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Highlights

The expression of a gene called CREB in certain neurons may function as a switch to regulate feelings of fear and its extinction.

Targeting this gene may provide new information and treatments for fear-based psychiatric conditions.

Fear and fear extinction learning (the gradual reduction of fear by repeated exposure to the feared object) are adaptive processes caused by molecular changes in specific brain circuits, and they're perturbed in conditions such as anxiety and post-traumatic stress disorder. A new study by investigators at McLean Hospital and Massachusetts General Hospital reveals that the expression of a particular gene may function as a switch to regulate feelings of fear and its extinction. The findings point to a potential new target for diagnosing, treating, and preventing fear-related psychiatric illnesses.

The research, which is published in Nature Communications, focuses on neurons in the central amygdala that produce a corticotropin-releasing hormone (Crh) and are involved in the brain's response to threats. The scientists examined how different gene pathways are activated within Crh neurons after the expression or extinction of fear.

"This precise analysis utilized a new cell-type-specific technology called translating ribosome affinity purification, or TRAP, to identify gene expression only within the Crh amygdala cells," said co-senior author Nikolaos P. Daskalakis, MD, PhD, who is the director of the Neurogenomics and Translational Bioinformatics Laboratory at McLean Hospital. "The results showed that diverse gene networks are activated or inhibited by fear versus extinction learning."

Additional analyses demonstrated that fear extinction learning requires that Crh neurons reduce their expression of a regulatory gene named CREB, which codes for a protein called cAMP response-element binding protein. Indeed, overexpression of CREB in Crh neurons in mice increased their fear response.

"CREB is well known to be involved in learning and memory, and these data suggest that it may act as a molecular switch that regulates expression of fear and its extinction," said co-senior author Kerry J. Ressler, MD, PhD, McLean's chief scientific officer, McLean's chief of the Center of Excellence in Depression and Anxiety Disorders, and co-director of the Silvio O. Conte Center for Stress Peptide Advanced Research, Education & Dissemination (SPARED) at McLean Hospital.

Targeting CREB expression in Crh neurons in the brain's amygdala may provide a better understanding of the mechanisms behind fear-based psychiatric illnesses and represent a promising treatment strategy.

"Fear is one of the most basic emotions we all experience in response to trauma--and also one of the most complex to study," says Magali Haas, MD, PhD, CEO and president of Cohen Veterans Bioscience, the nonprofit biotech research organization fast-tracking diagnostics and therapeutics for trauma-related and other brain disorders. "We are proud to support this latest research into how animal models' brains process fear, which could provide important parallels in humans and lead to new ways to diagnose or treat disorders such as PTSD."

ST. LOUIS - Research from Saint Louis University finds that high fat or "ketogenic" diets could completely prevent, or even reverse heart failure caused by a metabolic process.

The research team, led by Kyle S. McCommis, Ph.D., assistant professor in Biochemistry and Molecular Biology at SLU, looked at a metabolic process that seems to be turned down in failing human hearts.

In an animal model, drastic heart failure in mice was bypassed by switching to high fat or "ketogenic" diets, which could completely prevent, or even reverse the heart failure.

"Thus, these studies suggest that consumption of higher fat and lower carbohydrate diets may be a nutritional therapeutic intervention to treat heart failure," McCommis said.

The findings, "Nutritional Modulation of Heart Failure in Mitochondrial Pyruvate Carrier-Deficient Mice" were published online Oct. 26 in Nature Metabolism. This research, which was initiated during McCommis' postdoctoral and junior faculty positions at Washington University School of Medicine, then was completed at Saint Louis University School of Medicine.

The heart's myocardium requires vast amounts of chemical energy stored in nutrients to fuel cardiac contraction. To maintain this high metabolic capacity, the heart is flexible and can adapt to altered metabolic fuel supplies during diverse developmental, nutritional, or physiologic conditions. Impaired flexibility, however, is associated with cardiac dysfunction in conditions including diabetes and heart failure.

The mitochondrial pyruvate carrier (MPC) complex, composed of MPC1 and MPC2, is required for pyruvate import into the mitochondria. This study demonstrates that MPC expression is decreased in failing human and mouse hearts, and that genetic deletion of the MPC in mice leads to cardiac remodeling and dysfunction.

"Interestingly, this heart failure can be prevented or even reversed by providing a high-fat, low carbohydrate "ketogenic" diet," McCommis said. "A 24-hour fast in mice, which is also "ketogenic" also provided significant improvement in heart remodeling."

Diets with higher fat content, but enough carbohydrates to limit ketosis also significantly improved heart failure in mice lacking cardiac MPC expression.

"Our study reveals a critical role for mitochondrial pyruvate utilization in cardiac function, and highlights the potential of dietary interventions to enhance cardiac fat metabolism to prevent or reverse cardiac dysfunction and remodeling in the setting of MPC-deficiency," McCommis said.
Ongoing studies will seek to uncover the importance of ketone body versus fate metabolism in this process of improved cardiac remodeling.

Take-aways

Diets enriched with higher levels of fat but enough carbohydrate and protein to limit ketosis were also able to significantly improve or even prevent cardiac remodeling and dysfunction in a mouse model.

These studies suggest that consumption of higher fat and lower carbohydrate diets may be a nutritional therapeutic intervention to treat heart failure.

Like ketogenic diet, prolonged fasting increases the cardiac reliance on fatty acid oxidation and reduces ketolytic flux despite increased cardiac ketone body delivery. The 24-hour fast reduced blood glucose levels, and strongly enhanced plasma concentrations of non-esterified fatty acids and ketone bodies.

Ketogenic diet consumption for only three weeks and the concordant increase in fat metabolism was associated with reverse remodeling of the failing hearts to essentially normal size.

These results suggest that ketogenic diets do not enhance cardiac ketone body metabolism, but rather stimulates fatty acid oxidation, which may be responsible for the improved cardiac remodeling and performance.

Findings from a new study conducted by a team of researchers at Dartmouth's Geisel School of Medicine and published in the journal Preventive Medicine Reports, show that involving pediatric practices in the promotion of private well water testing can influence parental compliance.

More than 43 million people living in primarily rural areas of the U.S. rely on private unregulated wells for their drinking water--including northern New England, where 40 to 50 percent of the population depend on private wells. This puts families, and particularly vulnerable populations such as children, potentially at risk for ingesting harmful contaminants such as arsenic.

Inorganic arsenic, a tasteless and odorless metalloid, is known to contaminate 10 to 20 percent of bedrock wells in New Hampshire. This raises a significant public health concern given arsenic is associated with a myriad of health conditions, including bladder and other cancers, and growing evidence indicates impacts on children's health and development.

Yet, efforts to encourage well owners to periodically test their private wells, an activity that has fallen on the public health system (which lacks regulatory authority), have only seen limited success. Previous surveys in New Hampshire, for example, have reported that nearly 60 percent of residents hadn't tested their wells in at least three years and 15 percent had never had their wells tested. Lack of awareness among the physician community about the health risks of well water, parental confusion about which chemicals to test for, poor lab access, and the cost of testing have all been cited as reasons for poor compliance.

"We wanted to see if we could move the needle on testing by integrating it into the clinical environment as part of routine pediatric preventive care," explains Carolyn Murray, MD, MPH, director of the Community Outreach and Translation Core for the Dartmouth Children's Environmental Health and Disease Prevention Research Center and lead author on the study.

The research team conducted the study with 11 pediatric and family medicine clinics that are members of the Dartmouth CO-OP Primary Care Practice-based Research Network--a 250-member voluntary research organization of primary care practitioners located in New Hampshire, Vermont, and Maine. Parents of children under 12 months of age who use a private well were eligible, and a total of 240 kits were dispensed (at no cost).

To determine the most effective practice approaches to achieve successful well water testing, two interventions (with two study arms each) were assessed. The first compared differences in testing completion when water analysis results were provided only to the parents versus being provided to both the parents and clinic. The second tested the effectiveness of doing after-visit parental reminders to complete testing versus not doing follow-up reminders.

"I'd say we were very successful at getting all of the practices on board with asking parents, 'Where do you get your drinking water?' and raising clinician awareness of the prevalence of arsenic in private wells," says Murray, who is also an assistant professor of medicine, community and family medicine, and of The Dartmouth Institute for Health Policy and Clinical Practice at the Geisel School of Medicine. "What we did learn was that there's a lot more complexity to people's testing behavior beyond just cost and beyond just the doctor saying, 'You should do this.'"

Well water testing completion rates ranged from 10 to 61 percent across the practices and study arms, with an average of 29 percent. The study arm with both parent and clinic access to results and a follow-up system of reminders for parents was more than twice as likely to achieve test completion than other study arms. But having clinicians (versus other staff) distribute the kits, irrespective of study arm, was the strongest predictor of testing completion overall.

"I think our main takeaway was that we can engage primary care practices in screening for drinking water source and promoting well water testing," says Murray. "But we need to get more creative in how we work with clinicians and care teams on this important health issue. There's definitely room for improvement, but we're off to a good start."

Margaret Karagas, PhD, director of the Dartmouth Children's Environmental Health and Disease Prevention Research Center and senior author on the study, agrees. "This was a great translational research opportunity, building on our close partnership with the Dartmouth CO-OP to test implementation strategies to reduce environmental threats to children's health and the health of their families."

A preliminary analysis of photon therapy treatment group 1 from the phase II NRG Oncology clinical trial NRG-BN001 indicates that there is no statistically significant overall survival (OS) or toxicity differences between dose-intensification radiation therapy (DI-RT) using intensity-modulated radiation therapy (IMRT) and standard-dose radiation therapy (SD-RT) with temozolomide treatments for patients with newly diagnosed glioblastoma (GBM). Although there were no differences between arms, results suggest that MGMT methylation and RPA are predictive of progression-free survival (PFS). The proton therapy treatment group 2 of this trial is ongoing. The preliminary results were presented at the virtual edition of the American Society for Radiation Oncology's (ASTRO) Annual Meeting in October 2020.

NRG-BN001 enrolled 229 eligible patients to be randomly assigned to receive either SD-RT or DI-IMRT. Patients were also stratified by RPA class and MGMT methylation status. Of the 229 trial participants, 58% were MGMT unmethylated and 75% were RPA class IV. Researchers were primarily studying OS rates between the two treatments; however, secondary objectives of the trial were to track PFS, treatment-related toxicity between arms, patient-reported symptom burden, and change to neurocognitive function.

Results demonstrated no significant difference in grade 3 or greater toxicity between the SD-RT and DI-IMRT treatments. The median OS rate for DI-IMRT was 18.7 months (95% CI: 16.0, 23.5) and 16.3 months for the SD-RT arm (95% CI: 13.9, 19.8). At 30 months, 30.4% of the patients on the DI-IMRT arm (95% CI: 21.8, 39.1) and 21.6% of the patients on the SD-RT arm (95% CI: 12.7, 30.6) were still living. Median PFS also exhibited no difference (HR=1.23, 95% CI: 0.93, 1.64, p=0.18).

While there was no difference in median OS between treatment arms, median OS was significantly shorter for MGMT unmethylated GBM (15.1 months, 95% CI: 13.9, 17.8) when compared to MGMT methylated GBM (28.3 months, 95% CI: 21.5, 38.3, p

"Although this first group of IMRT dose-intensification did not cross significance threshold for further testing in a phase III trial, it is important to note the predictive implications of MGMT methylation and RPA class with regards to progression-free and overall survival. Future research of treatment intensification should continue to account for these factors in this disease," stated Vinai Gondi, MD, the Director of Research at the Northwestern Medicine Chicago Proton Center, Co-director of the Brain Tumor Center at Northwestern Medicine Cancer Center, Warrenville, and lead author of the NRG-BN001 abstract.

The second group of this trial will be surveying DI-RT with proton therapy in place of IMRT. This group continues to accrue patients, and results will be announced at a future time.

"We look forward to the results that come from this study's second group involving dose-intensification using proton therapy. Proton therapy is hypothesized to further improve survival by preventing radiotherapy-related circulating lymphopenia, which has been shown to impact survival in this patient population," Gondi added.

BOSTON - A new study shows that Black individuals with extensive-stage small cell lung cancer are less likely to receive chemotherapy for their disease compared to white and other racial groups. Led by researchers at Boston Medical Center, the results indicate that individuals who are Black, elderly, uninsured, or have non-private health insurance and lower education levels, were less likely to be treated with chemotherapy for this type of lung cancer. Published in JTO Clinical and Research Reports, the official journal of the International Association for the Study of Lung Cancer, this study is one of the largest to investigate the racial and health disparities in treating patients with extensive-stage small cell lung cancer, and highlights the impact that race and insurance status have on cancer care in the U.S.

Given the tendency of this type of lung cancer to rapidly progress, current recommendations and practices favor starting treatment as soon as possible after a patient is diagnosed with extensive-stage small cell lung cancer (ES-SCLC). Analyzing the National Cancer Database (NCDB) between the years 2004 and 2016, researchers discovered that Black patients had lower odds of receiving chemotherapy compared to white patients, but had improved survival, with the median survival of 8.3 months compared to eight months. This is an unexpected finding given that the disease is highly sensitive to chemotherapy, and this treatment is the most important predictor of survival.

"Our study highlights the disparities that can exist in healthcare, and the impact that race and socioeconomic status can have on a patient's experience throughout their treatment," says Umit Tapan, MD, a thoracic oncologist at Boston Medical Center and the study's corresponding author.

In this large-scale analysis, racial and socioeconomic factors impacting systemic therapy delivery and survival in ES-SCLC were identified through a total of 82,592 ES-SCLC patients between 2004 and 2016, as identified through the NCDB. The analysis showed that chemotherapy was administered to 92.1 percent of patients. Insurance and income status played a large role in treatment and survival of patients. Black patients were more likely to be uninsured or have public health insurance compared to white and other race groups, and patients with non-private insurance or without insurance were less likely to receive chemotherapy treatment. Private insurance was associated with the highest survival of 9.2 months, followed by patients with Medicaid at 8.3 months. Lower income is associated with worse survival, which has been found for all lung cancer diagnoses.

"While our study looked specifically at patients with extensive-stage small cell lung cancer, our results further demonstrate the impact that socioeconomic status can have on the health of patients, whether it be access to treatment or their outcomes," said Tapan, also an assistant professor of medicine at Boston University School of Medicine. Another important point highlighted in the study shows that Black patients had higher odds of receiving chemotherapy between 2010 and 2016 compared to 2004-2009, which the authors suggest is a positive impact of the Patient Protection and Affordable Care Act (ACA) in 2010.

Further studies are needed to address the underlying reasons for lack of chemotherapy receipt in Black patients with ES-SCLC, and to guide the appropriate interventions to mitigate these disparities.

NEW YORK, NY (Oct. 26, 2020)--Cardiovascular disease is now the number one cause of maternal mortality in the United States, but a new study suggests that care from a multidisciplinary cardio-obstetrics team may improve pregnancy outcomes and reduce hospital readmission rates. The study was conducted by researchers from Columbia University Vagelos College of Physicians and Surgeons and NewYork-Presbyterian at a single center in northern Manhattan with an established cardio-obstetrics team.

It is estimated that cardiovascular disease complicates up to 4% of pregnancies in the United States. "We suspect that some percentage of cardiac disease in pregnant women may go unnoticed or undetected, so it's hard to say exactly how common these problems are among pregnant women," says study co-author Ersilia DeFilippis, MD, a postdoctoral clinical fellow in the Department of Medicine at Columbia University Vagelos College of Physicians and Surgeons. "Even in a normal pregnancy, women can experience shortness of breath or notice leg swelling. Therefore, even when cardiac disease may be present, these symptoms may be inadvertently minimized by women themselves or their providers."

The study reviewed data on 306 pregnant women with cardiovascular disease who were referred to the cardio-obstetrics team at NewYork-Presbyterian/Columbia University Irving Medical Center between 2010 and the end of 2019. The most common types of heart disease were arrhythmia, congenital heart disease, cardiomyopathy, and valvular disease. Other types of heart disease -- including coronary artery disease and high blood pressure, which are more common in older women -- were less prevalent among the study participants. Most women came from the surrounding community, which includes a large population of traditionally underserved minorities, and about 40% were obese.

Nearly half of the women in the study were at highest risk for cardiac complications during their pregnancy (based on a standardized assessment that includes 10 predictors of cardiac acuity).

Rates of preeclampsia were higher than in the general population, which is likely due to higher rates of obesity in the study group. Women with preexisting cardiovascular disease also have greater risk for preeclampsia.

Most of the infants were delivered at term, with few fetal complications. Less than 2% of the women were readmitted to the hospital within the first 30 days of discharge, most for symptoms of heart failure. (The national 30-day readmission rate among pregnant women in the general population is 3.6%.) Readmission rates remained low during the first year after delivery. One woman who had pulmonary hypertension and Eisenmenger syndrome, a high-risk condition, deteriorated following her pregnancy and died about three months after delivery.

"Despite the high cardiovascular risk in our study population, we found low rates of maternal and fetal complications and a low rate of hospital readmissions after delivery compared to previously published national rates," says Jennifer Haythe, MD, associate professor of medicine at Columbia University Vagelos College of Physicians and Surgeons, Cardiology Director of the cardio-obstetrics program at NewYork-Presbyterian/Columbia University Irving Medical Center, and senior author of the study.

"While cardiologists have been managing the care of pregnant women for decades, the notion of a dedicated cardio-obstetrics team is a recent development aimed at reducing maternal death rates due to cardiovascular disease," Haythe adds. "This study shows that programs like ours may help provide improved cardiovascular care to an otherwise underserved population, though more research is needed to evaluate the impact of these programs."

DALLAS, October 26, 2020 -- People with severe obesity (BMI >35) and a prior heart attack who undergo weight-reduction surgery may lower their risk of a second heart attack, major cardiovascular event, heart failure and death compared to people with similar medical histories who did not have weight-reduction surgery, according to new research published today in Circulation, the flagship journal of the American Heart Association.

"It is well known that obesity is associated with an increased risk for Type 2 diabetes and heart disease," said lead study author Erik Näslund, M.D., Ph.D., professor in the department of clinical sciences, Danderyd Hospital, Karolinska Institutet in Sweden. "It has also been shown that weight-reduction surgery can improve Type 2 diabetes and cardiovascular disease. What has yet to be proven is: if you have had a heart attack, can weight-reduction surgery reduce your risk of having another heart attack, which was the focus of our study."

In the study from Sweden, Näslund and colleagues measured the trends between weight-reduction surgery and subsequent heart attacks, stroke and death in people with severe obesity who had experienced a prior heart attack. The study linked information from two health registries--the Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART) registry and the nationwide Scandinavian Obesity Surgery Registry (SOReg).

Researchers compared data from 2005 to 2018 of 509 severely obese patients who had heart attacks to 509 severely obese patients who had heart attacks and then subsequently had either gastric bypass surgery or sleeve gastrectomy surgery (the two most common types of weight-reduction surgery) between 2007 and 2018. Each patient in the study who had weight-reduction surgery was matched to a patient who did not have surgery and with the same degree of obesity, (the average BMI of both groups was 40). The patients were also matched according to gender, age, health status and health history.

Patient data was gathered for a follow-up period of up to eight years (median of 4.6 years), and researchers statistically analyzed variables that may have affected risk for the patients who had heart attacks, strokes or died during the follow-up period.

Researchers found:

Weight-reduction surgery was associated with a lower risk of heart attack and a lower risk of new onset heart failure, yet there was no statistical difference in the risk of stroke between the surgery and non-surgery groups.

The patients who had weight-reduction surgery had half the risk of death compared to those who did not have surgery.

The rate of serious surgical complications was similar to that seen among weight-reduction surgery patients without prior heart attacks.

While patients' weight in the surgery group was markedly lower one year after surgery (median BMI was 29 after one year), researchers note that the weight loss alone was likely not the driving force in the association between surgery and decreased risk. Additional health changes at two years after surgery included:

A large number of surgery patients had significant improvements in sleep apnea (67% remission) as well as improvement in hypertension (22 % remission), cholesterol and triglyceride levels (29 % remission); and

more than half of the patients with Type 2 diabetes experienced clinical remission of the disease after the weight-reduction surgery.

The study authors did not have information about the socioeconomic status of patients, and there was no data on weight beyond the two-year follow-up mark for the group who had surgery, and no follow-up weight data for the non-surgery group. Additionally, within the surgery group, there was a substantially higher number of patients who had gastric bypass, thus, any difference in outcomes between gastric bypass patients and the patients who had the sleeve gastrectomy procedure could not be evaluated. Researchers were also unable to assess if the timing between each surgery group patient's heart attack and weight-reduction surgery was a key factor for complications. A randomized controlled trial is needed to confirm the results of this study.

Researchers at Karolinska Institutet and Danderyd Hospital in Sweden have studied the risk of additional myocardial infarctions and early death in severely obese patients who undergo metabolic surgery following a myocardial event. The registry study covering 1,018 individuals shows a lower risk of additional myocardial infarctions and improved survival that cannot be simply attributed to the loss of weight. The study is published in the journal Circulation.

According to the WHO and the Body Mass Index measurement it devised, there are currently two billion people who are overweight today, 650 million of whom are classified as obese, with a body mass index (BMI) greater than 30 kg/m2.

Severe obesity (in this study defined as BMI greater than 35 kg/m2) increases the risk of several health problems, including type 2 diabetes, hypertension, cardiovascular disease and cancer.

People who lose weight can improve their health and it has previously been shown that after metabolic surgery, diabetes and hypertensions go into a period of remission in which the symptoms disappear, at least temporarily.

In the current study, researchers at Karolinska Institutet, Orebro University and Uppsala University examined the risk of additional myocardial infarction and early death in people with severe obesity and a previous infarction who subsequently underwent metabolic surgery.

By cross-referencing the quality registries SOReg (Scandinavian Obesity Surgery Registry) and SWEDHEART (for people who have suffered myocardial infarction) between 1995 and 2018, the researchers were able to identify severely obese individuals who underwent a gastric bypass or gastric sleeve procedure as a treatment for their obesity after suffering a myocardial infarction.

A gastric bypass involves disconnecting much of the stomach and part of the small intestine; a gastric sleeve involves removing most of the stomach to leave a tube-like structure that leads food into the intestines.

The group of 509 individuals who underwent surgery was matched with people of the same gender, age and BMI, and who had suffered a myocardial infarction in the same year but not undergone metabolic surgery.

"We found that individuals operated on for their obesity were at a much lower risk of suffering another myocardial infarction, of death and of developing heart failure," says the study's first author Erik Naslund, professor at the Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet and consultant surgeon at Danderyd Hospital. "These data suggest that severely obese people who suffer a myocardial infarction should be offered metabolic surgery for their obesity as a secondary prevention."

According to the researchers, it is unlikely the weight loss is the only reason for the study's observed correlation between metabolic surgery and a lower risk of cardiopathic events, such as stroke, myocardial infarction or early death.

One theory is that metabolic surgery per se has a positive impact on cardiometabolic risk factors, which is to say physiological conditions that increase the risk of cardiovascular disease.

"Many of the patients who underwent metabolic surgery in this study had clinical remission of type 2 diabetes, hypertension and dyslipidemia (high blood lipids). An earlier study, Look AHEAD, demonstrated that long, intensive non-surgical lifestyle intervention in patients with type 2 diabetes resulted in weight loss of 6 per cent, but did not lower the risk of myocardial infarction."

Before the results of the study can become part of clinical praxis, more research is needed in which severely obese people who have suffered myocardial infarction are randomly assigned to either surgery or to regular post-infarction care.

DALLAS, Oct. 26, 2020 -- At a time when stroke is on the rise among young adults, nearly 30% of U.S. adults younger than age 45 do not know all five of the most common stroke symptoms, according to new research published today in Stroke, a journal of the American Stroke Association, a division of the American Heart Association.

Stroke is the No. 5 cause of death and a leading cause of disability in the United States. Each year, 10% to 15% of the nearly 795,000 people in the U.S. who have a stroke are young adults -- between ages 18 and 45. Recent studies suggest stroke incidence is declining in the general population, yet, stroke incidence and hospitalizations have increased by more than 40% in young adults in the past several decades.

"While the medical community has made significant improvements to reduce the severity and complications of strokes with early interventions, these efforts are of limited value if patients do not recognize stroke symptoms," said study author Khurram Nasir, M.D., M.P.H., M.Sc., chief of the division of cardiovascular prevention and wellness at Houston Methodist DeBakey Heart and Vascular Center in Houston, Texas. "Time is critical for treating stroke. The earlier people recognize symptoms, the better their chances are to reduce long-term disability from stroke."

To assess how well the U.S. population understands common stroke symptoms, Nasir and colleagues reviewed responses to the 2017 National Health Interview Survey. As part of the annual survey, adults are asked several questions about stroke including identifying five of the most common stroke symptoms, which in this survey were noted as:

Numbness of face/arm/leg;

Confusion/trouble speaking;

Difficulty walking/dizziness/loss of balance;

Trouble seeing in one/both eyes; and

Severe headache.

In a targeted subset of the full survey, researchers analyzed answers from 9,844 younger adults, under age 45, which statistically represents 107.2 million young adults in the U.S. population. Average age of the younger respondents was 31, half were women and 62.2% were non-Hispanic white.

The researchers found:

Almost one in three (28.9%) respondents were not aware of all five common stroke symptoms.

About 3% of respondents, representing nearly 3 million young adults, were not aware of any stroke symptom.

Hispanic adults and adults not born in the U.S. were about twice as likely to be unaware of any of the common stroke symptoms, compared to non-Hispanic White people and those born in the U.S.

Young adults with a high school diploma or lower education level were nearly three-times as likely to be unaware of any stroke symptom, compared to young adults with higher education levels,

Nasir said the high number of young adults who remain unaware of stroke symptoms is surprising, and along with continued social inequities, these are major concerns.

"With the growing risk of stroke among younger adults in the U.S., our study sheds light on particularly vulnerable individuals and communities that already experience a disproportionately greater burden of stroke and cardiovascular risk factors, as well as reduced access to health care services," he said. "We hope that highlighting the continued impact of current health disparities may advance focused public health strategies and educational initiatives to increase awareness of and appropriate response to stroke symptoms."

The researchers also found that nearly 3% of young adults surveyed would not contact emergency medical services if they did see someone experiencing perceived stroke symptoms. "That finding could be a matter of life and death," said Mitchell S. V. Elkind, M.D., M.S., FAHA, FAAN, president of the American Heart Association.

"With proper, timely medical attention, stroke is largely treatable. The faster you are treated, the more likely you are to minimize the long-term effects of a stroke and even prevent death," said Elkind, professor of neurology and epidemiology at Vagelos College of Physicians and Surgeons and attending neurologist at New York-Presbyterian/Columbia University Irving Medical Center in New York City. "Calling 9-1-1 is critical because trained EMS personnel can start the care protocol en route to the hospital and have specialized teams standing by, ready at the hospital to administer the most appropriate treatment immediately."

Elkind says the American Heart Association/American Stroke Association advocates the use of the letters in "F.A.S.T." to spot stroke signs and to know when to call 9-1-1:

Face drooping

Arm weakness

Speech slurred

Time to call 9-1-1

Nasir said F.A.S.T. is among a number of creative and community-engaged initiatives that have aimed to increase public recognition of common stroke symptoms, and he stresses an urgency to address contemporary health inequities head-on through such tailored and multidisciplinary public health approaches.

"Our results show that novel strategies are required at the population level to increase symptom awareness among young adults, where we have found a higher-risk population with substantial variations in symptom recognition," he said.

A possible limitation of the study is that those surveyed responded with a "yes" or "no" when asked if something was a common stroke symptom. This could lead to an overestimation of actual awareness rates, according to the authors.

Not all pregnant women are universally screened for hepatitis B virus (HBV) in Ontario, even though this screening is recommended, and the majority of those who test positive do not receive follow-up testing or interventions, leading to infections of newborns, found new research in CMAJ (Canadian Medical Association Journal).

An estimated 257 million people worldwide are chronically infected with HBV, which is a risk for cirrhosis of the liver and liver cancer.

The World Health Organization recommends that countries such as Canada provide a first vaccine against HBV in newborns at birth. However, only 3 provinces and territories vaccinate at birth, 5 vaccinate starting at 2 months of age, and 5 provinces, including Ontario, vaccinate schoolchildren in grades 6 and 7. Complete province and territory information can be found here https://www.canada.ca/en/public-health/services/provincial-territorial-immunization-information.html.

"One rationale for not vaccinating at birth is that universal prenatal screening and related interventions prevent transmission from mother to baby," explains Dr. Jordan Feld, a liver specialist at the Toronto Centre for Liver Disease, University Health Network, and the University of Toronto. "However, our study shows that screening is imperfect, and that children born in Canada are becoming infected with hepatitis B before getting vaccinated as teenagers. That is why we should reconsider our current vaccination strategy in Ontario."

To understand the uptake of prenatal HBV screening in Ontario and determine the number of HBV infections in children before adolescent vaccination in the province, researchers analyzed data from ICES, Public Health Ontario and Better Outcomes & Registry Network (BORN) Ontario between 2003 and 2013.

In children under 12 years of age, 139 Canadian-born children tested positive for HBV. This represents a minimum number of infections in Canadian-born children, because most children are never tested, and the infection has few or no symptoms early in life. These infections could have been prevented by vaccination at birth. Once the infection is established in a newborn, it is usually lifelong, requiring close follow-up, and puts people at risk of complications.

"Canadian guidelines recommend changes to provincial hepatitis B immunization strategies if women are not screened universally and/or children become infected. We have met this threshold, and a change is needed," explains Dr. Mia Biondi, a primary care nurse practitioner in the community, and researcher at the Toronto Centre for Liver Disease. "Infant hepatitis B vaccination could be seamlessly integrated into primary care in line with well-baby visits and other vaccinations. It's a simple solution."

The authors recommend that Ontario move to HBV vaccination at birth and improve existing systems to ensure that all women are screened for HBV during pregnancy. If the test is positive, they should receive follow-up to prevent spread and ensure they receive appropriate HPV care.

Highlights

Social determinants of health are associated with patient-reported outcomes in adults who are eligible to undergo kidney transplantation evaluations.

Results from the study will be presented online during ASN Kidney Week 2020 Reimagined October 19-October 25.

Washington, DC (October 25, 2020) -- Certain social determinants of health predict patient-reported outcomes in potential kidney transplant recipients, according to a study that will be presented online during ASN Kidney Week 2020 Reimagined October 19-October 25.

In the 955-participant study, patients' experience of discrimination in a medical setting, greater depressive symptoms, and a lower sense of mastery (or control over the forces that affect one's life) predicted worse physical, mental and kidney-related quality of life. Lower levels of patient-reported medical mistrust predicted greater patient satisfaction with clinical services.

"In our study, social determinants of health predicted patient-reported outcomes, suggesting that these factors are important for future research and intervention development," said lead author Samuel Swift (University of New Mexico, Albuquerque). "Transplant teams can use knowledge of how these key social determinants of health predict patient-reported outcomes to improve the experience of patients with kidney failure undergoing transplant evaluation."

Study: "Do Social Determinants of Health Predict Patient Reported Outcomes in Transplant-Eligible End-Stage Renal Disease Patients"

ASN Kidney Week 2020 Reimagined, the largest nephrology meeting of its kind, will provide a forum for more than 13,000 professionals to discuss the latest findings in kidney health research and engage in educational sessions related to advances in the care of patients with kidney and related disorders. Kidney Week 2020 Reimagined will take place October 19-October 25.

Indian and Pakistani women are diagnosed with breast cancer, including more aggressive forms of the disease, at a younger age, according to Rutgers researchers.

South Asians are the fastest-growing major ethnic group in the United States with breast cancer rates increasing within the population, but little is known about the disease in this socio-culturally unique population.

The study, published in the International Journal of Cancer, examined the characteristics of breast cancer in Indian- and Pakistani-American and non-Hispanic white women in the United States using data from the National Cancer Institute's Surveillance, Epidemiology and End Results Program. The researchers, who are part of the Rutgers School of Public Health and Rutgers Cancer Institute of New Jersey, reviewed incidence data among Indian and Pakistani women between 1990 and 2014. They also reviewed disease characteristics, treatment and survival data between 2000 and 2016 for 4,900 Indian and Pakistani women and 482,250 non-Hispanic white women with breast cancer.

They found that the occurrence of breast cancer in Indian and Pakistani women was lower than in non-Hispanic white women; however, the number of Indian and Pakistani women diagnosed with breast cancer increased over the years.

Indian and Pakistani women with breast cancer were more likely to be diagnosed at a younger age and at more advanced stages of the disease. In addition, they received more subcutaneous or total mastectomies than non-Hispanic white women. While the researchers found that Indian and Pakistani women were less likely to die of breast cancer than their non-Hispanic white counterparts, their health was tracked for a shorter time.

"Our results provide an insight into breast cancer in Indian and Pakistani women, suggesting several hypotheses to guide future scientific studies to better understand the risk factors influencing disease etiology and prognosis," said Jaya M. Satagopan, lead author and director of the Center for South Asian Quantitative Health and Education at the Rutgers School of Public Health.

Prior cancer research has shown that fewer Indian and Pakistani women participate in scientific studies and that several sociocultural factors may delay their seeking health care. Research also has shown poor mammogram screening rates in Indian and Pakistani women, which is linked to a lack of family support, lack of transportation, modesty, fear, beliefs that cancer is divine punishment for past deeds, having lived in the United States for less than 10 years, low English proficiency and a lack of faith in the health system.

"Our study indicated that there are important differences in this population that justify further studies to better understand biological, sociocultural, and system level factors such as interactions with the health system, affecting breast cancer screening patterns, diagnosis, risk and survival among South Asian women, given the paucity of literature on this topic," said Elisa V. Bandera, co-leader of the Cancer Prevention and Control Research Program at Rutgers Cancer Institute of New Jersey and professor at Rutgers Robert Wood Johnson Medical School, who is the study's senior author.

The study recommends identifying strategies to better engage Indian and Pakistani women in breast cancer studies and to improve interactions between health care providers and Indian and Pakistani women to identify sociocultural factors associated with screening decisions and health care use in this population.

"As the South Asian population in the United States -- and especially in New Jersey -- grows, it is imperative that we work to promote health equity in cancer prevention, screening, early diagnosis and treatment through community engagement and a team science approach," said Anita Kinney, director of the Center for Cancer Health Equity at Rutgers School of Public Health and Rutgers Cancer Institute of New Jersey and professor at the Rutgers School of Public Health, who is also one of the study's authors.

A novel agent that targets a mutated form of the KRAS gene - the most commonly altered oncogene in human cancers and one long considered "undruggable" - shrank tumors in most patients in a clinical trial with manageable side effects, researchers reported today at the 32nd EORTC-NCI-AACR Symposium on Molecular Targets and Therapeutic, which is taking place online.

The KRYSTAL-1 (NCT03785249) phase I/II trial tested the agent, adagrasib (MRTX849), in patients with non-small lung cancer (NSCLC), colorectal cancer, and other solid tumors such as pancreatic, endometrial, and ovarian cancer. At today's symposium, Pasi A. Jänne, MD, PhD, Director of the Lowe Center for Thoracic Oncology at Dana Farber Cancer Institute, reported that of 51 patients with NSCLC participating in the trial, 45% had an objective response, meaning their tumors shrank by 30% or more and did not grow or spread to other parts of the body. The disease control rate was 96%, meaning that 49 of the patients had a partial or complete response or stable disease.

Among the 14 patients in the phase I/Ib cohort who had been followed for a longer period of time (median time of 9.6 months), an objective response was seen in six (43%). Five of these six patients were still in ongoing treatment as of the cut-off date, with four of these six patients on the duration of treatment has lasted for more than 11 months.

Adagrasib targets a KRAS mutation called G12C, which is associated with a poor prognosis and lack of response to standard treatments. The mutation occurs in approximately 14% of lung adenocarcinomas, the most common subtype of NSCLC, 3-4% of colorectal cancers, and 2% of pancreatic cancers. This translates into well over 100,000 people each year worldwide.

Adagrasib works by irreversibly and selectively binding to KRAS G12C in its inactive state, blocking its ability to send cell-growth signals and leading to cancer cell death.

Until recently no KRAS inhibitor had moved beyond preclinical testing, but in 2018 adagrasib was among several KRAS inhibitors approved by the U.S. Food and Drug Administration (FDA) for study in clinical trials beginning in January 2019. All patients in the KRYSTAL-1 phase I/II trial had advanced cancer and had previously received standard treatment for their disease, including chemotherapy and immunotherapy.

As part of the trial, researchers analyzed the treatment-related adverse side effects in all 110 patients who participated in the phase I/Ib and II parts of the trial, including those with colorectal cancer and other solid tumors, as well as those with NSCLC. Side effects included nausea (54%), diarrhea (51%), vomiting (35%), fatigue (32%), and increased levels of an enzyme that indicates minor liver irritation (20%). The only serious adverse side effect to occur in more than one patient was low sodium in the blood, which occurred in two patients.

"KRAS G12C patients are a population for which there are no proven targeted therapies. Once chemotherapy or immune therapy fails in a patient, treatment options are limited," said Jänne. "The fact that we are seeing responses in 45% of patients with adagrasib is incredibly meaningful as it opens up the possibility of a new treatment option for this subset of lung cancer patients."

Results for 31 trial participants with colorectal cancer or other solid tumors were presented by Melissa L. Johnson, MD, associate director of the Lung Cancer Research Program and Drug Development at the Sarah Cannon Research Institute, Tennessee Oncology.

Of 18 patients with colorectal cancer who could be evaluated, three (17%) had a confirmed objective response and two of them continue to receive treatment. Disease control was seen in 17 of the patients (94%) and 12 of these patients continue to be treated, including ten of 18 patients on treatment for greater than four months.

Among the six patients with other solid tumors who could be evaluated, a partial response was confirmed in one patient each with endometrial cancer, pancreatic cancer, ovarian cancer, and cancer of the bile duct (cholangiocarcinoma). Two appendiceal cancer patients who were treated achieved stable disease. All six patients remain on the treatment.

Researchers are also looking at combining adagrasib with other targeted therapies, such as pembrolizumab for NSCLC, cetuximab for colon cancer, investigational SHP-2 inhibitor, TNO-155, in either NCSLC or colon cancer and afatinib for NSCLC.

New results from early clinical trials of a drug that targets a cancer-causing mutation in the KRAS gene have shown that it can shrink tumours and is well-tolerated by patients.

In two presentations on Sunday at the 32nd EORTC-NCI-AACR [1] Symposium on Molecular Targets and Cancer Therapeutics, which is taking place online, researchers involved in the KRYSTAL-1 phase I/II clinical trial said that adagrasib (MRTX849) showed clinical activity and manageable adverse side effects in patients with non-small cell lung cancer (NSCLC), colorectal cancer and other solid tumours such as pancreatic, endometrial and ovarian cancer.

Scientists have been trying to develop new drugs that target the KRAS mutation for decades as the gene is one of the most common mutations in cancer. Adagrasib targets a KRAS mutation called G12C; patients who have cancer with this mutation have a poor prognosis and the tumours are resistant to standard treatments. The KRAS G12C mutation occurs in approximately 14% of lung adenocarcinomas, the most common subtype of NSCLC; it is also present in 4% of colorectal cancers and 2% of pancreatic cancers. This means it affects well over 100,000 people each year worldwide and represents an unmet need.

Adagrasib works by irreversibly and selectively binding to KRAS G12C in its inactive state, blocking its signalling to other cells and preventing tumour cell growth and proliferation; this leads to cancer cell death.

Until 2018, no KRAS inhibitor had moved beyond preclinical testing, but in 2018 adagrasib was among the KRAS inhibitors given permission by the US Food and Drug Administration (FDA) to be investigated in clinical trials that started in January 2019. The KRYSTAL-1 phase I/II clinical trial of adagrasib is being conducted in more than 50 sites in the USA and Mirati Therapeutics, the company that has rights to and is developing the drug, is planning to expand clinical developments to other regions, starting in early 2021.

Patients with advanced NSCLC, colorectal cancer and other solid tumours with the KRAS G12C mutation were enrolled in the phase I and Ib part of the KRYSTAL-1 trial and, as the trial progressed, further patients were enrolled in the phase II part. All patients had advanced cancer and had previously received standard treatment for their disease, including chemotherapy and immunotherapy. While they were in the KRYSTAL-1 trial, they received 600mg of adagrasib taken orally twice a day.

Dr Pasi A. Jänne, Director of the Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, and Professor of Medicine at Harvard Medical School, Boston, USA, presented the results for 79 NSCLC patients up to 30 August 2020 to the Symposium. He said: "Among 51 patients for whom we had information on the clinical activity of adagrasib, 45% had an objective response, meaning that their tumours shrank by 30% or more and did not grow or spread to other parts of the body. This includes five patients who had an unconfirmed partial response by 30 August and who were subsequently confirmed as having a partial response in later scans. The disease control rate was 96%, meaning that 49 out of the 51 patients showed a partial or complete response or had stable disease."

Among the 14 patients in the phase I/Ib part of the trial who had been followed for a longer period of time (median time of 9.6 months), an objective response was seen in six (43%) and in four out of these six patients the duration of treatment has lasted for more than 11 months.

The researchers also analysed the treatment-related adverse side effects in all 110 patients included in the phase I/Ib and II parts of the trial, including those with colorectal cancer and other solid tumours, as well as those with NSCLC. Side effects included nausea (54%), diarrhoea (51%), vomiting (35%), fatigue (32%) and increased levels of an enzyme that indicates minor liver irritation (20%). The only serious adverse side effect to occur in more than one patient was low sodium in the blood, which occurred in two patients.

Prof Jänne said: "KRAS G12C patients are a population where there are no proven targeted therapies. Once chemotherapy or immune therapy fails in a patient, the treatment options are limited. The fact we are seeing responses in 45% of patients, which indicates that adagrasib may be an effective therapy, is incredibly meaningful as it opens up the possibility of a new treatment option for this subset of lung cancer patients.

"I'm thrilled to see how well adagrasib is working. Having been involved in multiple other studies of targeted therapies for lung cancer patients, the fact that we now have ones that are showing clinical activity in patients with KRAS G12C mutant cancers is super exciting and wonderful news for lung cancer patients."

Dr Melissa L. Johnson, Associate Director of the Lung Cancer Research Program and Drug Development at the Sarah Cannon Research Institute, Tennessee Oncology, Nashville, USA, presented updated results for 31 patients with colorectal cancer and other solid tumours up to the data cut-off point of 30 August 2020.

Out of 18 colorectal cancer patients who could be evaluated, three (17%) had a confirmed objective response and two of them continue to receive treatment. Disease control was seen in 17 of the patients (94%) and 12 of these patients continue to be treated.

Among the six patients with other solid tumours who could be evaluated, a partial response was confirmed in a patient with endometrial cancer and in a patient with pancreatic cancer. Unconfirmed partial responses occurred in one patient with ovarian cancer and one with cancer of the bile duct (cholangiocarcinoma). All six patients remain on the treatment.

"I think the clinical activity of adagrasib is highly encouraging in these patients," said Dr Johnson. "In some patients, the tumour size decreased and this shrinkage was durable, with some evaluable patients still on treatment after 11 months. The unique molecular structure of adagrasib means it takes about 24 hours for concentrations of the drug to reduce by a half, and most of the drug is distributed to the tissues of the body, which appears to result in deep and durable responses."

Adagrasib's long half-life enables it to inhibit KRAS continuously between doses. This helps to prevent what is known as a feedback loop, which occurs when the KRAS pathway is not completely inhibited and becomes hyperactive, leading to tumour regrowth.

"We believe that preventing feedback loops may lead to more durable responses in the tumour over a longer period of time and better tumour shrinkage," said Dr Johnson.

"Adagrasib is generally well tolerated and the adverse side effects are manageable. While 32% of treatment-related adverse events were significant, only 7% of these led to treatment discontinuation," she said.

The KRYSTAL-1 trial continues and the researchers are also looking at combining adagrasib with other targeted therapies, such as cetuximab for colon cancer and afatinib or pembrolizumab for lung cancer.

William R. Sellers, Professor of Medicine at the Dana-Farber Cancer Institute, Harvard Medical School, USA, is co-chair of the EORTC-NCI-AACR Symposium on behalf of the NCI and was not involved with the research. He commented: "Finding drugs that successfully and selectively inhibit the action of mutant versions of the KRAS gene has been an important goal in cancer drug discovery for years. Mutations in KRAS are common in a number of major cancers that are often hard to treat. Although preliminary, the results of the KRYSTAL-1 trial so far look very promising. Certainly I look forward to the peer review of these data and to the longer-term follow-up of treated patients so we can evaluate the durability of the benefit. It will also be interesting to see how adagrasib performs in combination with other existing therapies. These data also suggest that targeting other forms of mutant KRAS will be clinically important."

Highlights

In a recent study, a new algorithm achieved good performance for predicting which hospitalized patients will develop acute kidney injury requiring dialysis.

Results from the study will be presented online during ASN Kidney Week 2020 Reimagined October 19-October 25.

Washington, DC (October 24, 2020) -- A new artificial intelligence-based algorithm may help clinicians predict which patients with COVID-19 face a high risk of developing acute kidney injury (AKI) requiring dialysis. The research will be presented online during ASN Kidney Week 2020 Reimagined October 19-October 25.

Preliminary reports indicate that acute AKI is common in patients with COVID-19. Using data from more than 3,000 hospitalized patients with COVID-19, investigators at the Icahn School of Medicine at Mount Sinai trained a model based on machine learning, a type of artificial intelligence, to predict AKI that requires dialysis. Only information gathered within the first 48 hours of admission was included, so predictions could be made when patients were admitted.

The model demonstrated high accuracy (AUC of 0.79), and features that were important for prediction included blood levels of creatinine and potassium, age, and vital signs of heart rate and oxygen saturation.

"A machine learning model using admission features had good performance for prediction of dialysis need. Models like this are potentially useful for resource allocation and planning during future COVID-19 surges," said co-author Lili Chan, MD, MS. "We are in the process of deploying this model into our healthcare systems to help clinicians better care for their patients."