Body

New research published in Diabetologia (the journal of the European Association for the Study of Diabetes [EASD]) shows that cardiorespiratory fitness (CRF), high-intensity physical activity (HPA) and low sedentary time (ST) are all associated with a lower risk of type 2 diabetes. The study is by Jeroen van der Velde and Annemarie Koster, Maastricht University, Netherlands, and colleagues.

While previous research has individually connected CRF, HPA and ST with cardiometabolic health, the majority of studies on HPA and ST did not account for CRF, and this study is the first to examine combinations of ST and CRF.

It is known that differences in CRF between individuals are partly explained by differences in frequency and intensity of physical activity. Further, recent studies have shown that high levels of ST were associated with a lower CRF.

Nonetheless, an estimated 10 to 50% of CRF is explained by factors other than physical activity, including genetic differences and behavioural or environmental elements.

This means that someone could engage regularly in HPA and not have high CRF, or have high CRF without frequently engaging in HPA. The authors say: "Thus, although to some extent they are interrelated, HPA, ST and CRF should be considered different traits and may be independently associated with cardiometabolic health."

This study used data from 1993 people aged 40-75 years from the Maastricht Study, all living in the southern part of the Netherlands. ST and HPA were measured using an accelerometer device. CRF was assessed using cycle-ergometer testing, with various calculations used to determine power output and oxygen consumption.

The researchers found that higher ST, lower HPA and lower CRF were independently associated with greater odds for type 2 diabetes and also metabolic syndrome (a cluster of factors indicating poor metabolic health, such as high blood pressure and large waist circumference).

The authors then looked at high, medium and low levels and ST, HPA and CRF in combination with each other. Compared with those who had both high CRF and high HPA, the group with low CRF and low HPA had a 5.7 times higher risk of metabolic syndrome and a 6.4 times higher risk of type 2 diabetes.

Similarly, all subgroups with medium or low CRF had higher odds for the metabolic syndrome, prediabetes and type 2 diabetes, irrespective of ST. Even in those with high CRF, high ST was associated with a trebling of risk of metabolic syndrome and a doubling of risk of type 2 diabetes, suggesting that high CRF may not be enough to 'counteract' the poor health outcomes associated with high ST. This adds to the accumulating evidence that reducing a person's daily amount of ST could be an important part in improving their cardiometabolic health.

The highest risk of metabolic syndrome and type 2 diabetes was observed in the group with low CRF and high ST; this group had a nine-times higher risk of metabolic syndrome, a trebling of risk of prediabetes and an eight times higher risk of type 2 diabetes when compared with the group with high CRF and low ST.

The authors say: "High ST, low HPA, and low CRF were each associated with several markers of cardiometabolic health and higher risk for the metabolic syndrome and type 2 diabetes independent of each other. A combination of low CRF and low HPA, and a combination of low CRF and high ST, were associated with a particularly high risk of having the metabolic syndrome and type 2 diabetes."

Furthermore, they discovered that a change from low to medium CRF appeared to be more beneficial than from medium to high CRF, since the difference in risk of type 2 diabetes and metabolic syndrome was higher between low and medium CRF than between medium and high CRF.

The authors add: "In order to improve cardiovascular risk and to prevent type 2 diabetes these data support the development of new strategies that target all three components: ST, HPA, and CRF. However, at this stage our study is limited by its cross-sectional design, which makes it difficult to determine causality. Future work that incorporates health changes over time is needed to determine if the observed associations hold true."

They conclude: "We also need to find out what amount of ST is associated with a clinically relevant increase in risk and which levels of HPA and CRF are associated with clinically relevant lower risk for the metabolic syndrome and type 2 diabetes."

Bottom Line: Among a small cohort of patients with HIV-associated Kaposi's sarcoma treated with immune checkpoint inhibitors, more than 65 percent had partial or complete remission.

Journal in Which the Study was Published: Cancer Immunology Research, a journal of the American Association for Cancer Research

Author: Natalie Galanina, MD, oncologist at Moores Cancer Center at UC San Diego Health

Background: "Despite the successful and prevalent use of antiretroviral medications to treat human immunodeficiency virus (HIV)-positive patients, about 15 percent of this population still develops Kaposi's sarcoma, which is an incurable malignancy with significant morbidity," said Galanina. "Due to a paucity of novel therapeutic options for this disease in recent decades, we wanted to investigate if immune checkpoint inhibition was effective in treating this virally mediated cancer."

The standard of care for patients with Kaposi's sarcoma is liposomal doxorubicin, a type of chemotherapy. While roughly half of patients respond to this therapy, most suffer relapses and require repeated treatments, noted Galanina. Because the standard of care is not curative, and Kaposi's sarcoma can persist in patients with an undetectable viral load, new treatments for this disease represent a clinically unmet need, she explained.

How the Study Was Conducted: Galanina and colleagues analyzed data from nine men with Kaposi's sarcoma treated with anti-PD-1 immune checkpoint inhibitors at Moores Cancer Center between August 2013 and December 2017. All patients had received retroviral therapy and a median of one prior line of treatment for Kaposi's sarcoma. Eight patients were treated with nivolumab (Opdivo), while one patient was treated with pembrolizumab (Keytruda).

In addition to survival data, the researchers utilized next-generation sequencing data from tissue and circulating tumor DNA to analyze tumor mutational burden (TMB) and PD-L1 expression levels, biomarkers for anti-PD-1 treatment.

Results: Following treatment with immune checkpoint inhibition, five patients had a partial response, three patients had stable disease, and one patient had complete remission. All patients remained on treatment, and no patient had shown disease progression at 6.5 months of follow-up.

PD-L1 expression was negative in all four evaluable patients. Furthermore, all three evaluable patients had low TMB (between 1-4 mutations per megabase).

"Typically, checkpoint blockade immunotherapy is more effective in patients with high TMB and/or high expression of PD-L1, yet we saw many patients who responded to treatment without these characteristics," said Galanina. "It is possible that the viral immunogenomic mutanome is sufficient to induce changes to the immune system, enabling a response to treatment with checkpoint inhibition."

While treatment with standard chemotherapy can have significant side effects, patients treated with PD-1 inhibitors experienced limited toxicity in this study, noted Galanina. "Importantly, treatment with PD-1 inhibitors did not cause myelosuppression, which is an important finding in this patient population," she added.

Furthermore, seven patients treated with PD-1 inhibitors had an increase in both CD4+ and CD8+ T cell levels, although not statistically significant.

Author's Comments: "Based on these results, we think that PD-1 checkpoint blockade may present a promising, novel therapeutic option for HIV-associated Kaposi's sarcoma with high efficacy and low toxicity," said Galanina.

Study Limitations: Limitations of the study include a small sample size and the paucity of available archival tissue material to corroborate PD-L1 expression findings.

CHICAGO, Sept 7, 2018 -- Black adults experience dangerous spikes in high blood pressure, called a hypertensive crisis, at a rate that is five times the national average, according to a study presented at the American Heart Association's Joint Hypertension 2018 Scientific Sessions, an annual conference focused on recent advances in hypertension research.

Hypertensive crisis is a complication of high blood pressure in which blood pressure quickly and severely soars to life-threatening levels. People often can avoid this dangerous blood pressure escalation by keeping their blood pressure under control with medications and lifestyle modifications.

"We studied an inner-city population to find that being black is a risk factor for progressing from hypertension to hypertensive crisis," said study author Frederick A. Waldron, M.D., M.P.H., M.S., an emergency medicine physician at Newark Beth Israel Medical Center, Newark, New Jersey. "Now that we have effective antihypertensive medications available, hypertensive crisis and hypertensive emergency, a rare but further progression of hypertensive crisis in which organ damage occurs, should not exist to this degree among black or other patients."

In what Waldron said is the largest case control study to date on hypertensive crisis patients, researchers looked back at emergency department medical records of more than 15,000 patients from 2013 to 2016.

They defined hypertensive crisis as blood pressure at or above 200/120 mmHg and found:

Nearly 1,800, or 11.4 percent, of the 15,631 hypertensive patients that came through the emergency department in the three-year study were in hypertensive crisis.

Nearly 90 percent of those in hypertensive crisis were black.

One in four, or 25 percent, of patients with hypertensive crisis went on to develop catastrophic organ failure, including stroke, congestive heart failure, kidney failure or heart attack.

Being older than 65 years or male, as well as having anemia, chronic kidney disease or a history of stroke and cardiovascular diseases, including high cholesterol, predicted higher risk for hypertensive emergencies. Anemia has not been identified before as a hypertensive emergency risk factor, according to Waldron.

Insurance status and access to primary care did not affect patients' odds of having a hypertensive crisis.

"There is no good treatment for organ damage, so the best way to address this is to develop a preventative strategy," Waldron said. He suggests efforts to help patients take their medicine properly could help reduce hypertensive crises.

The numbers in the study may be underestimated due to differing definitions of hypertensive crisis. For example, the American Heart Association defines it as blood pressures at or above 180/120 mmHg. This study defined hypertensive crisis as above 200/120. Waldron said future studies should determine rate of adherence to blood pressure medications and follow patients in hypertensive crisis longer to determine true hypertension emergency incidence.

Whether an individual develops a neurodevelopmental disorder like autism or ADHD and the severity of that disorder depends on genetic changes beyond a single supposedly disease-causing mutation. A new study led by researchers at Penn State reveals that the total amount of rare mutations -- deletions, duplications, or other changes to the DNA sequence -- in a person's genome can explain why individuals with a disease-associated mutation can have vastly different symptoms. A paper describing the study appeared today in the journal Genetics in Medicine.

"Genetic sequencing tools can reveal a large number of mutations in a person's genome, but diagnosis typically focuses on identifying one primary mutation as the cause of a disorder," said Santhosh Girirajan, associate professor of biochemistry and molecular biology and of anthropology at Penn State and senior author of the paper. "However, this strategy does not explain why many individuals with the same primary mutation have very different features or symptoms. For example, when a parent and child have the same primary mutation but only the child develops the disorder. Our work reveals that the primary mutation likely sensitizes a person to a disorder, but the amount of other mutations elsewhere in the genome is what actually determines the cognitive ability and developmental features in that person."

The research team considered genetic, cognitive, and developmental information from individuals who contained one of two known disease-associated mutations, and of their families. Both mutations are deletions of genetic material on chromosome 16 -- one in a region referred to as 16p11.2 and the other 16p12.1 -- and are detected in a global screen for children with developmental delays. These primary mutations provide a frame of reference to study the additional mutations that make up an individual's "genetic background."

"Ninety-five percent of children who have the 16p12.1 mutation inherit it from their parents, so any difference in clinical features between the parent and child is due to what they have in the genetic background," said Girirajan.

Individuals with one of the primary mutations who expressed clinical features had significantly more mutations in the genetic background than their parents or siblings who did not express clinical features. The researchers also linked the number of mutations in the genetic background to head size, a feature of cognitive development, in individuals with the primary 16p11.2 deletion and to IQ scores in individuals with one of the two primary mutations or one of several other disease-associated primary mutations.

"This suggests that a child with a higher number of mutations in the genetic background is more likely to develop intellectual disabilities," said Girirajan. "The more mutations you have, the more different types of combinations you have that can potentially produce clinical features. Most of these mutations in the genetic background are passed on by the parents, and when the parents' mutations come together in a combinatorial way, the child ends up having more than what either parent had individually. The primary mutation is usually only passed on by one of the parents, and it turns out that the parent who does not pass on the primary mutation actually passes on more mutations in the genetic background. This tells us that getting information about family history, about the parents' genetic profile, is incredibly useful when trying to make a diagnosis."

The researchers suggest that the primary mutation sensitizes an individual to a particular disorder and that the genetic background sets the trajectory for potential clinical features.

"Some primary mutations may sensitize an individual to a lesser degree, requiring large numbers of mutations in the genetic background to produce symptoms associated with the disorder," said Lucilla Pizzo, graduate student in the Molecular Medicine program at Penn State and first author of the paper. "For example, an inherited mutation that has been passed on for many generations may not have produced strong symptoms in the parents or grandparents, but large numbers of mutations in the genetic background of the child could lead to clinical features. Other primary mutations may sensitize the genome to a greater degree, with fewer additional mutations required to produce symptoms associated with the disorder."

This study focused solely on genetic changes that occurred in the protein-coding portions of the genome. The researchers plan to expand their investigation to the rest of the genome.

Ultimately, the researchers hope this knowledge -- and continued studies of how mutations affect specific, measurable traits such as IQ and head size -- will change how clinicians obtain genetic data and offer diagnoses to their patients.

"We need more-thorough screens when a patient comes into a clinic so that we can consider more than just one mutation," said Girirajan. "With knowledge about the family history and genetic background, we can get closer to a more accurate prognosis and provide rehabilitation sooner. For example, a patient could start speech therapy or physical rehabilitation before the developmental delay hits."

A blood test that quickly and easily detects whether a person is at risk of a secondary heart attack is being developed by scientists at the Baker Heart and Diabetes Institute.

The Baker Institute's head of metabolomics, Professor Peter Meikle and his team have identified plasma lipid biomarkers (fats in the blood) that improve upon traditional risk factors in predicting heart disease and stroke.

He says the revolutionary blood test is proposed to be trialled in Australia over the next 2-3 years as part of a broader personalised precision health program currently under development. Eventually a GP will be able to order this test in order to better assess a patient's risk of developing heart disease.

"The test was developed after a study looked at 10,000 samples to find the bio markers that will determine whether a person is at risk of having another heart attack," said Prof Meikle.

"We hope to identify those individuals who are at greatest risk of a second heart attack so that they can be closely monitored and treated accordingly.

"While there are thousands of lipids in the blood, our challenge is to identify which ones best predict disease outcomes."

To date, a prototype of this test has been trailed in America, yet the prototype only provides GP's and patients with limited information on the basis of 2 lipid markers, and it is not yet available in Australia.

The test will be a simple blood test, similar to the process and cost of having a cholesterol test, and could be operated out of hospital pathology laboratories that already contain the necessary equipment.

"Our test will use up to ten lipid markers to better diagnose heart disease. It's a challenging, yet very exciting time. We effectively have the information and are in the process of refining the technology," said Prof Meikle.

"Once the protocols for a diagnostic heart disease blood test are in place; it will be possible to additional markers for the test to also be used in predicting diabetes and potentially Alzheimer's disease as well.

The test will reclassify a patient's risk of heart attack and stroke. It will better identify who within the 'intermediate' risk category are in fact, at higher risk, and help guide physicians in the appropriate treatment of patients."

Sept. 7, 2018--A New York State requirement that all hospitals report compliance with protocols to treat severe sepsis and septic shock appears to improve care and reduce mortality from one of the most common causes of death in those who are critically ill, according to a new study published online in the American Thoracic Society's American Journal of Respiratory and Critical Care Medicine.

In "Mortality Changes Associated with Mandated Public Reporting for Sepsis: The Results of the New York State Initiative," Mitchell M. Levy, MD, and co-authors report that patients treated according to three- and six-hour sepsis "bundles"--a group of interventions designed to diagnose and treat sepsis and septic shock early--were 15 percent less likely to die than those whose care did not follow the protocols.

Patients who received the sepsis bundles also had shorter hospital stays. At hospitals with the highest rates of compliance with the three-hour bundle, length of stay was nearly three days shorter. At hospitals with the highest rates of compliance with the six-hour bundle, length of stay was more than a day shorter.

Sepsis occurs when the body reacts to an infection with an overwhelming inflammatory response. Severe sepsis can lead to the failure of one or more organs. Septic shock is a form of severe sepsis accompanied by extremely low blood pressure that is, in itself, life threatening.

The authors noted that the New York State mandate came about, in part, because of the tragic death in 2012 of an otherwise healthy 12-year-old boy named Rory Staunton from Queens, NY, who had undiagnosed sepsis. The case was widely reported in the New York and national media.

"Governor Andrew Cuomo and then Commissioner of Health Nirav Shah responded to Rory's preventable death by mandating public reporting of sepsis process and outcomes, with the goal of improving earlier diagnosis and management of sepsis," said Dr. Levy, professor of medicine and chief of pulmonary, critical care and sleep medicine at the Warren Alpert Medical School of Brown University. "The reason the state adopted these particular bundles is that our group had published evidence that there was a strong association between compliance with these interventions and improved survival in sepsis."

In April 2014, New York State became the first state in the nation to require its hospitals to report to the Department of Health whether sepsis protocols had been followed in treating patients, along with specific patient outcomes. The researchers looked at the medical records of 91,357 patients (median age 71) with either condition who were hospitalized at 183 hospitals over the first 27 months of the new reporting mandate.

The researchers found that over the study period, the health care team increasingly initiated the sepsis bundles. Overall, the sepsis protocols were initiated in 81.3 percent of patients, most often in the emergency room. The risk-adjusted mortality of these patients was 24.4 percent, compared to 28.8 percent in those not receiving the bundles.

The NYS Department of Health gave hospitals flexibility in developing their sepsis protocols, but required that

The three-hour bundle for all severe sepsis patients include drawing blood cultures before administering antibiotics and starting antibiotics and measuring blood lactate levels within three hours of arriving at the hospital.

The six-hour bundle for those with septic shock (systolic pressure

The authors noted that over the past three decades there has been a national movement towards public reporting of health care performance measures. The U.S. Centers for Medicare and Medicaid Services (CMS) and other states have followed New York's lead in sepsis reporting.

Whether the overall trend towards this kind of reporting has improved health outcomes is a subject for debate, according to the authors. In the case of the sepsis requirement, they wrote that while their study cannot prove a causal relationship between implementation of the protocols and lower mortality, the evidence is nonetheless strong.

"The New York State sepsis initiative provides strong evidence that compliance with sepsis performance measures is associated with improved survival in these critically ill patients," Dr. Levy said. "At least in sepsis, our study strongly supports the value of public reporting of outcomes."

Strabismus is a common condition in which the eyes do not align properly, turning inward, outward, upward or downward. Two to four percent of children have some form of it. Some cases can be treated with glasses or eye patching; other cases require eye muscle surgery. But the treatments don't address the root causes of strabismus, which experts believe is neurologic.

For decades, Elizabeth Engle, MD, in Boston Children's Hospital's F.M. Kirby Neurobiology Center, has been studying rare forms of strabismus, such as Duane syndrome, in which strabismus is caused by limited eye movements. Her lab has identified a variety of genes that, when mutated, disrupt the development of cranial nerves that innervate the eye muscles. These genetic findings have led to many insights about motor neurons and how they develop and grow.

More recently, with postdoctoral research fellow Sherin Shabaan, MD, PhD, Engle's lab has been gathering families with common, non-paralytic strabismus, in which both eyes have a full, normal range of motion yet do not line up properly in any gaze direction.

Such "garden variety" forms of strabismus have been much harder to pin down genetically. While they clearly run in families, they don't follow predictable Mendelian dominant or recessive patterns of inheritance. Instead, they likely result from variations in multiple genes acting together.

Focusing on esotropia

Engle, Shabaan and colleagues decided to look specifically at esotropia, in which the eyes turn inward, making children appear cross-eyed. They enrolled about 1,200 U.S. patients of white European ancestry, most seen at Boston Children's. But even with careful exams of patients and their parents, it was difficult to establish clear inheritance patterns.

"Even within a family, a mom can have esotropia, and the child has exotropia [in which the eyes turn outward]," says Mary Whitman, MD, PhD, an ophthalmologist who joined the project. "Or grandma can have exotropia and the kid has esotropia. Or the mom remembers that 'there was something wrong with grandma's eyes.' Or you may have had eye surgery when you were 3 years old, but don't remember why."

Ultimately, the researchers further narrowed their investigation to 826 patients with "non-accommodative" esotropia, which cannot be corrected with glasses.

"Despite being so common in the general population, the causes of non-accommodative forms of strabismus remain undefined," notes Engle.

They decided to conduct a genome-wide association study (GWAS) - the first ever used to investigate esotropia.

GWAS, a technique that emerged about 15 years ago, searches across the genomes of large populations, using known genetic markers known as SNPs. It can be helpful in finding genetic variants that influence common, multi-gene traits like height, obesity, diabetes and hypertension. The identified genes can offer clues about the biology of the trait or disorder.

"We did not achieve the large number of participants that you typically need for a successful GWAS," says Engle. "But we had a very well-phenotyped cohort, so we decided to move forward."

Scratching the surface

Their findings, published last month in Investigative Ophthalmology & Visual Science, were interesting but -- not surprisingly, given the small number of participants -- a little disappointing.

"Normally with GWAS, you get tens to hundreds of hits," says Whitman. "We got one."

Their "hit," validated in a second cohort of 689 patients from the U.K. and Australia, was in an intron of a gene called WRB -- a non-coding bit of DNA that alters WRB's level of expression, or how frequently it's turned on.

Notably, WRB is an "imprinted" gene, meaning that its expression varies depending on which parent it came from. In the study, patients with strabismus were more likely to have inherited the genetic variant from their father. Also, WRB is on chromosome 21, and children with trisomy 21 (commonly known as Down syndrome) have a higher incidence of strabismus, an intriguing connection.

The bigger disappointment was that the discovery didn't shed any immediate light on how strabismus develops. WRB is known to be involved in the processing of proteins, a "housekeeping" job critical to the function of all cells. While many of the genes Engle found in the past act in specific brain regions, WRB is expressed pretty much throughout the body.

"It remains difficult to say how it's contributing to strabismus," says Engle.

Collaborator David Hunter, MD, PhD, chief of ophthalmology at Boston Children's, has a different take on the results. "These findings represent more than 10 years of hard work rounding up families, conducting careful examinations and collecting samples," he says. "At long last we have an established a genetic association with strabismus more definitive than anyone has ever been able to demonstrate. We may be poised to learn something very unexpected and very important about the elusive cause of this common condition."

The search continues

To extend their findings, Engle and her colleagues are reaching out internationally, hoping to identify new cohorts of strabismus patients. This would increase the statistical power of GWAS analyses and hopefully yield further genetic associations.

"This study is a stake in the ground," says Engle. "Eventually, we hope to be able to sculpt a picture of pathways that may influence your susceptibility to strabismus."

"Considering how common strabismus is, it's surprising that we know nothing about it genetically," adds Whitman. "If we find genetic causes, we can compare how people with different genetic causes respond to different treatments. Surgery is successful in about 85 percent of patients, but some patients require multiple surgeries. If we figured out what was causing the strabismus, it could open up new options for treating it."

Amsterdam, September 6th 2018 - A new peer-reviewed study funded by Fontem Ventures and published in the Journal of Environmental Research and Public Health of 72 adult smokers willing to try vaping as an alternative to smoking found that after 90 days, 37% of them had completely replaced their cigarettes and switched to the blu vaping products.

"Our data show that it is possible to facilitate significant behavioural change on the part of smokers as a result of providing them with access to high quality e-cigarette products, at least for a short period of time," said Professor Neil McKeganey, Director of Centre for Substance Use Research, who conducted the study.

The 72 adult smokers were given access to the blu PRO open system e-cigarette and a range of commercially available blu flavours and nicotine strengths through the duration of the study.

After 90 days the researchers found:

36.5% switched to vaping completely;

Reduction in daily smoking from 88.7% of participants at baseline to 17.5%;

Reduction in cigarettes per day from an average of 14.38 to an average of 3.19 per day;

Decrease in the average number of days per month that participants smoked, from 27.87/30 at baseline to 9.22/30 days after 90-days.

Non-tobacco flavour e-liquids were preferred by the majority of participants

The number of smokers who switched to vaping completely increased from baseline to day-30 and continued to rise throughout the study duration (90 days). The finding suggests that the use of vaping products may have additional benefits with longer use - i.e. a proportion of smokers completely switched within the first month of use, but a larger proportion needed more than 2 months to make the switch and gradually switch over a longer period.

"All participants found the flavours used were important in helping them to switch or cut down and 92.1% believed that the blu PRO had helped them to cut down or replace smoking completely at 90 days," said Professor McKeganey.

"In contrast to these impressive results, licensed nicotine replacement therapies have been shown to be substantially less satisfying to smokers as evidenced by their modest efficacy, in some cases less than 15% smoking abstinence after 3 months use*" said Dr Grant O'Connell, Corporate Affairs Manager, Fontem Ventures.

"The 40% of UK smokers who have not even tried an e-cigarette should be encouraged to try products such as blu as an alternative to smoking. It is also clear from the data that vapers who continue to smoke, termed dual users, are undergoing a longer-term transition from smoking to non-smoking, moving through different stages of use that are not evident in snapshot surveys," said Dr O'Connell.

TORONTO, September 6, 2018 - Foods high in unsaturated fats may protect against cardiovascular disease, and new research published today in Nature Communications has uncovered why.

Apolipoprotein A-IV, known as ApoA-IV, is a plasma protein. Levels of ApoA-IV increase after the digestion of foods, particularly foods high in unsaturated fats, such as olive oil. Higher levels of ApoA-IV in the blood have been reported to be associated with lower rates of cardiovascular disease.

New research from the Keenan Research Centre for Biomedical Science (KRCBS) of St. Michael's Hospital demonstrates that ApoA-IV is an inhibitory factor for platelets, which are small blood cells that play a key role in multiple diseases, particularly in bleeding and cardiovascular diseases.

These new findings suggest that ApoA-IV is a blocker of platelet surface glycoproteins GPIIbIIIa (also named integrin αIIβ3). Integrin αIIβ3 is a platelet receptor that is necessary for platelets to clump together in the blood (called platelet aggregation). Platelet aggregation can cause vessel occlusion that blocks blood flow, leading to thrombosis, which is the most common cause of mortality and morbidity worldwide.

"Platelet aggregation can save lives, because it can stop bleeding in damaged vessels," said Dr. Heyu Ni, Platform Director for Hematology, Cancer and Immunological Diseases at the KRCBS, who is the principal investigator of this study. "But we usually don't want platelets to block blood flow in the vessels. This is thrombosis, and if vessel occlusion occurs in the heart or brain, it can cause heart attack, stroke or death."

Platelets bind together with a series of connectors. For one platelet to bond to another, the platelet receptor integrin αIIβ3 first binds to fibrinogen - an abundant protein that bridges platelets in blood - and fibrinogen molecules then bind another integrin αIIβ3 on a second platelet. Then fibrinogen and likely also other proteins allow many platelets to bind one another, leading to platelet aggregation.

Examining both lab models and humans, Dr. Ni, who is also a scientist at Canadian Blood Services Centre for Innovation, and his team have shown that ApoA-IV can link to the integrin αIIβ3 and block fibrinogen binding, decreasing platelet aggregation in a vessel. The ApoA-IV protein can also change its shape to accommodate increased blood flow, and become more effective to protect vessels from complete blockage.

"This is the first study to link ApoA-IV with platelets and thrombosis," Dr. Ni said. "With this work, we have also explained why higher levels of ApoA-IV can slow down plaque build-up in blood vessels, known as atherosclerosis, because this process is also related to platelet function."

The researchers also examined ApoA-IV's interaction with food. After every meal, platelets are stimulated, which makes it easier for them to bond together or bond to white blood cells. ApoA-IV increases in circulating blood almost immediately after meals containing unsaturated fats and decreases platelet hyperactivity and bonding, thus reducing the inflammation after meals and the risk of heart attack and stroke.

The study also found that ApoA-IV has its own circadian rhythm. It is most active overnight and least active in the morning.

"Mother Nature wants us to sleep well," Dr. Ni said. "So we are protected by this protein while we sleep, and most likely to experience a cardiovascular event after waking up in the morning."

Dr. Ni and his team are excited about these findings because they show that foods with high unsaturated fats, along with appropriate sleep patterns, create the perfect combination for the protein ApoA-IV to play a positive role in reducing the chances of cardiovascular disease in the form of atherosclerosis, heart attack, or stroke.

This new knowledge has many potential applications, Dr. Ni explained. Future studies will focus on better understanding this protein and how to harness its protective potential to build therapies targeted at cardiovascular disease and other diseases that arise from platelet activation and aggregation.

CHICAGO --- Many overweight and obese women gain too much weight during pregnancy, further ratcheting up their already-increased risk of serious complications for themselves and their babies.

A new group of trials funded by the National Institutes of Health (NIH) showed that pregnant women can safely limit their weight gain with diet and exercise interventions. It is the largest set of trials in the U.S. to target pregnancy weight gain of overweight and obese women. The trials included diverse socioeconomic groups, which means the findings are generalizable to a large population.

"This is an important study because it affirms that women can change behaviors to control the amount of weight gained in pregnancy," said lead author Dr. Alan Peaceman, chief of maternal fetal medicine at Northwestern University Feinberg School of Medicine and a Northwestern Medicine high-risk obstetrician.

However, the reduced weight gain -- about four pounds per woman -- did not result in fewer obstetrical complications, including cesarean sections, diabetes, hypertension, and preeclampsia, or change the average birth weight of the baby.

"We think that by the time these women are already in the second trimester, it may already be late to change important outcomes," Peaceman said. "To lower the risk of obstetrical complications, they may have to start changing their lifestyle before or immediately after they conceive."

Investigators are hopeful that there will be longer-term benefits of the interventions in the infants, such as less childhood obesity or fewer metabolic abnormalities such as childhood diabetes.

The study was published Sept. 6 in the journal Obesity.

Seven teams of investigators recruited 1,150 participants for the LIFE-Mom trials (579 women had the lifestyle intervention, 571 had standard care), which ran from the second trimester to birth. Each trial offered a varied lifestyle intervention, but all aimed to improve diet quality and reduce calories, increase physical activity and incorporate behavior strategies such as self-monitoring.

Overweight and obese women are "hard nut to crack"

Overweight and obese women are a critical group to target, because they have higher rates of excess pregnancy weight gain and of retaining that weight postpartum. They also are more likely to have children who are obese. The majority of U.S. women of reproductive age are overweight or obese.

About 62 percent of the women in the intervention groups, versus 75 percent in the control groups, exceeded the National Academy of Medicine recommendations for pregnancy weight gain. The recommendation is overweight women limit their pregnancy weight gain to 15 to 25 pounds and obese women to 11 to 20 pounds, compared to 25 to 35 pounds for non-overweight women.

The fact that so many women in the intervention groups still exceeded the recommended weight gain shows the challenges of encouraging pregnant women to adhere to recommended diet and activity levels at a time when overeating and reluctance to exercise tend to increase, Peaceman said.

"It's a very hard nut to crack," he said.

A seesaw history of pregnancy weight gain

The advice doctors gave women about pregnancy weight gain has varied widely from decade to decade. In the 1950s, doctors often instructed their patients not to gain more than 15 pounds, Peaceman said.

By the late 1970s and early 1980s, mothers weren't gaining enough weight and were having small babies, which could lead to developmental problems in childhood. Then doctors started encouraging women to gain more weight.

"Doctors essentially told them that they could eat for two," Peaceman said.

"Then women started gaining excessively, but it wasn't thought to be a medical issue, just a cosmetic one," Peaceman said. "The attitude was, 'there's more weight for you to lose when you're done, but that is not a major medical concern'."

In the early 2000s, physicians started noticing that excessive pregnancy weight gain was associated with certain pregnancy complications: higher incidence of high blood pressure, gestational diabetes and cesarean sections.

"Then we started seeing more worrisome things," Peaceman said. "Excess maternal weight gain was not just associated with bigger babies, but those babies ended up with an increased risk of obesity and childhood diabetes."

A few researchers began investigating whether they could help women avoid excess weight gain during pregnancy. Trials testing different strategies for limiting pregnancy weight gain in overweight and obese women had mixed results, in part due to different populations studied and the lack of standardized clinical outcome measures.

"That's why NIH recognized the need to do this study in diverse populations and with standardized clinical outcome measures," Peaceman said. "It provides more reliable evidence."

Montreal, September 6, 2018 - Several new medicines have been found to be more effective than traditional ones used to treat multidrug-resistant tuberculosis (MDR-TB), according to a new international collaborative study led by Dr. Dick Menzies, senior scientist at the Research Institute of the McGill University Health Centre (RI-MUHC) in Montreal. These findings precipitated a complete overhaul of worldwide TB treatment guidelines, with the results of this work published today in the British medical journal The Lancet.

Approximately 600,000 cases of MDR-TB emerge each year, claiming 240,000 lives. Diagnosis and treatment remains a major challenge with only one in four affected patients being diagnosed and even fewer being treated successfully. Present treatment practices of MDR-TB employ expensive, antiquated drugs that lead to toxic side effects such as constant nausea, hearing loss and renal failure.

Dr. Menzies, who is also a respirologist at the MUHC, and his colleagues combined the data of over 12,000 patients suffering with MDR-TB from 50 studies conducted in 25 countries. By compiling such a large amount of data, researchers were able to determine that new TB drugs such as bedaquiline, linezolid, and the later generation fluoroquinolones achieve excellent results in the treatment of MDR-TB, demonstrating consistently better cure rates and reduced mortality compared to currently used treatments. These new drugs were also effective in treating XDR-TB (extensively drug-resistant TB). In addition, the study showed that daily injections for treating MDR-TB may no longer be necessary (except in the most serious of cases).

The World Health Organization (WHO) has already responded to this study's findings by announcing landmark changes in line with this MDR-TB regimen and, also, positioning fully oral regimens over injectable agents.

"The guidelines committee simply erased the old treatment recommendations and started over. They gave the treatment guidelines a complete make-over," says Dr. Menzies, who is a senior scientist from the Translational Research in Respiratory Diseases Program of the RI-MUHC and a professor of Medicine, and of Epidemiology and Biostatistics at McGill University.

A committee responsible for making recommendations about treatment of MDR-TB with representatives of the American Thoracic Society (ATS), Centres for Disease Control and Prevention (CDC), European Respiratory Society (ERS), and Infectious Disease Society of America (IDSA) have also considered this new information.

"Although these guidelines are not yet finalized, I believe this committee will make similar wholesale changes to the way MDR-TB is treated. Given that each of these new drugs may increase cure rates by as much as 10 per cent, we hope that the new combinations will result in cure rates of up to 90 per cent - which would be extraordinary," says Dr. Menzies, who just last month released a game-changing study on Latent TB treatment in the New England Journal of Medicine.

"The results confirm what TB clinicians around the world are seeing with their own eyes," commented Dr. Paul Farmer of the Department of Global Health and Social Medicine at Harvard University. "It's our hope that after 20 years of recommending these toxic regimens (...) we can finally turn to new and safer therapies based on demonstrably safer and better tolerated drugs."

Tuberculosis is among the top 10 causes of worldwide deaths and the leading global infectious disease killer.

September 5, 2018 - Addictions nursing specialists have a unique role to play in caring for patients, families, and communities affected by the crisis. A series of original research and expert commentaries provide the nursing specialist's perspective on the opioid crisis, appearing in the July/September special issue of Journal of Addictions Nursing (JAN), the official journal of the International Nurses Society on Addictions (IntNSA). The journal is published in the Lippincott portfolio by Wolters Kluwer.

"The opioid crisis is at the forefront of the US and global drug use problem conversation," writes JAN Editor-in-Chief Christine Vourakis, PhD, RN, FIAAN, FAAN, in an introductory editorial. "The Journal of Addictions Nursing is adding its contribution to the literature to offer a nursing perspective in addressing this international scourge."

Nursing Research and Viewpoints on the Opioid Crisis

The special issue presents seven original research papers understanding and addressing the needs of people with opioid abuse and opioid abuse disorder. The papers were selected by two eminent clinicians and educators who served as Guest Editors of the special issue: Ann M. Mitchell, PhD, RN, AHN-BC, FIAAN, FAAN, of University of Pittsburgh and Diane Snow, PhD, APRN, BC, PMHNP-BC, FAANP, FIAAN, of University of Texas, Arlington.

In a Guest Editorial, Dr. Mitchell introduces the seven studies - drawing attention to the "numerous programs and treatment options that are available to impact the overdose and mortality rates among persons who use opioids." The research topics include:

Unique insights into the unmet social support needs of Iranian women undergoing methadone maintenance therapy for OUD.
Integrating information on medication-assisted treatment and other evidence-based therapies for OUD into the graduate nursing curriculum
A review of evidence showing the effectiveness of the "rescue" medication naloxone to prevent fatal overdose among people who use opioids
A program to educate emergency department personnel about their state's prescription drug monitoring program, including its impact on opioid prescribing rates
The benefits of screening for adverse childhood experiences among individuals with substance abuse disorders enrolled in a recovery program
Evaluation of an overdose-prevention program, including prescribing of naloxone, for homeless adults who use opioids
An educational intervention on opioid overdose and naloxone distribution to primary care providers at a Veterans Administration clinic

For the special issue, JAN's regular columns turn their focus to the opioid crisis. The columnists discuss the prevalent "syndemics" of OUD interacting with other conditions, specifically HIV infection and suicide; the importance of medication-assisted treatment as part of the overall approach to treatment for OUD; efforts to overcome barriers to accessing care for OUD, particularly the stigma attached to this condition; and the role of the behavioral resource nurse in helping individuals dealing with medical conditions as well as substance use withdrawal.

In another Guest Editorial, Dr. Snow shares a set of clinical "pearls" to improve outcomes for the patient using opioids. Her tips include assessing risk factors for OUD, managing the psychiatric disorders that often accompany OUD, educating patients and families about the effectiveness of medication-assisted treatment, and offering ongoing support and encouragement to promote safety. Dr. Snow concludes, "We each bear a responsibility to take action to address opioid problems wherever we work, wherever we have influence."

The Editors hope their special issue will provide nurses and other health professionals with knowledge from several sources to inform their evidence-based practice in caring for individuals affected by the opioid crisis. Dr Snow adds: "I encourage nurses and advanced practice nurses to seek certification in addictions nursing as a certified addiction registered nurse [CARN] or certified addiction registered nurse-advanced practice [CARN-AP]." For more information, visit http://www.intnsa.org

Click here to read the entire issue on the opioid crisis.

Of the 8.6 million deaths from conditions treatable by health care, poor-quality care is responsible for an estimated 5 million deaths per year - more than deaths due to insufficient access to care (3.6 million)

Global efforts to expand access to care through Universal Health Coverage will be wasted if health system quality does not improve

An estimated 5 million deaths per year in low and middle income countries (LMICs) are the result of poor quality care, with a further 3.6 million the result of insufficient access to care, according to the first study to quantify the burden of poor quality health systems worldwide.

While many LMICs have made significant progress in improving access to care, a new reality is at hand: poor quality care in the health system is now responsible for a greater number of deaths than insufficient access to care. The total number of deaths from poor-quality care per year is estimated to be five times higher than annual global deaths from HIV/AIDS (1 million), and over three times more than deaths from diabetes (1.4 million).

The findings come from a new analysis published in The Lancet, as part of The Lancet Global Health Commission on High Quality Health Systems - a two-year project bringing together 30 academics, policy-makers and health systems experts from 18 countries who examined how to measure and improve health system quality worldwide.

"Quality care should not be the purview of the elite, or an aspiration for some distant future; it should be the DNA of all health systems," said Commission Chair, Dr. Margaret E Kruk, of Harvard T. H. Chan School of Public Health, Boston (USA) [1]. "The human right to health is meaningless without good quality care. High quality health systems put people first. They generate health, earn the public's trust, and can adapt when health needs change. Countries will know they are on the way towards high-quality, accountable health systems when health workers and policymakers choose to receive health care in their own public institutions." [1]

The epidemic of poor-quality care

The over 8 million excess deaths due to poor quality health systems lead to economic welfare losses of US$ 6 trillion in 2015 alone. The Commission found systematic deficits in quality of care in multiple countries, across a range of health conditions and in both primary and hospital care. These include:

Approximately 1 million deaths from neonatal conditions and tuberculosis occurred in people who used the health system, but received poor care.

Poor-quality is a major driver of deaths amenable to health care across all conditions in LMICs, including 84% of cardiovascular deaths, 81% of vaccine preventable diseases, 61% of neonatal conditions and half of maternal, road injury, tuberculosis, HIV and other infectious disease deaths.

Insufficient access to care was a proportionally greater contributor to deaths from cancer (89%), mental and neurological conditions (85%), and chronic respiratory conditions (76%), highlighting the need to increase access to care for these conditions alongside improving quality.

Data from over 81000 consultations in 18 countries found that, on average, mothers and children receive less than half of the recommended clinical actions in a typical visit, including failures to do postpartum check-ups, incorrect management of diarrhoea or tuberculosis, and failures to monitor blood pressure during labour (see Commission figures 2, 3 & 4).

A third (34%) of people in LMICs report poor user experience, citing lack of respect, long wait times, and short consultations. Similarly, confidence and trust in health systems are low. For instance, in India, half of households report bypassing their nearby public facility, with 80% citing at least one quality concern (see Commission figure 8).

Poor-quality care is more common among the vulnerable in society. The wealthiest women attending antenatal care are four times more likely to report blood pressure measurements, and urine and blood tests compared to the poorest women; adolescent mothers are less likely to receive evidence-based care; and children from wealthier families are more likely to receive antibiotics. People with stigmatised health conditions, such as HIV/AIDS, mental health and substance abuse disorders, as well as other vulnerable groups such as refugees, prisoners and migrants are less likely to receive high quality care.

In India, an estimated 1.6 million deaths per year were due to poor quality care (and a further 838,000 deaths due to insufficient access to care); in China 630,000 deaths per year were due to poor quality care (and 653,000 deaths due to poor access); in Brazil, 153,000 deaths per year were due to poor quality care (and 51,000 due to insufficient access). In Nigeria 123,000 deaths per year were due to poor quality care, and 253,000 due to insufficient access [Country data provided in the Appendix]. These are conservative figures after subtracting cases of disease that should have been prevented by strong public health measures.
"The impact of poor quality care goes well beyond mortality, but can lead to unnecessary suffering, persistent symptoms, loss of function, and a lack of trust in the health system. Other side effects are wasted resources and catastrophic health expenditures. Given our findings, it is not surprising that only one quarter of people in low and middle income countries believe that their health systems work well," adds Dr. Kruk [1].

The right to high quality care

The Commission proposes several ways to address health system quality, starting with public accountability for and transparency on health system performance.

The Commission found that many current improvement approaches have limited effectiveness. Additionally, commonly used health system metrics such as availability of medicines, equipment or the proportion of births with skilled attendants do not reflect quality of care and might lead to false complacency about progress. The Commission calls for fewer, but better measures of health systems quality, and proposes a dashboard of metrics that should be implemented by counties by 2021 to enable transparent measurement and reporting of quality care.

"The vast epidemic of low quality care suggests there is no quick fix, and policy makers must commit to reforming the foundations of health care systems. This includes adopting a clear quality strategy, organizing services to maximize outcomes not access alone, modernizing health worker education, and enlisting the public in demanding better quality care. For too long, the global health discourse has been focused on improving access to care, without sufficient emphasis on high quality care. Providing health services without guaranteeing a minimum level of quality is ineffective, wasteful and unethical," says Dr. Muhammad Pate, co-Chair of the Commission and Chief Executive of Big Win Philantropy and former Minister of State for Health in Nigeria [1].

In a linked Comment, Dr. Tedros Adhanom Ghebreyesus, Director General of WHO, adds: "Quality is not a given. It takes vision, planning, investment, compassion, meticulous execution, and rigorous monitoring, from the national level to the smallest, remotest clinic.... The strength of a country's core capacities under the International Health Regulations depends on the quality of its health services. The same nurse who vaccinates children and cares for new mothers will also need to detect an unusual communicable disease. Similarly, people and communities are at the heart of quality health service delivery. We cannot talk about quality without placing them at the centre. When people are actively engaged in their own health and care, they suffer fewer complications and enjoy better health and wellbeing."

Writing in support of the findings and recommendations from the Commission, 19 leading global health organisations [2] including the World Bank's Health, Nutrition, and Population Department, Asian Development Bank, Global Fund to Fight AIDS, Tuberculosis and Malaria, UNICEF, as well as the Ministries of Health of Argentina, Japan, Malawi, Indonesia, and South Africa, have signed the Bellagio Declaration on High Quality Health Systems, calling for action and state: "High quality health systems are at the heart of global equity. Quality care should not be a privilege for a lucky few, in a few facilities, in a few countries. Health systems must effectively protect, treat and respect all people, especially the vulnerable. As countries work to achieve universal health coverage let us use this moment to ignite a movement for high quality health systems."

AURORA, Colo. (September 5, 2018) - Adolescents under the age of 18 seeking abortions without a parent's consent often undergo a series of humiliating, burdensome and unpredictable hurdles as they try to navigate the legal system, according to a new study led by Kate Coleman-Minahan of the University of Colorado College of Nursing.

As part of the Texas Policy Evaluation Project, Coleman-Minahan, PhD, RN and other researchers investigated the judicial bypass experience by which adolescents seek legal permission to obtain an abortion without parental consent.

The study was published online today in the Journal of Adolescent Health.

Currently, 37 states require parental involvement in obtaining an abortion. This study focused specifically on Texas.

"This is the first study to describe adolescents' experiences with a judicial bypass," said Coleman-Minahan, assistant professor at the CU College of Nursing and lead author of the study. "We found that the bypass process functions as a form of punishment for adolescents."

The researchers conducted interviews with 20 adolescents between the ages of 16-19 about their experiences trying to obtain bypass. Those interviewed were 16-17 years old at the time they went to court. Many had experienced family trauma, adverse childhood experiences including household substance abuse, or a general fear for their own safety if they told their parents about their decision to seek an abortion.

Once they began the bypass process, they were confronted with more obstacles. Just arranging transportation to the courthouse was sometimes difficult. When they got inside, they faced an often unpredictable process. One young woman spoke of being intimidated by the criminal defendants sitting in the room. Judges, on occasion, would ask for a detailed sexual history which she had to explain within earshot of multiple court staff including a court reporter who records the hearing.

Each adolescent was issued a court-appointed guardian-ad-litem (GAL), ordered to act in her best interest. In four cases, the GAL appointed by the judge was a pastor or deacon at a church. One respondent recalled her GAL "telling me it's never the right option to have an abortion." This GAL also brought staff from an adoption agency to court with her, breaching the young woman's anonymity and exposing her to more judgment, the study said.

The researchers found that several judges didn't hide their personal disapproval of the adolescent's decision to seek an abortion. Sometimes they denied the bypass request altogether.

"Some judges and GALs based their decision or treatment of adolescents on their own personal opinion of abortion," Coleman-Minahan said. "Multiple participants cried during the interview when describing the hearing, saying they still think about it, even months later."

The process, researchers said, seemed like punishment itself, for having sex, getting pregnant and having wanted an abortion.

"Proponents of parental involvement and bypass laws claim they protect adolescents from alleged negative emotional consequences of abortion, yet our results suggest the bypass process itself causes emotional harm through unpredictability, humiliation and shame," the study said.

According to Coleman-Minahan, the fact that this is happening in Texas means it's probably happening in states with similar laws as well. Colorado requires parental notification and also has an option for a judicial bypass.

She said all of these findings should be weighed when considering forced parental involvement and judicial bypass policies. States, she said, should consider the real-life consequences of policies that are purportedly created to protect adolescents.

DALLAS, September 5, 2018 -- Firefighters who died from cardiac arrest were much more likely than those who died of other causes to show signs of both atherosclerotic and hypertensive heart disease at autopsy, according to new research in Journal of the American Heart Association, the Open Access Journal of the American Heart Association/American Stroke Association.

Among firefighters, more job-related deaths stem from cardiac arrest than from any other cause. To understand which heart diseases affect firefighters who die of cardiac arrest, this study looked at autopsy reports for firefighters who had died in the line of duty. Results showed that the most common diseases were narrowed arteries, or coronary artery disease, and structural abnormalities. These abnormalities included an enlarged heart (cardiomegaly) and increased wall thickness (hypertrophy) of the heart's primary chamber for pumping blood, or left ventricle.

"Firefighters face many dangers, but the greatest risk is from underlying cardiovascular disease in combination with the physiological strain that the work places on the firefighter," said study lead author Denise L. Smith, Ph.D., Tisch Distinguished Professor and director of the First Responder Health and Safety Laboratory at Skidmore College in Saratoga Springs, New York. "Medical screening is necessary to establish that a firefighter is healthy enough to do this strenuous work."

In terms of specific risks, narrowing of the arteries, enlarged heart and prior heart attack all were all independently associated with a greatly increased likelihood of death from cardiac arrest than firefighters who died of other causes. Similarly, firefighters who had a prior heart attack were 6 times more likely to have a duty-related death. an enlarged heart or a prior heart attack.

The researchers looked at autopsy records for U.S. male firefighters who died on duty between 1999 and 2014. Of 627 total deaths, 276 resulted from cardiac arrest and 351 from trauma. At the time of death, the firefighters were between 18 and 65 years old.

In the United States, approximately 1 in 7 people will die of sudden cardiac arrest. The life-threatening condition occurs when the heart's electrical system stops working properly. Symptoms include unresponsiveness and gasping for air or not breathing. Immediate medical treatment is critical, including CPR and calling 9-1-1.

Cardiac arrest differs from a heart attack, which occurs when a blockage prevents blood flow to the heart, although heart attack and other heart conditions can cause cardiac arrest. Since cardiac arrest often is the first sign of underlying heart disease, screening and treatment for common heart diseases are critical.

"Historically, screening has focused more on risk factors for coronary artery disease," Smith said. "While this screening remains essential, it is important that clinicians also consider testing to identify an enlarged heart and increased wall thickness."

Several limitations could have affected the study's results. Among these limitations were differences in autopsy descriptions of heart disease, the use of a cut-off weight for an enlarged heart, and lack of information about other risk factors such as smoking and high blood pressure.

To control risk factors, the American Heart Association recommends lifestyle changes known as Life's Simple 7®: manage blood pressure, control cholesterol, reduce blood sugar, get active, eat better, lose weight and stop smoking.