use such algorithms to apply their secret sauces to the same DNA and RNA sequences. The sequences will come from cancers such as melanoma and lung cancer, which tend to have many hundreds of mutations (see ‘Mutation map’ image) and thus could provide ample possibilities for a vaccine.

A handful of other laboratories will then test whether any T cells in the tumour recognize those fragments, and are stimulated by them — a sign of a good vaccine target. The alliance will not publicly announce a winner, but hopes to use the most accurate algorithms to design vaccines for clinical trials.

Algorithms can provide a quick answer to a complicated question — crucial if personalized vaccines are to be deployed on a large scale. But ultimately, Srivastava says that the best way to improve the algorithms is to collect more data from animal studies to learn about how T cells naturally respond to mutations. His lab and others are making hundreds of putative vaccines tailored to an individual tumour, and administering them to mice to see which are capable of fighting the cancer.

And Drew Pardoll, a cancer immunologist at Johns Hopkins University in Baltimore, Maryland, worries that algorithms may never account for some factors that influence T-cell responses. For example, mutations may be less suitable for a vaccine if they have arisen early in tumour development, giving the immune system time to begin viewing them as ‘normal’. Pardoll argues that the field needs faster, easier and more accurate laboratory tests to determine which mutations best trigger a T-cell response. “We don’t yet know enough about the rules to make perfect predictions,” he says. “You can algorithm until the cows come home and you’re not really going to know if you’re improving things.”

But in the absence of speedy lab tests, companies need algorithms, argues Robert Ang, chief business officer at Neon Therapeutics of Cambridge, Massachusetts. “There is already evidence to show that this approach works despite the imperfect algorithms,” he says. “Improving the algorithms even more could be very meaningful.”

Source: Nature

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