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Research Briefs July 2016

Disparities in Deaths Among Urban AI/ANs

Of all the 15 leading causes of death for urban American Indians and Alaska Natives (AI/ANs), the largest disparity compared with urban whites is in chronic liver disease and cirrhosis, according to a Centers for Disease Control and Prevention study. Data from 1999 to 2009 showed urban AI/ANs died from chronic liver disease and cirrhosis at four times the rate of urban whites.

In fact, urban AI/ANs had significantly higher death rates than urban whites for all but two of the 15 leading causes. However, when they were compared with rural AI/AN populations, the study found urban AI/ANs had significantly lower death rates for 13 of the top 15 leading causes of death (Alzheimer’s disease and viral hepatitis were higher). Viral hepatitis and cirrhosis are risk factors for liver cancer. Urban AI/ANs have a significantly higher cancer death rate than urban whites, but a lower rate than that of rural AI/ANs. The researchers note that rural residence has been associated with later diagnoses of cancer stages, inadequate cancer treatment, and increased mortality.

One reason the disparities between urban AI/ANs and other groups are not always obvious, the researchers say, is that urban AI/ANs are often misclassified racially, meaning the magnitude of health disparities is likely underestimated. Another factor is “historical trauma” shared by both urban and rural AI/AN populations: A long history of anti-Native policies, suppression of cultural identities, and pandemics has damaged AI/AN social structures. The trauma manifests in high rates of substance abuse, chronic stress, and other risk factors, as well as poverty and low education, which correlate with poor health outcomes.

The “alarming” disparities could be addressed with evidence-based interventions to reduce alcoholism and other factors that contribute to chronic liver disease and cirrhosis in AI/AN populations, the researchers say.

Source: American Journal of Public Health Research, May 2016

Finding Synchronous Cancers

Up to 6% of patients with head and neck squamous cell carcinoma (HNSCC) also have synchronous second primary cancers (SPCs). However, the synchronous cancers may be missed in a usual examination that relies on computerized tomography (CT) and magnetic resonance imaging (MRI) scans.

Clinicians from Odense University Hospital in Denmark report on a patient who presented with only tongue pain as a symptom but was found to have four SPCs. The CT and MRI results were inconclusive due to artifacts from metal dental fillings. However, a positron emission tomography (PET)-CT scan “easily revealed” the three coinciding malignancies because of their increased metabolic activity, the authors say.

Their patient had four primary cancers: one squamous cell carcinoma (SCC) on the left side of the tongue, one in the fold between the tongue and the floor of the mouth (the two tumors were near each other but separate entities), a third SCC in the right aryepiglottic fold, and a grade-2 follicular lymphoma diagnosed “by coincidence” in the lymph nodes of the neck.

The three SCCs in the upper aerodigestive tract were in line with the concept of field cancerization, the clinicians note. Multiple adjacent but independent tumors in the mucosa may arise from exposure to carcinogens, which can induce dysplastic changes that lead to malignancy. Although synchronous cancer of the head and neck regions and follicular lymphoma are rare, one of the potential risk factors for follicular lymphoma is smoking, the authors say. Their patient had smoked for 56 years.

The authors recommend a “more liberal approach” to examination and a “generous use” of PET-CT for patients with malignancies of the head and neck regions, particularly in patients with obvious risk factors, such as a long history of smoking or alcohol abuse. They add that PET-CT is also a useful tool in assessing tumor dissemination and prognosis of individual carcinomas—an important benefit in planning different treatments.

Source: BMJ Case Reports, May 2016

Pros, Cons of Culture-Independent Diagnostic Tests

Culture-independent diagnostic tests (CIDTs) are helping to identify infections from foodborne illness faster. Without a bacterial culture, CIDTs cut the time needed to diagnose to hours.

CIDTs are making it easier to find cases that were not previously diagnosed, according to a Morbidity and Mortality Weekly Report article on findings from the Centers for Disease Control and Prevention (CDC) Foodborne Diseases Active Surveillance Network. In 2015, the percentage of foodborne infections diagnosed only by CIDT was “markedly higher”—about double—compared with the percentage in 2012–2014, the report says. For instance, the incidence of Cryptosporidium was significantly higher in 2015 than the average for the previous three years.

But without a bacterial culture, public health officials can’t get the detailed information they need to track outbreaks and trends. The CDC is working with partners to develop advanced tests that, without culture, will give the needed data for diagnosis as well as preventive clues. In the short term, the CDC advises clinical laboratories to work with public health laboratories to make sure a culture is done whenever a CIDT indicates that someone with diarrheal illness has a bacterial infection.

Source: CDC, April 15, 2016

The Mortality Mystery of Sepsis Survivors

More than one in five older patients who survives sepsis dies within two years for reasons not explained by their health status before the sepsis, according to University of Michigan researchers.

Many studies have found that people who survive sepsis have a high risk of dying within months, but researchers had been divided on whether it’s from the burden of comorbidities or from the sepsis itself. In this study, the researchers divided 14,529 participants in the ongoing U.S. Health and Retirement Study into four cohorts: patients admitted to a hospital with sepsis, adults not currently hospitalized, patients admitted with nonsepsis infection, and patients admitted with an acute sterile inflammatory condition.

Sepsis “substantially” increased the risk of late mortality: More than 40% of those who survived for 30 days after the admission for sepsis died in the next two years. Compared with patients not currently in the hospital, those with sepsis had double the risk of dying within 31 days to two years. Compared with patients admitted for nonsepsis infection or sterile inflammatory conditions, roughly one in 10 patients with sepsis had a late death related to sepsis.

The findings suggest that pre-existing health conditions don’t explain all of the sepsis deaths, which could mean the problem may be more amenable to intervention than previously thought, the researchers say. Patients might benefit from intervention during the admission for sepsis, rather than generic post admission care. On the other hand, if the results are interpreted strictly as a prognostic association, physicians should perhaps discuss advance directives and end-of-life planning with patients—even when they survive sepsis in the hospital.

Source: BMJ, May 2016

Deciding on a Definition of Hyperkalemia

How many patients have hyperkalemia? It depends on your definition of hyperkalemia—and that can vary widely, say researchers from Bayer Pharma AG in Berlin. They found an almost 10-fold difference between the most restrictive and the most liberal operational definitions.

It’s hard for clinicians to make good therapeutic decisions for heart failure patients when they have to rely on diverse thresholds or data from clinical trials, which may not reflect actual practice, the researchers contend. Guidelines define hyperkalemia as a value of serum potassium (K+) greater than 5.5 mmol, but recent clinical trials have varied between 5.5 mmol/L or greater and 6 mmol/L or greater. The researchers tested six definitions, calculating the number of incident cases of hyperkalemia per 100 person-years. Incident rates ranged from 0.92 to 7.93 per 100 person-years according to the definition.

They settled on a definition of serum K+ 10% or more above the upper bound of normal range. They applied that definition to 19,194 heart failure patients who had at least one laboratory value of serum K+ recorded after the diagnosis of heart failure. Based on the selected definition, the researchers identified 2,176 patients (11.3%) who were considered to have had an episode of hyperkalemia over a mean follow-up period of 3.9 years, for an incidence rate of 2.90 per 100 person-years.

Few studies have evaluated the incidence of hyperkalemia in real-life clinical practice, the researchers say. Their study “has the novelty” of investigating the effects of differing diagnostic thresholds on resulting incidence rates, highlighting the importance of applying a precise definition of the outcome. Another strength is the high proportion of cases (99%) that were ascertained using an operational definition of hyperkalemia based on laboratory data, thereby reducing misclassification, compared with assessment based only on diagnostic codes.

Source: BMC Family Practice, May 2016

Treating Deep Venous Thrombosis at Home

Since the 1990s, controlled trials have shown that home treatment of deep venous thrombosis (DVT) with low-molecular-weight heparin is both effective and safe. Yet only 34% of people who could be treated at home are. Although the numbers grew significantly from 2007 to 2012, the total increase was only 5.8%, according to researchers from Michigan State University.

Most patients treated at home are 50 years of age or younger and have no comorbid conditions. Keeping similar patients in the hospital cost nearly $3 billion between 2007 and 2012. The researchers say two very small studies have been done on home treatment of patients with carcinoma and other serious conditions; to their knowledge, none had been done on trends in home treatment according to comorbidity and age. In particular, they cite new oral anticoagulants, which were not yet approved in the U.S. for most of the study period. The researchers conducted a retrospective study to find out what impact those drugs had.

Of 245,000 patients from four regional emergency departments, 96 had a diagnosis of DVT and no clinical evidence of pulmonary embolism. Of those, only 11.5% were discharged to home, and none received new oral anticoagulants. Among patients with no comorbid conditions, only 11 of 40 were treated at home. None of those with any comorbidities were treated at home. One-third of hospitalized patients were discharged in two days or less; 25% of those received new oral anticoagulants.

Their study, although limited in size, suggests that home treatment did not increase with the new drugs, the researchers say. However, none of the 79 low-risk patients who were treated for DVT at home with rivaroxaban (Xarelto, Janssen Pharmaceuticals), an oral factor Xa inhibitor approved in 2012, had a recurrent DVT or major bleed while on treatment. Three had recurrent DVT when the drug was stopped.

Source: American Journal of Medicine, April 2016

The Real Risks of Diabetes Drugs

Type-2 diabetes is associated with hypoglycemia, hyperglycemia, lower-limb amputation, blindness, and kidney failure. But the clinical evidence for certain diabetes drugs is based largely on surrogate endpoints, such as reduction of hemoglobin A1c (HbA1c), say researchers from University Park in Nottingham, United Kingdom, rather than “hard clinical endpoints, such as increased survival rates or reduced incidence of complications.”

Their study included more than 55,000 person-years of exposure to glitazones (mostly piaglitazone) and more than 70,000 person-hours of exposure to gliptins (mostly sitagliptin). Previous studies have either been clinical trials with limited sample sizes and durations or observational studies that focused on one drug or drug combination. By contrast, their study looked at a range of complications in relation to drug treatment. More than 99% of the patients had smoking status recorded, 87% had ethnic group recorded, and more than 82% had complete data for all five clinical values (body mass index, cholesterol, systolic blood pressure, serum creatinine, and HbA1c).

Overall, they found a reduced risk of blindness and a higher risk of hypoglycemia associated with glitazones and a lower risk of hypoglycemia associated with gliptins. Among combination treatments, they found differences depending on whether glitazones and gliptins were prescribed as monotherapy or dual or triple therapy. For instance, gliptins and glitazones were associated with an increased risk of kidney failure compared with metformin monotherapy only when used as monotherapy or in combination with sulphonylureas. Compared with metformin monotherapy, dual treatment with glitazones and sulphonylureas was associated with a 93% increased risk of hyperglycemia, 106% increased risk of amputation, 114% increased risk of severe kidney failure, and more than a 13-fold increased risk of hypoglycemia.

Dual treatment combinations for glitazones or gliptins with metformin showed reduced risks of hyperglycemia compared with metformin monotherapy and no significant increases in risk for the other outcomes. Triple therapy with metformin, sulphonylureas, and glitazones was associated with significantly less blindness but more hypoglycemia. Triple therapy of metformin, sulphonylureas, and gliptins was also associated with significantly higher risk of hypoglycemia. In fact, triple therapy involving gliptins or glitazones does not appear to have consistent measurable advantages compared with dual therapy or monotherapy with metformin for the five outcomes.

Source: BMJ, March 2016

A Potential Treatment for Chondrosarcoma

The gene BIRC5 is an “important player” in chondrosarcoma survival, say researchers from Leiden University in the Netherlands and Athens University in Greece. They propose that targeting survivin, a protein encoded by BIRC5, is a potential avenue for treating the tumor that accounts for 20% of all malignant bone cancers.

Chondrosarcomas are “intrinsically resistant” to chemotherapy and radiotherapy, the researchers say, leaving surgery as the only curative option. So they aimed to identify genes that could be used in targeted drug treatment.

They screened for 51 apoptosis-related genes. When the screening pinpointed survivin as essential for chondrosarcoma survival, the researchers used immunohistochemistry to analyze cytoplasmic survivin expression in 207 chondrosarcomas of different subtypes. Survivin is highly expressed, they found, in tumor tissue and cell lines of conventional as well as rare subtypes of chondrosarcoma.

The researchers also tested sensitivity to YM155 (a survivin-inhibiting compound) and found chondrosarcoma cells lines were highly sensitive. They say their findings suggest that YM155, which is already in phase 1 and 2 clinical trials for other tumors, could be readily applicable in clinical trials for chondrosarcoma patients. Although some larger phase 2 studies have not shown promising antitumor activity in diffuse large B-cell lymphoma, non–small-cell lung cancer, melanoma, or prostate cancer, that doesn’t mean it can’t help in chondrosarcoma patients, they say. In particular, they note, in chondrosarcoma YM155 does not induce apoptosis but blocks the cell cycle. TP53 mutant cell lines were sensitive; thus, TP53 mutation may be a biomarker that can allow preselecting patients for treatment.

Source: Oncogenesis, May 2016

Predicting Whose Flu Will Be Worse

What really makes flu vaccines effective—if they are? Researchers from the National Institute of Allergy and Infectious Diseases (NIAID) tested the conventional wisdom about what makes them work and found some “interesting clues.”

That conventional wisdom has held that higher levels of antibodies against hemagglutinin (HA) are key. HA is a protein that helps the virus enter the human cell and initiate infection. But NIAID found that higher levels of antibody against neuraminidase (NA) actually better predict who will have to weather the effects of mild-to-moderate flu. NA allows newly formed flu viruses to exit the host cell and replicate in the body.

The researchers divided 65 healthy volunteers into two groups, based on their levels of anti-HA antibodies. The participants were given an intranasal dose of 2009 H1N1 influenza virus, monitored for nine days, and followed for eight weeks.

Those who had high levels of anti-HA antibodies had a significantly lower incidence of mild-to-moderate flu, and the flu’s duration was somewhat shorter. But those participants were just as likely to have some flu symptoms as those with low levels of HA antibodies. That suggests, the researchers say, that high HA antibody levels may limit viral shedding—and the spread of virus—but may not prevent the flu.

High NA antibody levels, however, had a “more robust” effect. Participants with high NA antibody levels had less severe disease, shorter duration of viral shedding and symptoms, and fewer and less severe symptoms.

HA and NA antibody levels together may be a better predictor of whether someone develops mild-to-moderate flu than either alone, the researchers conclude, but NA antibodies are the best way to predict disease severity.

Source: National Institutes of Health, April 19, 2016