Body

Researchers at the Karolinska Institutet, University of Oxford and University of Copenhagen have shown that elevated levels of lipids known as ceramides can be associated with a ten-fold higher risk of death from cardiovascular disease. Treatment with liraglutide could keep the ceramide levels in check, compared with placebo. The results have been published in the Journal of the American College of Cardiology.

Approximately 16 percent of the Swedish population suffers from obesity (BMI over 30), which is one of the greatest risk factors for cardiovascular diseases such as myocardial infarction and stroke. The World Health Organisation (WHO) estimates that cardiovascular diseases are the main cause of mortality worldwide, with more than 17 million deaths a year.

"Understanding the link between obesity and cardiovascular diseases is important and can lead the way to the development of new therapies," says principal investigator docent Craig Wheelock at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet.

Fat has traditionally been seen as simply storage tissue, but in recent years it has been shown to be a 'biochemical laboratory' capable of producing signalling molecules that exert potent biological functions. Understanding how adipocytes produce and release these molecules opens the possibility of reprogramming them with the aim of preventing future incidence of cardiovascular disease.

Applying a mass-spectrometry method called metabolomics, the Wheelock Laboratory was able to measure levels of multiple metabolites secreted by two kinds of human fat tissue.

The fat that accumulates around the heart in obese individuals secreted different metabolites relative to subcutaneous fat. Notably, thoracic adipose tissue (which surrounds the heart) from obese individuals secreted higher levels of ceramides, a kind of lipid that belongs to the sphingolipid family. In particular, elevated levels were observed of a lipid variant called C16:0-ceramide, which is based on palmitic acid - a saturated fat consisting of 16 carbon atoms. Ceramides are found in high levels in cell membranes and are also important signalling molecules.

The researchers were also able to show that ceramides secreted from adipose tissue damaged human blood vessels by initiating a process called oxidative stress, which can eventually lead to heart attacks and stroke.

"These results show emphatically that fat is not just energy-storage tissue but also a source of important bioactive molecules that can have powerful immunomodulatory functions," Wheelock says. "In addition, all tissue is not equal, and the type of fat is clearly important in determining the observed biological function."

To understand the significance of the cardiovascular effects of the ceramides, the researchers studied 633 patients with atherosclerosis, who were monitored for more than five years. They found that elevated levels of both C16:0-ceramide and its glycosylated variant could be linked to a ten-fold increase in the risk of fatal cardiovascular disease, even after controlling for other risk factors including age and weight. The results were consistent with earlier studies by other research groups.

"The results suggest that it could be worth incorporating the measurement of different kinds of sphingolipids, both in their original form as well as the glycosylated variants, to better gauge the risk of the occurrence of a fatal cardiovascular event," says co-author Antonio Checa, researcher at Karolinska Institutet who developed the sphingolipid platform and conducted the analyses.

The results also gave the researchers reason to examine if high ceramide levels in the blood can be effectively reduced. In the last part of the study, 32 volunteers were placed on a low-calorie diet for eight weeks before being split into two groups, one that received a placebo and one that received liraglutide, a GLP 1-analogue drug that is approved for the treatment of obesity and type 2 diabetes. Both groups continued the low-calorie diet for another 44 weeks. One year after the study onset, ceramide levels in the blood had increased significantly in the control group, while levels remained stable in the liraglutide group.

"The most important findings are that we add to the evidence that there is a direct correlation between risk of fatal cardiovascular disease and ceramide levels in the blood, and that this can be treated with an existing medication," Wheelock says.

The study was led and coordinated by Professor Charalambos Antoniades at the University of Oxford.

"We reveal for the first time the role that the ceramides play as messengers that bring about the damaging effect on blood vessels that we see in obesity," Charalambos Antoniades says. "This presents unique opportunities for the improved diagnosis and treatment of cardiovascular disease."

Press release - Abstract 743: Effects of a very low-calorie ketogenic diet on androgen levels in overweight/obese men: a single-arm uncontrolled study

New research reveals that a low-calorie ketogenic diet can help testosterone levels in overweight men, reducing overall levels of obesity

A very low-calorie ketogenic diet can help testosterone and sex hormone (SHBG) levels in overweight men, according to a study being presented at the 23rd?European Congress of Endocrinology (e-ECE 2021), on Monday 24 May 2021 at 14:06 CET (http://www.ece2021.org). The study found that after following a recommended low-calorie ketogenic diet for four weeks, body weight, fat mass and body mass index (BMI) significantly decreased and a substantial increase of total testosterone and SHBG levels were also found. Testosterone is responsible for sexual and reproductive functions. However, it plays a significant role in calorie utilisation and metabolism as well.

This study was the first of its kind to examine the effect of a very low-calorie ketogenic diet on testosterone and SHBG levels and therefore highlighted the tight relation between insulin action, energy balance, and testicular function. As men who are overweight or obese can also suffer from low levels of testosterone and SHBG levels, the data suggests that further research into a low-calorie ketogenic diet and its effect on male testosterone and SHBG levels may be a promising area for additional research.

The worldwide prevalence of obesity nearly doubled between 1980 and 2008. According to country estimates for 2008, over 50% of men in the WHO European Region were overweight, and roughly 20% were obese. Obesity can lead to diabetes and heart disease, as well as psychological problems.

To tackle this, various lifestyle changes, activities and treatments are widely recommended, and a ketogenic diet is becoming increasingly recognised as one of them. The diet consists of little protein and very little carbohydrates, and when done as very-low calorie a daily intake of less than 800 calories is advised. A very low-calorie ketogenic diet has previously been found to reduce body weight, glycaemia and insulinemia, but its effects on total testosterone and SHBG levels were less clear, until now.

Dr Angelo Cignarelli and a team of colleagues from the University of Bari in Italy investigated whether this controlled diet would have the same, positive effect that it does on overall bodyweight on total testosterone and SHBG levels. The 17 male subjects in the study underwent a low-calorie ketogenic diet for four weeks, and various tests were carried out before and after one (1) and four (4) weeks.

"We aimed to evaluate the response of total testosterone and sex hormone levels to a very low-calorie ketogenic diet in a cohort of overweight or obese non-diabetic male subjects and what we found was that there is a noticeable relation between a specific, controlled diet and insulin action, energy balance, and testicular function," says Dr Cignarelli.

This is the first study that has evaluated the early response of androgen levels to the institution of a very low-calorie ketogenic diet, and highlights the relation between insulin action, energy balance, and testicular function. Results from this study now prove that a very low-calorie ketogenic diet can positively effect on total testosterone and SHBG levels. Further analysis will provide information about the effect of this nutritional intervention on additional clinical outcomes related to testosterone such as sexual function, muscle strength and quality of life.

LEBANON, NH - By 2030, pancreatic ductal adenocarcinoma (PDAC), the most lethal form of pancreatic cancer, is projected to become the second leading cause of cancer-related deaths in the United States. Not only are therapeutic options limited, but nearly half of all PDAC patients who have their tumors removed surgically experience disease recurrence within a year, despite receiving additional chemotherapy. For more advanced stages, only about one-third of patients have a limited response to approved chemotherapy.

A team of researchers led by Dartmouth and Dartmouth-Hitchcock's Norris Cotton Cancer Center (NCCC) Director Steven D. Leach, MD, and Surajit Dhara, PhD, Senior Research Scientist in the Leach laboratory, in collaboration with colleagues at Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, are developing the first prognostic and therapeutic epigenetic biomarker for PDAC patients.

Their discoveries will help predict which patients are likely or not likely to benefit from traditional chemotherapy. The likely "responder" patients can be confidently treated with traditional chemotherapy regimens, while the likely "non-responder" patients can be given an alternate regimen--potentially a combination of epigenetic therapy. The technology addresses a pressing clinical need by introducing the first ever epigenetic precision medicine approach to pancreatic cancer, as a means toward better outcomes and quality of life for all patients.

Epigenetic therapy can reactivate expression of the regulatory genes that have been silenced in chemo-resistant tumors and therefore make the tumors responsive to chemotherapy.

The team's work, entitled "Pancreatic cancer prognosis is predicted by an ATAC-array technology for assessing chromatin accessibility," is newly published in Nature Communications.

"We have a discovery and an invention emanating from this work," says Dhara. "By investigating all epigenetic elements that regulate genes in PDAC, we discovered that only about 1,092 elements are associated with chemotherapy resistance and early recurrence of this disease. Of those, 723 elements are silenced in chemo-resistant tumors, and are optimally predictive."

To translate this knowledge into the clinic, Leach and Dhara invented a novel technology platform called "ATAC-array" that assesses gene regulatory elements as a means to predict chemotherapy response and the potential benefit of epigenetic therapy in patients with PDAC. The technology is DNA-based and can potentially be performed on fine-needle aspiration specimens collected from tumors at the time of diagnosis.

Although there are nine FDA-approved epigenetic drugs, and more in the pharma pipeline, a fundamental means of distinguishing tumors that would benefit from epigenetic reprogramming therapy is still lacking. "We currently appear to be at the dawn of a new era in which epigenetic reprogramming is poised to become increasingly relied upon to optimize therapeutic effectiveness in multiple tumor types," says Leach. "With this work, we have pioneered a precision epigenetic approach in PDAC, a treatment approach that is now ready to be translated into the clinic."

Leach and Dhara have co-founded Episteme Prognostics, Inc.-- a precision medicine company developing therapeutic biomarkers for pancreatic cancer--in order to translate this work directly to the clinic as rapidly as possible.

Oncotarget published "The acylfulvene alkylating agent, LP-184, retains nanomolar potency in non-small cell lung cancer carrying otherwise therapy-refractory mutations" which reported that KEAP1 mutant NSCLCs further activate NRF2 and upregulate its client PTGR1. LP-184, a novel alkylating agent belonging to the acylfulvene class is a prodrug dependent upon PTGR1.

The authors hypothesized that NSCLC with KEAP1 mutations would continue to remain sensitive to LP-184. LP-184 demonstrated highly potent anticancer activity both in primary NSCLC cell lines and in those originating from brain metastases of primary lung cancers.

LP-184 activity correlated with PTGR1 transcript levels but was independent of mutations in key oncogenes and tumor suppressors.

Correlative analyses of sensitivity with cell line gene expression patterns indicated that alterations in NRF2, MET, EGFR and BRAF consistently modulated LP-184 sensitivity.

These correlations were then extended to TCGA analysis of 517 lung adenocarcinoma patients, out of which 35% showed elevated PTGR1, and 40% of those further displayed statistically significant co-occurrence of KEAP1 mutations.

The gene correlates of LP-184 sensitivity allow additional personalization of therapeutic options for future treatment of NSCLC.

The gene correlates of LP-184 sensitivity allow additional personalization of therapeutic options for future treatment of NSCLC.

Dr. Aditya Kulkarni from The Lantern Pharma, Inc. said, "KEAP1, KRAS, TP53 and STK11/LKB1 are among the commonly altered genes with considerable clinical prevalence in non-small cell lung cancers (NSCLC)."

The authors profiled primary and metastatic in vitro models of NSCLC for their sensitivity to LP-184 as well as standard of care agents, evaluated gene correlates of LP-184 response, and obtained evidence on in vivo anti-tumor effect of LP-184.

Mutated KEAP1 and concomitant decreased KEAP1 activity in cancer cells induces greater nuclear accumulation of NRF2, causing enhanced transcriptional induction of antioxidants, xenobiotic metabolism enzymes, and drug efflux pumps, thereby rendering KEAP1 mutations predictive of chemotherapy resistance in NSCLC patients.

The identification of a trend toward detrimental overall survival among a subset of platinum-treated NSCLC patients harboring co-occurring KRAS and STK11 mutations could label a more aggressive molecular subtype of NSCLC.

They therefore investigated LP-184 sensitivity in NSCLC cell lines harboring individual or concomitant mutations in KEAP1, KRAS, TP53 and STK11.

They sought to assess LP-184 activity in a panel of selected NSCLC adenocarcinoma cell lines, determine associations between genomic and transcriptomic profiles and responses of cell lines tested, and compare in vitro potency of LP-184 with that of approved chemotherapy agents.

The Kulkarni Research Team concluded in their Oncotarget Research Output, "Our key findings demonstrate that the alkylating agent LP-184 has nanomolar potency in several NSCLC cell lines and is more potent than selected approved alkylating chemotherapeutics. Additionally, LP-184 has the potential to target tumors with elevated PTGR1 regardless of presence of other co-occurring mutations but is especially found to be effective in the background of clinically significant KEAP1 mutations. We propose further evaluation of LP-184 in multiple PTGR1 high NSCLC settings that may not necessarily be mutually exclusive, including in highly prevalent KEAP1 and KRAS mutant tumors (Figure 6), and in patients with lack of actionable targets or resistance-related genes with no effective therapy options available."

DALLAS, Sunday, May 23, 2021 - Late last week, the U.S. Centers for Disease Control and Prevention (CDC) alerted health care professionals that they are monitoring the Vaccine Adverse Events Reporting System (VAERS) and the Vaccine Safety Datalink (VSD) for cases of young adults developing the rare heart-related complication myocarditis, after receiving a COVID-19 vaccine manufactured by Pfizer-BioNTech or Moderna. The COVID-19 Vaccine Safety Technical Work Group (VaST) of the CDC's Advisory Committee on Immunization Practices (ACIP) is reviewing several dozen cases of myocarditis that have been reported in adolescents and young adults: more often in males rather than females; more frequently after the second dose rather than the first dose of either the Pfizer-BioNTech or Moderna vaccine; and typically appearing within 4 days of vaccination.

The benefits of COVID-19 vaccination enormously outweigh the rare, possible risk of heart-related complications, including inflammation of the heart muscle, or myocarditis. The American Heart Association/American Stroke Association, a global force for longer, healthier lives, urges all adults and children ages 12 and older in the U.S. to receive a COVID vaccine as soon as they can.

The following statement reflects the views of the American Heart Association/American Stroke Association and its science leaders:

President Mitchell S.V. Elkind, M.D., M.S., FAHA, FAAN,

Immediate Past President Robert A. Harrington, M.D., FAHA,

President-Elect Donald M. Lloyd-Jones, M.D., Sc.M., FAHA,

Chief Science and Medical Officer Mariell Jessup, M.D., FAHA, and

Chief Medical Officer for Prevention Eduardo Sanchez, M.D, M.P.H., FAAFP.

"We strongly urge all adults and children ages 12 and older in the U.S. to receive a COVID vaccine as soon as they can receive it, as recently approved by the U.S. Food and Drug Administration and the CDC. The evidence continues to indicate that the COVID-19 vaccines are nearly 100% effective at preventing death and hospitalization due to COVID-19 infection. According to the CDC as of May 22, 2021, over 283 million doses of COVID-19 vaccines have been administered in the U.S. since December 14, 2020, and more than 129 million Americans are fully vaccinated (i.e., they have received either two doses of the Pfizer-BioNTech or Moderna COVID-19 vaccine, or the single-dose Johnson & Johnson/Janssen COVID-19 vaccine).

"We commend the CDC's continual monitoring for adverse events related to the COVID-19 vaccines through VAERS and VSD, and the consistent meetings of ACIP's VaST Work Group, demonstrating transparent and robust attention to any and all health events possibly related to a COVID-19 vaccine. The few cases of myocarditis that have been reported after COVID-19 vaccination are being investigated. However, myocarditis is usually the result of a viral infection, and it is yet to be determined if these cases have any correlation to receiving a COVID-19 vaccine, especially since the COVID-19 vaccines authorized in the U.S. do not contain any live virus.

"We remain confident that the benefits of vaccination far exceed the very small, rare risks. The risks of vaccination are also far smaller than the risks of COVID-19 infection itself, including its potentially fatal consequences and the potential long-term health effects that are still revealing themselves, including myocarditis. The recommendation for vaccination specifically includes people with cardiovascular risk factors such as high blood pressure, obesity and type 2 diabetes, those with heart disease, and heart attack and stroke survivors, because they are at much greater risk of an adverse outcome from the COVID-19 virus than they are from the vaccine.

"We also encourage everyone to keep in touch with their primary care professionals and seek care immediately if they have any of these symptoms in the weeks after receiving the COVID-19 vaccine:

chest pain including sudden, sharp, stabbing pains;

difficulty breathing/shortness of breath;

abnormal heartbeat;

severe headache;

blurry vision;

fainting or loss of consciousness;

weakness or sensory changes;

confusion or trouble speaking;

seizures;

unexplained abdominal pain; or

new leg pain or swelling.

"We will stay up to date with the CDC's recommendations regarding all potential complications related to COVID-19 vaccines, including myocarditis, pericarditis, central venous sinus thrombosis (CVST) and other blood clotting events, thrombosis thrombocytopenia syndrome (TTS), and vaccine-induced immune thrombosis thrombocytopenia (VITT).

"The American Heart Association recommends all health care professionals be aware of these very rare adverse events that may be related to a COVID-19 vaccine, including myocarditis, blood clots, low platelets, or symptoms of severe inflammation. Health care professionals should strongly consider inquiring about the timing of any recent COVID vaccination among patients presenting with these conditions, as needed, in order to provide appropriate treatment quickly. As detailed in last month's AHA/ASA statement, all suspected CVST or blood clots associated with the COVID-19 vaccine should be treated initially using non-heparin anticoagulants. Heparin products should not be administered in any dose if TTS/VITT is suspected, until appropriate testing can be done to exclude heparin-induced antibodies. In addition, health care professionals are required to report suspected vaccine-related adverse events to the Vaccine Adverse Event Reporting System, in accordance with federal regulations.

"We also support the CDC recommendations last week that loosen restrictions on mask wearing and social distancing for people who are fully vaccinated. For those who are unable to be vaccinated, we reiterate the importance of handwashing, social distancing and wearing masks, particularly for people at high risk of infection and/or severe COVID-19. These simple precautions remain crucial to protecting people who are not vaccinated from the virus that causes COVID-19.

"Individuals should refer to their local and state health departments for specific information about when and where they can get vaccinated. We implore everyone ages 12 and older to get vaccinated so we can return to being together, in person - enjoying life with little to no risk of severe COVID-19 infection, hospitalization or death."

MYOCARDITIS AND PERICARDITIS

Both myocarditis and pericarditis are most often the result of an infection and/or inflammation caused by a virus.

Myocarditis is inflammation of the middle layer of the wall of the heart muscle, and it can weaken the heart muscle and the heart's electrical system, which keeps the heart pumping regularly. Severe myocarditis can lead to heart failure, abnormal heartbeat and sudden death. Signs and symptoms of myocarditis are chest pain, abnormal heartbeat (arrhythmia) and unexpected shortness of breath. Approximately 10 to 20 per 100,000 people are diagnosed with myocarditis in the U.S. annually, and many cases resolve on their own or with treatment, leading to a full recovery.

Pericarditis is a condition often related to myocarditis, and involves swelling and inflammation of the pericardium, a sac-like structure with two thin layers of tissue that surround the heart to hold it in place and help it function properly. Pericarditis can progress and lead to severe complications, including cardiac tamponade, which results from too much fluid in the pericardium that can cause a sharp drop in blood pressure and can be fatal; and chronic constrictive pericarditis, when scar-like tissue develops in the pericardium causing it to become stiff, affecting the heart's ability to contract. Symptoms of pericarditis are sharp, stabbing chest pain that comes on suddenly; fever; weakness; and trouble breathing or shortness of breath. Approximately 45,000 people in the U.S. are hospitalized with pericarditis each year.

TYPICAL VACCINE- RELATED SYMPTOMS

According to the CDC, typical COVID-19 vaccine symptoms are tiredness, headache, muscle pain, chills, fever and nausea. Symptoms typically appear within 24 - 48 hours and usually pass within 36-48 hours after receiving the vaccine. If symptoms are severe and include difficulty breathing, seek immediate medical attention - call 911 or go to the nearest emergency room.

What The Study Did: Medication use among hospitalized patients for COVID-19-related treatment in a large university health care system was examined in this study.

Authors: Jonathan H. Watanabe, Pharm.D., Ph.D., of the University of California, Irvine, School of Pharmacy & Pharmaceutical Sciences, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamanetworkopen.2021.10775)

Editor's Note: Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

Nearly half a billion people on the planet have diabetes, but most of them aren't getting the kind of care that could make their lives healthier, longer and more productive, according to a new global study of data from people with the condition.

Many don't even know they have the condition.

Only 1 in 10 people with diabetes in the 55 low- and middle-income countries studied receive the type of comprehensive care that's been proven to reduce diabetes-related problems, according to the new findings published in Lancet Healthy Longevity.

That comprehensive package of care - low-cost medicines to reduce blood sugar, blood pressure and cholesterol levels; and counseling on diet, exercise and weight - can help lower the health risks of under-treated diabetes. Those risks include future heart attacks, strokes, nerve damage, blindness, amputations and other disabling or fatal conditions.

The new study, led by physicians at the University of Michigan and Brigham and Women's Hospital with a global team of partners, draws on data from standardized household studies, to allow for apples-to-apples comparisons between countries and regions.

The authors analyzed data from surveys, examinations and tests of more than 680,000 people between the ages of 25 and 64 worldwide conducted in recent years. More than 37,000 of them had diabetes; more than half of them hadn't been formally diagnosed yet, but had a key biomarker of elevated blood sugar.

The researchers have provided their findings to the World Health Organization, which is developing efforts to scale up delivery of evidence-based diabetes care globally as part of an initiative known as the Global Diabetes Compact. The forms of diabetes-related care used in the study are all included in the 2020 WHO Package of Essential Noncommunicable Disease Interventions.

"Diabetes continues to explode everywhere, in every country, and 80% of people with it live in these low- and middle-income countries," says David Flood, M.D., M.Sc., lead author and a National Clinician Scholar at the U-M Institute for Healthcare Policy and Innovation. "It confers a high risk of complications such as including heart attacks, blindness, and strokes. We can prevent these complications with comprehensive diabetes treatment, and we need to make sure people around the world can access treatment."

Flood worked with senior author Jennifer Manne-Goehler, M.D., Sc.D., of Brigham and Women's Hospital and the Medical Practice Evaluation Center at Massachusetts General Hospital, to lead the analysis of detailed global data.

Key findings

In addition to the main finding that 90% of the people with diabetes studied weren't getting access to all six components of effective diabetes care, the study also finds major gaps in specific care.

For instance, while about half of all people with diabetes were taking a drug to lower their blood sugar, and 41% were taking a drug to lower their blood pressure, only 6.3% were receiving cholesterol-lowering medications.

These findings show the need to scale-up proven treatment not only to lower glucose but also to address cardiovascular disease risk factors, such as hypertension and high cholesterol, in people with diabetes.

Less than a third had access to counseling on diet and exercise, which can help guide people with diabetes to adopt habits that can control their health risks further.

Even when the authors focused on the people who had already received a formal diagnosis of diabetes, they found that 85% were taking a medicine to lower blood sugar, 57% were taking a blood pressure medication, but only 9% were taking something to control their cholesterol. Nearly 74% had received diet-related counseling, and just under 66% had received exercise and weight counseling.

Taken together, less than one in five people with previously diagnosed diabetes were getting the full package of evidence-based care.

Relationship to national income and personal characteristics

In general, the study finds that people were less likely to get evidence-based diabetes care the lower the average income of the country and region they lived in. That's based on a model that the authors created using economic and demographic data about the countries that were included in the study.

The nations in the Oceania region of the Pacific had the highest prevalence of diabetes - both diagnosed and undiagnosed - but the lowest rates of diabetes-related care.

But there were exceptions where low-income countries had higher-than-expected rates of good diabetes care, says Flood, citing the example of Costa Rica. And in general, the Latin America and Caribbean region was second only to Oceania in diabetes prevalence, but had much higher levels of care.

Focusing on what countries with outsize achievements in diabetes care are doing well could provide valuable insights for improving care elsewhere, the authors say. That even includes informing care in high-income countries like the United States, which does not consistently deliver evidence-based care to people with diabetes.

The study also shines a light on the variation between countries and regions in the percentage of cases of diabetes that have been diagnosed. Improve reliable access to diabetes diagnostic technologies is important in leading more people to obtain preventive care and counseling.

Women, people with higher levels of education and higher personal wealth, and people who are older or had high body mass index were more likely to be receiving evidence-based diabetes care. Diabetes in people with "normal" BMI is not uncommon in low- and middle-income countries, suggesting more need to focus on these individuals, the authors say.

The fact that diabetes-related medications are available at very low cost, and that individuals can reduce their risk through lifestyle changes, mean that cost should not be a major barrier, says Flood. In fact, studies have shown the medications to be cost-effective, meaning that the cost of their early and consistent use is outweighed by the savings on other types of care later.

CLEVELAND - Follow-up data from the landmark SPRINT study of the effect of high blood pressure on cardiovascular disease have confirmed that aggressive blood pressure management -- lowering systolic blood pressure to less than 120 mm Hg -- dramatically reduces the risk of heart disease, stroke, and death from these diseases, as well as death from all causes, compared to lowering systolic blood pressure to less than 140 mm Hg. Systolic blood pressure (SBP) is the upper number in the blood pressure measurement, 140/90, for example.

In findings published in the May 20, 2021 issue of the New England Journal of Medicine, investigators presented new evidence of the effectiveness of reducing SBP to a target range of less than 120 mm Hg.

Jackson T Wright Jr. MD, PhD., and Mahboob Rahman MD, investigators from University Hospitals Cleveland Medical Center and Case Western Reserve University School of Medicine, played a lead role in the design, conduct, analyses and publication of the SPRINT trial. UH and CWRU coordinated one of the five Clinical Center Networks (CCNs) across the country selected to conduct the trial that had recruited more than 9,300 participants.

"This final report of the findings from SPRINT, now including all cardiovascular and mortality trial events, confirms the benefit of more aggressive BP lowering compared the previously recommended target of less than 140/90 mmHg," said Dr. Wright, Director of the Clinical Hypertension Program at UH and Professor Emeritus of Medicine at CWRU.

SPRINT was a randomized controlled clinical trial sponsored by the National Heart, Lung, and Blood Institute, part of the National Institutes of Health. Beginning in late 2009, it enrolled more than 9,000 participants at least 50 years old who had SBP 130 to 180 and had increased cardiovascular disease risk. The NIH ceased randomly assigned treatments in 2015, when data was presented to the Data and Safety Monitoring Board showing treatment to SBP of less than 120 decreased the rate of a composite cardiovascular disease (CVD) outcome by 25 percent and the rate of all-cause death by 27 percent.

Researchers reported these findings in 2015, but continued to collect data into July 2016. The current paper confirms and enhances the earlier findings.

SPRINT's primary outcome was lower risk of having one of a composite of different types of cardiovascular disease outcomes related to blood pressure. These included heart attack, an acute coronary syndrome not resulting in a heart attack, stroke, acute heart failure, or death from cardiovascular disease.

The final results showed the risk of the primary outcome of the trial was decreased 27 percent and death from all causes was decreased by 25 percent in the group treated to less than 120 mm Hg compared to the group treated to less than 140 mm Hg.

"One criticism of the original SPRINT findings was that, of the components of the primary outcome, only heart failure and death due to CVD were significantly lower in the intensively treated group," Cora E. Lewis, MD, Professor and Chair of the Department of Epidemiology in the University of Alabama at Birmingham School of Public Health, and primary investigator of the study. "The final results found that risk of heart attack, along with heart failure, and death from CVD, was significantly lower in the group treated to less than 120, and the risk of the primary outcome excluding heart failure was still significantly lower in the more intensively treated group."

SPRINT also collected data on safety of the interventions. The investigators anticipated that serious adverse events, including hospitalizations overall, as well as hospitalizations and emergency room visits for specific conditions of interest, might be related to more intensive treatment of blood pressure with medicines. The final paper reports that overall serious adverse events did not differ, but there were more cases of some of the conditions of interest in the group treated to SBP of less than 120, including low blood pressure, fainting and acute injury to the kidneys, which usually resolved within one year. Falls leading to injury did not differ.

Hypertension, high blood pressure, is a hugely important risk factor for the leading cause of death worldwide: cardiovascular disease or CVD, said Dr. Rahman. "CVD has been the number one killer in the U.S. for decades, even in 2020, when we were dealing with COVID-19, which was the number three killer that year in the U.S. Elevated blood pressure is the leading contributor to preventable deaths worldwide of 67 risk factors studied (including tobacco)."
"The take-home message from SPRINT is to talk to your doctor about your blood pressure to determine a good goal for you based on your overall cardiovascular disease risk. Then work with your doctor to achieve that goal," said Dr. Rahman.

Prior to the SPRINT trial, research had shown that treating high blood pressure helped decrease risk of CVD, but the optimum SBP goal was unknown. In 2007, a group of experts in high blood pressure research suggested that determining the appropriate goal of SBP to reduce the risk of heart disease was of the utmost importance in preventing complications from hypertension.

"We know a lot about how to prevent and treat hypertension and SPRINT continues to greatly expand this knowledge, including the benefits of treatment on the heart, kidney and brain," said David Goff, M.D., Ph.D., director of the Division of Cardiovascular Sciences at NHLBI. "As we implement what we know, more research is still needed to develop more effective prevention strategies for hypertension, improve its monitoring and control, and reduce the large health disparities associated with this disorder. Research teams supported by the NIH are continuing to work on these challenges."

Beijing, 19 May 2021: the journal Cardiovascular Innovations and Applications (CVIA) has just published a new issue, Volume 5 Issue 4.

This issue brings together important research from leading cardiologists in US and China in a combination of reviews, original research and case reports.

REVIEWS

Pei Huang, Yi Zhang, Yi Tang, Qinghua Fu, Zhaofen Zheng, Xiaoyan Yang and Yingli Yu

Progress in the Study of the Left Atrial Function Index in Cardiovascular Disease:

A Literature Review (https://tinyurl.com/3vruva37)

Nikhil H. Shah, Steven J. Ross, Steve A. Noutong Njapo, Justin Merritt, Andrew Kolarich, Michael Kaufmann, William M. Miles, David E. Winchester, Thomas A. Burkart and Matthew McKillop

Better Than You Think--Appropriate Use of Implantable Cardioverter-Defibrillators at a Single Academic Center: A Retrospective Review (https://tinyurl.com/eurk05)

RESEARCH PAPERS

Zesen Han, Lihong Lai, Zhaokun Pu and Lan Yang

A Nomogram to Predict Patients with Obstructive Coronary Artery Disease: Development and Validation (https://tinyurl.com/eurk01)

Wenxiu Liu, Yutong Guo, Yue Liu, Jiaxing Sun and Xinhua Yin

Calcium-Sensing Receptor of Immune Cells and Diseases (https://tinyurl.com/eurk009)

Zeyi Cheng, Miaomiao Qi, Chengyuan Zhang and Yanxia Mao

Myocardial Fibrosis in the Pathogenesis, Diagnosis, and Treatment of Hypertrophic Cardiomyopathy (https://tinyurl.com/eurk008)

Diqing Wang, Zhengfei He, Sihua Chen and Jianlin Du

The Relationship between Abnormal Circadian Blood Pressure Rhythm and Risk of Readmission
in Patients with Heart Failure with Preserved Ejection Fraction (https://tinyurl.com/eurk014)

Yu-quan Zheng and Xiao-mei Li

Comparison of Diagnostic Effects of T2-Weighted Imaging, DWI, SWI, and DTI in Acute Cerebral Infarction (https://tinyurl.com/eurk012)

CASE REPORTS

Lei Zhang, Tiewei Lv, Xiaoyan Liu, Chuan Feng, Min Zheng, Jie Tian and Huichao Sun

A Case of Pediatric Heart Failure Caused by Anomalous Origin of the Left Coronary Artery from

the Pulmonary Artery: Case Report and Literature Review (https://tinyurl.com/euk585)

Yiqian Ding, Wei Li, Yanqiu Liu, Min Ye, Liangping Cheng, Donghong Liu, Hong Lin and Fengjuan Yao

Mediastinal Tuberculoma Mimicking Malignant Cardiac Tumor: A Case Report (https://tinyurl.com/eurk587)

Li Jingxiu, Zhang Fujun, Wei Xijin and Peng Ding

Using Three-Dimensional Lorenz Scatter Plots to Detect Patients with Atrioventricular Node Double Path Caused by Interpolated Ventricular Premature Systoles: A Case Study (https://tinyurl.com/006eka)

Simon Fraser University researchers have validated a faster, cheaper COVID-19 test that could kickstart the expansion of more widespread rapid testing. Study results have been published in The Journal of Molecular Diagnostics.

"This research offers a cheaper, faster alternative to the most reliable and sensitive test currently used worldwide, without sacrificing sensitivity and reproducibility," says molecular biology and biochemistry professor Peter Unrau, who led the team evaluating the COVID-19 test kit.

The researchers suggest the test could be deployed in remote locations, clinics and airports due to its ease of use and portability.

The microchip real-time PCR test can provide accurate results in 30 minutes and requires 10 times less reagents than the tube-based RT-PCR tests approved by the Centers for Disease Control and Prevention (CDC). Supply chain shortages of reagents and test kits during the pandemic has slowed the rapid expansion of clinical testing. This new COVID-19 test kit is another tool in the toolbox that uses less of the supply constrained reagents to achieve fast and accurate results.

Unrau, along with PhD candidate Razvan Cojocaru and Master's student Iqra Yaseen, first evaluated test sensitivity in the lab.

Then the test kit was sent to a clinical team at St. Paul's Hospital in Vancouver, British Columbia, Canada to determine its ability to detect COVID-19 in patient samples. The microchip PCR COVID-19 test kit results aligned with hospital testing results - demonstrating its effectiveness.

The kit comes preloaded with COVID-19 primers and probes making it easy to use, reducing the potential for user error and improving the reliability of test results.

The COVID-19 detection kits developed by Lumex Instruments Canada and validated by Unrau's team are low power (100 watt), compact, lightweight and available internationally.

Finnish researchers have been the first to determine the cause for the nonsyndromic early-onset hereditary canine hearing loss in Rottweilers. The gene defect was identified in a gene relevant to the sense of hearing. The study can also promote the understanding of mechanisms of hearing loss in human.

Hearing loss is the most common sensory impairment and a complex problem in humans, with varying causes, severity and age of onset. Deafness and hearing loss are fairly common also in dogs, but gene variants underlying the hereditary form of the disorder are so far poorly known.

Researchers from the University of Helsinki and the Folkhalsan Research Center focused on a rare type of hearing loss observed in Rottweilers. It begins early in puppyhood and progresses to deafness at the age of few months. A similar type of hearing loss was also seen in a small number of mixed-breed dogs, of which the majority had Rottweiler ancestry.

"We identified the variant in the LOXHD1 gene, which plays a key role in the function of the cilia of the cochlear sensory cells. While the exact mechanism of deafness is not known, variants of the same gene cause hereditary hearing loss in humans and mice as well," says Docent Marjo Hytonen from the University of Helsinki and the Folkhalsan Research Center.

Hearing impairment caused by the LOXHD1 gene defect is a recessively inherited trait, which means that to develop the disorder, the dog must have two copies of the defective gene, one from the father and one from the dam.

"Through our collaboration partner, we had the chance to investigate the prevalence and breed specificity of the gene variant in a unique global dataset of some 800,000 dogs. No surveys of similar scope have previously been published," says Professor Hannes Lohi from the University of Helsinki and the Folkhalsan Research Center.

New individual dogs that had inherited the gene defect and were also found to be deaf were identified in the screening.

"This enhances the significance of our finding. Thanks to our gene discovery, dogs used for breeding can now be tested for the defect. This makes it possible to avoid combinations that could result in puppies who will lose their hearing."

The recent study is part of a research programme led by Professor Lohi and investigating the genetic background of hereditary diseases. Currently ongoing are several projects whose goals include the determination of genetic causes for hearing loss.

According to Marjo Hytonen, the preliminary results are promising.

"We have observed that both previously unknown hereditary congenital hearing loss and adult-onset hearing loss occur in several dog breeds. In addition to dogs, the preliminary findings open new avenues for investigating human hereditary hearing defects."

Data will support BLA filing for afamitresgene autoleucel next year -

Responses observed across a broad range of antigen expression -

Initial safety and durability are encouraging -

PHILADELPHIA, PA., and OXFORDSHIRE, U.K., May 20, 2021 -- Adaptimmune Therapeutics plc (Nasdaq:ADAP), a leader in cell therapy to treat cancer, will report initial data from its Phase 2 SPEARHEAD-1 trial, with afamitresgene autoleucel (afami-cel, formerly ADP-A2M4), at the American Society of Clinical Oncology (ASCO) congress. Full abstracts were released online today. Data will be presented in an oral presentation by Dr. Sandra D'Angelo of the Memorial Sloan Kettering Cancer Center (Abstract #11504) on June 4th.

"Patients are seeing substantial benefit from afami-cel in SPEARHEAD-1 across a broad range of cell doses and levels of MAGE-A4 expression," said Adrian Rawcliffe, Adaptimmune Chief Executive Officer. "We have shown a high response rate and these responses are still evolving in many patients with increasing depths of response over time and encouraging durability. I am confident that SPEARHEAD-1 will support our BLA submission next year and offer a life-changing treatment for people with synovial sarcoma."

"Initial data from SPEARHEAD-1 indicate that afami-cel has the potential to offer people with synovial sarcoma a promising new treatment option where there is currently a great unmet medical need," said Dr. Sandra D'Angelo of the Memorial Sloan Kettering Cancer Center. "As clinicians, we want to be able to provide a treatment regimen that can help offer a better quality of life."

SPEARHEAD-1 data will be presented at the time of the oral presentation scheduled for June 4th during the sarcoma session taking place from 1:30 p.m. to 4:30 p.m. EDT.

Afami-cel is efficacious and well-tolerated in heavily pre treated patients based on initial data

At the time of data cut-off (March 29, 2021), 37 patients had received afami-cel (32 with synovial sarcoma, 5 with myxoid/ round cell liposarcoma [MRCLS])

Of the 37 patients who had received afami-cel, 4 patients were pending first efficacy assessment, and 33 had at least one scan as of data cut off (29 with synovial sarcoma, 4 with MRCLS)

The overall response rate was 39.3% (13/33), 41.4% (12/29) for synovial sarcoma; 25.0% (1/4) for MRCLS

Of the 29 patients with synovial sarcoma with at least one scan, 2 had complete responses (CRs), 10 had partial responses (PRs), 13 had stable disease (SD), 4 had progressive disease (PD)

The disease control rate for people with synovial sarcoma was 86.2% (25/29) (defined as either response or stable disease)

Of the 4 patients with MRCLS with at least one scan, 1 patient had a partial response, 2 had stable disease, and 1 had progressive disease

Objective responses have been reported across a wide range of cell doses and MAGE-A4 antigen expression levels

Initial durability data is encouraging, and the median duration of response has not been reached

To date, the safety profile of afami-cel has been favorable, with mainly low-grade cytokine release syndrome and tolerable/reversible hematologic toxicities.

Overview of SPEARHEAD-1 trial design

SPEARHEAD-1 is a Phase 2, open-label trial for people with advanced synovial sarcoma or MRCLS to evaluate the efficacy, safety, and tolerability of afami-cel. Afami-cel SPEAR T-cells target MAGE-A4+ tumors. MAGE-A4 is highly expressed in synovial sarcoma and MRCLS in the context of HLA A*02. Compelling clinical responses in patients with synovial sarcoma were previously reported with afami-cel in a Phase 1 trial (CTOS 2020).

Approximately 90 patients are planned to be treated: 45 in Cohort 1 and 45 in Cohort 2. Enrollment in Cohort 1 is complete, and Cohort 2 is currently recruiting. The primary efficacy analysis will be for Cohort 1 only, which will be used to support the BLA filing next year. No formal hypothesis testing is planned for Cohort 2. Cohort 2 will strengthen the efficacy and safety database and will aid in descriptive sub group analyses.

Eligible patients were ? 16 and

The primary endpoint is overall response rate per RECIST v1.1 by independent review. The primary endpoint will be evaluated using a one-sided exact-based Clopper-Pearson 97.5% confidence interval (CI). If the lower bound of the CI exceeds the response rate reported with historical second line therapy(ies), the trial will have met the pre-specified threshold for demonstrating efficacy.

An independent Data Safety Monitoring Board reviews ongoing safety and benefit:risk during the interventional phase of the trial.

People with Alzheimer's disease (AD) are less likely to have cataract surgery than people without Alzheime's disease. The procedure rate starts to decrease already one year after the diagnosis, according to a new study from the University of Eastern Finland.

The lower likelihood of cataract surgery among people with cognitive disorders has been reported previously. This study is the first to report an association between the AD diagnosis and a lower incidence of cataract surgery, and a decrease in the procedure rate related to the time since the diagnosis.

The decrease in the incidence of cataract surgery among people with newly diagnosed AD is concerning because the benefits of this low-risk procedure would probably be similar for people with and without AD.

"The results of the study indicate that people with AD might have a higher threshold for cataract procedures. However, persons with cognitive disorders should be actively referred to ophthalmologic consultations because cataract surgery can improve their cognitive and physical functioning. The stigma of the disease should not lead to fewer referrals to cataract surgery," the authors say.

The study was conducted as part of the Medication Use and Alzheimer'sDisease Study (MEDALZ), in a cohort which includes 70,718 Finnish community dwellers with AD diagnosed between years 2005 and 2011. They were compared to persons of the same age and gender without AD.

TROY, N.Y. -- Heart disease and cancer are the leading causes of death in the United States, and it's increasingly understood that they share common risk factors, including tobacco use, diet, blood pressure, and obesity. Thus, a diagnostic tool that could screen for cardiovascular disease while a patient is already being screened for cancer, has the potential to expedite a diagnosis, accelerate treatment, and improve patient outcomes.

In research published today in Nature Communications, a team of engineers from Rensselaer Polytechnic Institute and clinicians from Massachusetts General Hospital developed a deep learning algorithm that can help assess a patient's risk of cardiovascular disease with the same low-dose computerized tomography (CT) scan used to screen for lung cancer. This approach paves the way for more efficient, more cost-effective, and lower radiation diagnoses, without requiring patients to undergo a second CT scan.

"In this paper, we demonstrate very good performance of a deep learning algorithm in identifying patients with cardiovascular diseases and predicting their mortality risks, which shows promise in converting lung cancer screening low-dose CT into a dual screening tool," said Pingkun Yan, an assistant professor of biomedical engineering and member of the Center for Biotechnology and Interdisciplinary Studies (CBIS) at Rensselaer.

Numerous hurdles had to be overcome in order to make this dual screening possible. Low-dose CT images tend to have lower image quality and higher noise, making the features within an image harder to see. Using a large dataset from the National Lung Screening Trial (NLST), Yan and his team used data from more than 30,000 low-dose CT images to develop, train, and validate a deep learning algorithm capable of filtering out unwanted artifacts and noise, and extracting features needed for diagnosis. Researchers validated the algorithm using an additional 2,085 NLST images.

The Rensselaer team also partnered with Massachusetts General Hospital, where researchers were able to test this deep learning approach against state-of-the-art scans and the expertise of the hospital's radiologists. The Rensselaer-developed algorithm, Yan said, not only proved to be highly effective in analyzing the risk of cardiovascular disease in high-risk patients using low-dose CT scans, but it also proved to be equally effective as radiologists in analyzing those images. In addition, the algorithm closely mimicked the performance of dedicated cardiac CT scans when it was tested on an independent dataset collected from 335 patients at Massachusetts General Hospital.

"This innovative research is a prime example of the ways in which bioimaging and artificial intelligence can be combined to improve and deliver patient care with greater precision and safety," said Deepak Vashishth, the director of CBIS.

A new paper in JNCI Cancer Spectrum, published by Oxford University Press, indicates that several non-genetic factors--including greater red meat intake, lower educational attainment, and heavier alcohol use--are associated with an increase in colorectal cancer in people under 50.

In the United States, incidence rates of early-onset colorectal cancer have nearly doubled between 1992 and 2013 (from 8.6 to 13.1 per 100,000), with most of this increase due to early-onset cancers of the rectum. Approximately 1 in 10 diagnoses of colorectal cancer in this country occur in people under 50.

Researchers have observed the rise particularly among people born since the 1960s in studies from the United States, Canada, Australia, and Japan. During the same period there have been major changes in diets among younger generations across the developing world. Such changes include decreases in consumption of fruits, non-potato vegetables, and calcium-rich dairy sources. This is coupled with an increase in processed foods (e.g., meats, pizza, macaroni and cheese, etc.) and soft drinks. Average nutrient intakes of fiber, folate, and calcium among the U.S. population are also lower than recommended.

The increase in early onset colorectal cancer is concerning to researchers because these cancers often have worse outcomes than those diagnosed in older people. It has led to recommendations that colorectal cancer screening begin at younger ages.

Previous research has outlined potential risk factors for early-onset colorectal cancer including greater consumption of processed meat, reduced consumption of vegetables and citrus fruit, greater body mass index, sedentary lifestyles, greater alcohol use, smoking, reduced aspirin use, and diabetes. However, researchers have yet to perform a comprehensive, large-scale evaluation that compares the magnitude of these risks with those for late-onset colorectal cancer and assesses whether the risks for early-onset colorectal cancer correlate with specific types of colorectal cancer.

Using data pooled from 13 population-based studies, researchers here studied 3,767 colorectal cancer cases and 4,049 controls in people under 50 and 23,437 colorectal cancer cases and 35,311 controls in people 50 or above years.

Early-onset colorectal cancer was associated with not regularly using aspirins, greater red meat intake, lower educational attainment, heavier alcohol use, and (interestingly enough) also alcohol abstinence. Researchers also found that lower total fiber intake was linked more strongly to rectal than colon cancer.

Several other colorectal cancer risk factors trended toward an association with early-onset colorectal cancer, including history of diabetes and lower folate, dietary fiber, and calcium intake. However, neither BMI nor smoking were risk factors in the early-onset group, in contrast to the late-onset group.

According to Richard Hayes, the senior investigator for this research: "this first large-scale study of non-genetic risk factors for early-onset colorectal cancer is providing the initial basis for targeted identification of those most at risk, which is imperative in mitigating the rising burden of this disease."