Body

HERSHEY, Pa. -- According to the World Health Organization, cervical cancer is the fourth most common form of cancer affecting women worldwide, and those in developing countries face a higher risk of dying from it. If detected early, cervical cancer responds well to treatment, however not everyone receives cancer screenings.

A team of researchers, including those from Penn State College of Medicine, took a closer look at cervical cancer in sub-Saharan Africa (SSA) to determine the prevalence and key factors that influence cancer screenings. The group found that despite high mortality rates, cancer screenings are substantially low, and there are multiple reasons why.

In a new study, published in Cancer Epidemiology, the researchers reviewed demographic and health surveys from nearly 30,000 women, ages 21 to 49, living in the Ivory Coast, Benin, Kenya, Namibia and Zimbabwe. According to the findings, 19% of women underwent cervical cancer screenings from 2011 to 2018. However, the rates varied greatly by country, ranging from less than 1% in Benin to nearly 46% in Namibia.

"To the best of our knowledge, this is one of the few comprehensive studies, and perhaps the largest to date, to examine the prevalence and determinants of cervical cancer across multiple SSA countries," said Djibril Ba, lead author and epidemiology doctoral student. "The low prevalence of cervical-cancer screening among childbearing-aged women is concerning and suggests that there is a large group of women who remain unscreened with an increased risk of cervical cancer."

According to the researchers, there were several key determinants to accessing cancer screenings in SSA. Women who visited health care facilities within the past year were more likely to undergo procedures. The researchers found that older women and individuals with health insurance, higher socioeconomic status and a higher level of education were more likely to have cancer screenings. They suggest that increasing screenings across the region may be beneficial and lifesaving.

"Interventions aimed at increasing cancer screenings are needed in countries that traditionally prioritize infectious conditions over chronic conditions," said Edeanya Agbese, coauthor and research project manager from the Department of Public Health Sciences. "The resulting variation of screening presented in this study, coupled with the increased cancer burden in SSA, highlights the importance of such interventions, which can lead to early treatment options."

You can do a lot in four years: go from white to black belt in taekwondo, plant a dwarf apple tree and pick its fruit, see your grandchild off to college and attend her graduation or get your own degree. But the most severe complications of diabetes--from stroke to neuropathy to amputation--can make activities like these difficult or impossible for some people.

In a new study, West Virginia University School of Public Health researchers found that taking part in a year-long diabetes-prevention program supports the addition of 4.4 quality-adjusted life-years to participants' average lifespan.

"Fatalism can play a major role in community health--like, 'Oh, yeah, my family has diabetes. I'm going to get it eventually,'" said Adam Baus, a research assistant professor in the Department of Social and Behavioral Sciences, who led the study. "But that doesn't have to be the case. Not at all."

The results appear in Perspectives in Health Information Management.

Quality-adjusted life-years--or QALYS--don't just take lifespan into account. They also factor in physical, mental, social and functional health. QALYS help to measure disease burden, and show how the quality and quantity of life lived is impacted by taking part in interventions.

Baus and his colleagues analyzed data from West Virginia Health Connection, a new online network of clinical and community-based partners working together to prevent and control chronic diseases--like diabetes--in the state.

West Virginia Health Connection is a collaborative effort between the West Virginia Bureau for Public Health's Division of Health Promotion and Chronic Disease and the WVU School of Public Health's Office of Health Services Research.

The data encompassed 320 individuals who had completed the National Diabetes Prevention Program.

Using the Centers for Disease Control and Prevention's Diabetes Impact Tool, the researchers analyzed the data for demographic information; weight, height and BMI; and return-on-investment indicators, including diabetes incidence, medical costs and QALYS.

They found that participating in the program caused an increase of 0.2 QALYS after one year, with projected increases of 1.1 QALYS after three years and 4.4 QALYS after 10 years.

At the start of programming, 80.3% of participants were obese, 19.4% were overweight and only 0.3% had a normal weight. By the end of programming, participants had lost 13.6 pounds--or 6.3% of their total body weight--on average. Projecting three years out, this represents a 32.4 percent overall risk reduction for developing diabetes.

"It's really important for our community partners to be able to have a good, reliable analytic system that they can use to document the programming that they're providing and to be able to demonstrate the effectiveness of their program," said Baus, who directs the WVU Office of Health Services Research. "That's challenging for a lot of people in the community who might not be accustomed to tracking data. They need a good, secure way of doing that and some backbone support so that they can analyze their data and show their program's impact. It's really important for the longevity of their program."

Baus and his colleagues discovered that the program was associated with a $120 decrease in annual medical costs per participant. After three years of participation, annual savings amount to $341 per person. After 10 years? $989.

By year three, the net cost to run the program falls to $50 per person. Projecting 10 years out, the programming generates enough healthcare savings that it more than offsets the cost of running the program itself.

"There's some frustration historically among providers who know their patients could benefit from extra support through prevention programs like this but do not have an easy mechanism to make the referrals, know that patients are attending classes and know what the outcomes are over time," Baus said.

West Virginia Health Connection addresses this need by essentially putting all diabetes-prevention programming in the state under one roof, connecting primary care physicians and specialists to community-based health leaders providing this needed programming.

"It's a secure registry for health information to be collected and analyzed so that clinicians can document the care that they're providing and get reports on those data," Baus said. "It's really important for our community partners to be able to have a good, reliable analytics system that they can use to document the programming that they're providing and demonstrate the effectiveness of their efforts."

And it's especially important in West Virginia, which has the nation's second-highest rate of diabetes among adults, at 15%. As of 2018, another 11% of adults were diagnosed as pre-diabetic, and still more remain undiagnosed.

"Our state has significant public health burden with prediabetes and diabetes, but we also have amazing, committed partners working to reverse that trend," Baus said. "Working together, we can do this."

A new cancer vaccine could boost the positive effects of existing immunotherapy drugs, improving the success rate of treatments from 20% to 75% of cases, according to a new study by immunologists from the University of Konstanz. The vaccine, which incorporates a new immunostimulant that is safe for use in humans, was shown to partially eliminate tumours in mice. However, the study further demonstrated that combining the vaccine with an immune checkpoint inhibitor -- an established immunotherapy drug with a 20% success rate overall for patients -- can vastly improve the proportion of individuals who respond to treatments, eliminating tumours in 75% of cases in mice. The results suggest that this new approach of using a vaccine in combination with established drugs may be a potent anti-cancer immunotherapy to be tested in future clinical trials. The findings appeared in Nature Communications on May 18, 2021.

Cancer therapy has seen a major breakthrough in recent years due to a type of immunotherapy known as "immune checkpoint inhibition". Immune checkpoint inhibitors work by stopping the body's natural ramping down of its immune response, causing the body instead to sustain its attack on tumour cells. This has proven to be effective for certain types of cancers, such as melanoma and squamous cell skin cancer, lung cancer, kidney cancer, and liver cancer.

But not all cancer patients respond to this immunotherapy. For example, only 20% of patients with melanoma can be cured. An explanation for why many do not respond well is that immune checkpoint inhibitors rely on the body initiating an immune response, which the drugs then prolong. If the body does not recognise its tumour cells as foreign, the immune checkpoint inhibitors have no immune cells to work off.

Now, a team led by Professor Marcus Groettrup, Chair of Immunology at the University of Konstanz, has developed a technique that kickstarts an immune response to a tumour. The microparticle-based cancer vaccine, which uses the immunostimulant Riboxxim that has the approval for application in humans, can generate the body's T-cell response that is necessary for immune checkpoint blockade drugs to be effective.

"A major shortcoming in cancer vaccines is the availability of immunostimulants that can be used in humans," says Marcus Groettrup, senior author on the study. "We can show that our clinically applicable vaccine combined with immune checkpoint blockade leads to an increase in the proportion of mice that can be cured of existing tumours to 75 percent."

A cancer vaccine that's safe for humans

The aim of the study was to develop a particle-based cancer vaccine which effectively launches an immune response against tumours and that is suitable for transition into clinical application.

The team created particles measuring 1 micrometre (or 0.001 mm) that included a tumour protein and Riboxxim--a molecule that primes the immune system to launch a response. Riboxxim is produced by the company Riboxx Pharmaceuticals in Dresden, Germany.

Mice that were injected with a single dose of the microparticle-based vaccine launched a strong anti-tumour immune response that was still detectable after 8 weeks. Even very low doses of the vaccine were able to generate strong immune responses compared to other immunostimulants.

The team tested the vaccine against a range of fragments from cancer proteins, including those of prostate cancer, breast cancer, and melanoma. Strong cellular immune responses against all these antigen fragments were obtained in mice, suggesting that the new approach might be applied to a variety of cancers.

A synergistic combination

However, due to the body's natural down regulation of its immune response, the tumours gradually returned 30 days after vaccination. But if the vaccine was combined with an immune checkpoint inhibitor, the therapeutic benefits continued and tumours were eliminated.

"We were able to formulate a clinically applicable cancer immunotherapy which acts complementary to commonly used immunotherapy," says Dennis Horvath, who is joint-first author on the study together with Julia Koerner. Horvath is a doctoral student at the Cluster of Excellence 'Centre for the Advanced Study of Collective Behaviour' at the University of Konstanz (CASCB). He also uses this vaccination approach to study the effect of social stress on the immune response in mice, testing whether immunosuppression by stress will limit the therapeutic success of immunotherapy.

Based on the study's findings, the researchers suggest that these promising pre-clinical results should be transitioned into clinical application. "This might have a very beneficial impact on immunotherapy in certain types of cancer," says Groettrup.

The therapeutic concept developed in this study is currently being tested in a first small phase 1 clinical trial by project partners in the Netherlands to find out if it is similarly effective in humans.

A large survey of women in California shows significant racial and ethnic differences in the types of personal care products women use on a daily basis. Because many personal care products contain endocrine disrupting chemicals (EDCs) like parabens and phthalates that interfere with the body's hormones, the findings could shed light on how different products influence women's exposures to harmful chemicals that contribute to health inequities.

The study appears in the Journal of Exposure Science & Environmental Epidemiology as part of a special issue focused on health equity.

"We know Black women have higher levels of many EDCs in their bodies than other groups of women," says lead author Dr. Robin Dodson, an environmental exposure scientist at Silent Spring Institute. "What we don't know is what's driving these exposures, and therefore what's driving some of the health disparities we see in the U.S. population."

The new study aims to fill that gap by providing one of the first comprehensive inventories of the range and types of products women use across race and ethnicity.

Black women go through puberty at younger ages, and have higher rates of hormone-mediated problems such as pre-term birth, uterine fibroids, and infertility than other groups of women. Incidence rates of breast cancer and endometrial cancer among Black women are also increasing.

Given evidence linking exposure to EDCs with harmful health effects such as reproductive problems and cancer, and the lack of data on the kinds of products women of color use, researchers decided to partner with community groups in California to survey a diverse group of women.

The survey is part of a larger effort called the Taking Stock Study--a collaboration between Occidental College, Black Women for Wellness, LA Grit Media, Silent Spring Institute, and George Washington University Milken Institute School of Public Health.

The team surveyed 357 women living in California about their use of personal care products, focusing on women of reproductive age, between the ages of 18 and 34. Participants were asked about the types of products they use, how often they use them, and why they choose certain ones over others.

The researchers gathered information on 54 types of personal care products, including cosmetics, hair products, menstrual or intimate products such as douches, and body lotions. The team also asked about the use of scented products.

Women in the study reported using on average eight products a day, with some using up to 30 products daily. When researchers compared product use among Black, Hispanic/Latinx, Asian, and White women, they noted a number of differences:

For 28 of the products, use varied significantly by race/ethnicity, with the largest differences seen between Black and White women.

Hispanic/Latinx and Asian women reported using more cosmetics than Black and White women.

Black women reported using a higher number of hair products and more menstrual/intimate products.

The use of scented products was also common, with 70 percent of women preferring scented over unscented options. Scientists are concerned about exposure to fragrance ingredients in products because they often consist of dozens of undisclosed and unregulated chemicals, some of which have been linked with asthma and hormone disruption.

Dr. Bhavna Shamasunder, an environmental health researcher at Occidental College who is co-leading the Taking Stock Study, says racism may underlie these patterns. "Women of color can feel pressure to conform to European beauty norms, whether from workplaces or widespread media images. But to achieve straighter hair or a different skin tone through use of a product, you have to use pretty toxic chemicals."

"This study is important not only because it shows how women of color and Black women in particular are more highly exposed to dangerous chemicals, but it also reinforces the notion that racism is a public health issue," says Janette Robinson Flint, executive director of Black Women for Wellness.

Next, the team plans to collect urine samples from study participants to measure levels of EDCs in their bodies and compare their levels with the products they use. The researchers also plan on testing products for a range of chemicals to find out which products pose a greater risk.

Findings from the study will help communities develop guidance for women on how to protect themselves from harmful ingredients in their everyday products, as well as inform policies and the development of safer products.

For the first time, researchers can quantitatively predict blood flow conditions that likely cause pathological behavior of the human blood protein von Willebrand factor (vWF). Predictions from this new method of simulation, developed at Lehigh University, can be used to optimize the design of the mechanical pumps known as left ventricular assist devices used in heart failure patients. The method also has the potential to improve diagnosis and treatment of von Willebrand disease, the most common inherited bleeding disorder in the U.S., according to the Centers for Disease Control and Prevention.  

The article, “Predicting pathological von Willebrand factor unraveling in elongational flow,” appears today in the May 18 issue of Biophysical Journal. In it, the team of researchers used an enhanced sampling technique called Weighted Ensemble, in conjunction with Brownian Dynamics simulations (i.e., the WEBD method), to identify blood flow conditions that cause pathological unraveling of the human blood protein vWF. The method allowed them to compute the globular-to-unraveled transition rate of the protein on timescales inaccessible to standard simulation methods.

“This method is all about studying the kinetics of rare events,” says co-author Edmund Webb III, an associate professor of mechanical engineering and mechanics in Lehigh’s P.C. Rossin College of Engineering and Applied Science. “That typically means some type of transition. With proteins, that often comes down to folding.”

The protein known as vWF promotes blood clotting by helping platelets in blood stick to collagen within the walls of damaged blood vessels and form a plug that stops the bleeding from a wound.

Typically, vWF circulates in the blood as a compact ball, or globule. When it approaches an injury site, the increase in blood flow caused by the laceration prompts the globule to unravel. As the protein transitions into more of a string-like shape, sites that are typically shielded when vWf is in a globule shape become exposed. Those sites are “sticky”—and they bind with platelets and collagen to initiate blood clot formation. 

There are a number of ways in which the clotting process can go awry, leading to bleeding disorders. One of these is called von Willebrand disease (vWD), and it affects about 1 percent of Americans (or 1 in every 100 people), according to the CDC. Its primary symptoms include frequent nosebleeds, easy bruising, and heavy and/or longer bleeding after injury, childbirth, surgery, or dental work, or during menstrual periods. 

There are several types of vWD, and they range in severity based on the degree to which vWF is depleted in a patient’s blood. Some people don’t even know they have the condition, because the vWF concentration in their blood, though depleted, is still sufficiently high to initiate clotting. Some have to steer clear of certain activities to avoid injury. Others need regular infusions of vWF, because they are severely lacking in the protein. 

The lead study author is Sagar Kania, a Rossin College PhD student in mechanical engineering and mechanics. Kania and Webb performed the work with their Lehigh coauthors, Alp Oztekin, a professor of mechanical engineering and mechanics, Xuanhong Cheng, a professor of bioengineering and materials science and engineering, and X. Frank Zhang, an associate professor of bioengineering. 

The team focused on first understanding blood flow conditions in which otherwise healthy vWF would exhibit undesired unraveling. This is a question whose answer has a direct impact on the design of left ventricular assist devices (LVADs), which have been associated with causing unexpected vWF depletion and associated bleeding disorders, akin to vWD. The symptoms are essentially the same so, medically speaking, in addition to being hereditary, von Willebrand disease can be acquired either by the action of a medical device or as a result of a separate medical condition.

Undesired unraveling of vWF is considered a necessary first step to pathological vWF depletion and associated bleeding disorders. In normal conditions, vWF is made within the walls of blood vessels and then secreted into the blood. 

“And when it gets secreted, it’s way too big,” Webb says. 

So that secretion simultaneously activates an enzyme (called ADAMTS13) that cuts the very long proteins into shorter lengths that are appropriately sized for their blood-clotting duties. Those shorter proteins contract to a globule shape, and then flow through the blood until they encounter an injury site, at which point they unravel, stick to platelets and collagen, and initiate the process of plugging the hole in damaged blood vessels.

The specific problem that the team studied for this paper arises when vWF unravels when it shouldn’t. In other words, not in response to a wound. When that happens, the cutting enzyme may again be activated.

“So upon secretion into blood, von Willebrand factor proteins are circulating in normal blood flow conditions, and yet they’re unraveling because they are very long,” says Webb. “Since they are unraveling, they’re getting cut down to the normal size distribution. But in pathological conditions they continue to unravel, and they get cut to the point where they are too small to be functional. They become short segments that are no longer hemostatically active; so if you get a cut, you can’t clot because you don’t have enough properly sized von Willebrand factor circulating around.”

So what are the blood flow conditions that cause vWF to unravel when it shouldn’t? To answer that question, Kania and coauthors combined the enhanced sampling technique (Weighted Ensemble) with molecular scale (Brownian Dynamics) simulations. This required executing parallel simulations—computations that are performed across many computers at the same time—supported by Lehigh’s Sol and Hawk computational clusters, as well as resources from the Xtreme Science and Engineering Discovery Environment (XSEDE), a national supercomputing resource made possible by the National Science Foundation.  

“The big problem,” says Webb, “is that bleeding disorders can be associated with the clearance of von Willebrand factor on timescales that might be on the order of minutes to hours. Molecular-scale simulations have to go through time sequentially, using a really, really tiny time step. For us to get a one-second simulation is effectively a state-of-the-art calculation.” 

Webb further points out that developing a robust understanding of the statistical nature of rare unraveling events requires many such simulations, making such an approach intractable.

“What this paper did was use a new method of simulation combined with our preexisting method of simulation to answer questions on longer timescales. It’s generally referred to as timescale bridging, because we’re taking a model designed to address questions on the order of micro- to milliseconds and combining it with a new theoretical technique that allows us to answer questions about things that would happen on timescales of seconds, minutes, hours, even days.” 

It’s truly a novel approach to predicting this type of an event, he says.

“This Weighted Ensemble method and the marriage of it to this type of problem has never been done before,” Webb explains. “Sagar has made some predictions about pathological flow conditions that appear to be quantitatively more accurate than what previously exists in the literature. So we can now say, ‘If a certain blood flow exposure occurs, you’re going to have issues.’” 

The breakthrough is potentially very good news for patients with heart failure. It may help manufacturers of LVADs design the blood pumps so the flow they generate doesn’t create pathological conditions for vWF.

Beyond benefiting those in need of medical implants, the team’s method may eventually help medical professionals better understand and potentially manipulate the complex flow conditions affecting the size distribution of vWF in their patients. This could lead to improved treatment of both acquired and hereditary vWD.

The ultimate goal, Webb says, is to take this type of capability and knowledge beyond just vWF to develop targeted drug therapy using flow-responsive molecules that mimic the unraveling of vWF. So if a patient is at risk for heart attack or stroke because of plaque buildup (stenosis), the molecule could deliver a drug to that precise area.

“You design a molecule that unravels in specific flow fields associated with certain degrees of stenosis,” says Webb. “The hope is that you would get the drug to the spot where you want it, and not anywhere else in the body. We’re working on this right now.”

Transcatheter aortic valve implantation (TAVI) offers an effective, less invasive therapeutic alternative to surgical aortic valve replacement in patients with symptomatic, severe aortic stenosis. Although TAVI is demonstrated to be superior to medical therapy or surgery in patients who are at prohibitive or high risk for aortic valve surgery, less is known about TAVI in patients who are at low risk for complications or death from surgery. At EuroPCR 2021, Dr J Forrest will present the complete 2-year follow-up from the Evolut low risk trial.

The Evolut Low Risk trial is a randomized noninferiority trial in which TAVI with a self-expanding supraannular bioprosthesis (CoreValve, Evolut R, or Evolut PRO; Medtronic) was compared with surgical aortic-valve replacement in patients who had severe aortic stenosis and were at low surgical risk (30-day surgical mortality risk

The as-treated cohort consisted of 1414 patients. Attempted TAVI or surgery was performed in 730 and 684 patients, respectively. Completed 2-year follow-up was available for 97.3% in the TAVI group and 92.3% in the surgery group. At 12 months, the primary outcome occurred in 2.5% in the TAVI vs. 4.3% in the surgical group (p=0.057). At 24 months, the primary outcome occurred in 4.3% in the TAVI vs. 6.3% in the surgical group (p=0.084). In a landmark analysis from 12 to 24 months, the primary outcome occurred in 1.9% in the TAVI vs. 2.1% in the surgical group (p=0.742); thereby indicating no late adverse catch-up phenomenon in the less-invasive TAVI therapy group.

Also additionally reported, at 2-years, TAVI with a self-expanding supraannular bioprosthesis was superior to surgery in regards to valve hemodynamics and prosthesis-patient mismatch. Conversely, surgery was superior to TAVI in regards to the incidence of pacemaker implantation and > mild paravalvular leak.

How will the results change the daily practice of physicians?

These data are highly likely to encourage the offer of TAVI with a self-expanding supraannular bioprosthesis as a non-inferior, less invasive alternative treatment option to surgery for patients with symptomatic, severe aortic stenosis and low surgical risk. Physicians (and patients) are likely to interpret the results favourably with regards to the numerical values of the primary outcome of death or disabling stroke at 2-years between the two groups.

Physicians should counsel patients specifically regarding the higher rate of pacemaker implantation with TAVI (21.1%), however, these historical data do not incorporate the contemporary cusp-overlay implantation technique for the self-expanding supraannular bioprosthesis that significantly reduces conduction disturbance (and the need for subsequent pacemaker).

Longer-term follow-up is needed to evaluate the differences demonstrated in the impact on patient outcomes. Of note, patients will be followed for 10 years and so such data will be forthcoming.

Results of the interim analyses performed after 12 months in the first 111 patients enrolled in phase II Cool AMI trial evaluating safety and effectiveness of systemic therapeutic hypothermia as an adjunctive therapy in anterior STEMI undergoing PCI as compared to PCI only. Analyses showed significant differences among treatment groups, including longer randomization-to-balloon time and total ischemic time in treatment arm, justifying premature trial discontinuation.

Therapeutic mild systemic hypothermia, when achieved before reperfusion of the infarct related vessel, has shown to limit infarct size in experimental animal models. Despite encouraging initial in vivo results, several prior RCTs reported overall neutral effects. A potential advantage of hypothermia was detected in early presenters with anterior STEMI cooled prior to reperfusion.

Safety of this approach in anterior STEMI patients was initially tested in the COOL AMI EU pilot phase I trial, which results were previously presented at EUROPCR 2017 and published in Eurointervention.

The COOL AMI EU pivotal trial, is an industry initiated, multicenter, prospective, interventional, randomized-controlled phase II trial with a 1:1 randomization protocol comparing systemic therapeutic hypothermia in patients with recent onset anterior STEMI (Primary efficacy endpoint was set as a relative reduction of 20% in mean anterior myocardial infarct size (as % left ventricular mass) determined by cardiac magnetic resonance imaging at 4-6 days post-infarct in the cooling + PCI arm as compared to the PCI only arm.

The secondary safety endpoint was defined as a composite of cardiac death, myocardial infarction and clinically-indicated target lesion revascularization at 30 day follow-up. According to the statistical analysis plan, 500 patients were expected to be enrolled to detect a relative reduction of 20% in mean infarct size in the treatment group. Interim analyses were pre-specified as per protocol.

During the LBT sessions of the upcoming EUROPCR 2021 congress, results of the interim analyses performed at 12 months after enrolment of 111 patients (58 treatment arm, 52 controls) were presented by Dr. M Noc (Ljubljana, Slovenia). The interim analysis led to premature, sponsor promoted, trial discontinuation.

Trialists observed significant differences among treatment groups, including longer randomization-to-balloon time (61±21 vs 32±18 minutes, pNo significant differences were observed for the primary endpoint (infarct size as a % of LV mass at MRI at 4-6 days 21.3±12.2% in the treatment group vs 20.0±12.2% in the control group, p=0.540). A numerically greater, statistically non-significant increase in the incidence of the secondary endpoint was also observed in the cooling arm (MACE at 30 days n=5 (8.6%) vs n=1 (1,9%), p=0.117). Incidence of two per protocol specified serious adverse events (cardiogenic shock: n=6 (10.3%) vs n=0 (0%), p=0.028 and new onset paroxysmal atrial fibrillation: n=25 (43.1%) vs 2 (3.8%), pEarly interruption of the trial clearly limits the statistical power of the trial not allowing to definitely assess its safety and efficacy in anterior STEMI patients. While the experience acquired with COOL AMI EU pivotal trial will be of help in designing future trials assessing the effects of systemic hypothermia, additional evidence will be required to support its adoption.

The ISCHEMIA trial found no significant difference between an invasive vs. a conservative strategy in patients with chronic coronary syndromes and moderate to severe ischemia at a mean of 3.2 years. However, the cumulative difference in the estimates of cardiac death between the invasive and conservative strategies tended to increase numerically over time (e.g., 0.3% in favor of the invasive strategy at 2 years and 1.3% at 5 years). Because the ISCHEMIA trial was not powered for cardiac mortality and did not focus on long-term follow-up, the rationale for a meta-analysis emerged.

At EuroPCR 2021, Navarese and colleagues present the results of a new meta-analysis of revascularization plus medical therapy versus medical therapy alone. A total of 19,806 patients with chronic coronary syndromes undergoing elective revascularization from 25 randomized trials were pooled, and outcomes were extracted at the longest available follow-up. The primary endpoint was cardiac death. Secondary endpoints were all-cause death, spontaneous myocardial infarction, any myocardial infarction and stroke.

The authors found a statistically significant 21% relative risk reduction in cardiac death with revascularization plus medical therapy (risk ratio 0.79, 95% confidence interval 0.67 to 0.93, p

There was a parallel significant reduction in spontaneous myocardial infarction with revascularization plus medical therapy (risk ratio 0.74, 95% confidence interval 0.64 to 0.86, p

Overall, this meta-analysis suggests that the benefits of revascularization and optimized medical therapy are additive and their combination is required to achieve maximal and durable prevention of adverse events.

ATLANTA - MAY 18, 2021 - A new study finds breast cancer survivors in general have higher risk of new cancer diagnosis compared to healthy individuals. The article, which appears in CANCER, states that compared to the general population in the United States, the risk of new cancer diagnoses among survivors was 20% higher for those with hormone receptor (HR) positive cancers and 44% higher for those with HR-negative cancers.

Breast cancer is the most commonly diagnosed and prevalent cancer among women in the U.S., with over 3.9 million living breast cancer survivors as of 2019. The number of survivors is expected to increase with the aging population and advances in breast cancer treatment.

Subsequent primary cancer (SPC) after breast cancer is a well-known late effect, but the risk by breast cancer subtype and age at diagnosis was largely unknown except for contralateral breast, lung, and ovarian cancers. This study, led by Hyuna Sung, PhD, is the first to examine the risk of a range of SPCs including 26 types, and evaluate the risk by tumor subtypes and diagnosis age of breast cancer. This study included women (aged 20 to 84 years) diagnosed with invasive breast cancer from 1992-2015 and who survived for a year or more.

"With most women living decades after a breast cancer diagnosis, it is important to identify survivors at higher risk for future cancers and provide tailored recommendations for risk reduction and early detection," said Dr. Sung.

Data show that the risk differs by survivor characteristics, such as breast cancer subtypes and their diagnosis age. For example, several cancers including subsequent breast cancer, acute nonlymphocytic leukemia, ovarian cancer, and lung cancer are more likely to develop after HR-negative cancer than after HR-positive cancer. Women who were first diagnosed with breast cancer before age 50 also have greater risk for subsequent cancer than women with later onset breast cancer.

"Differential risk of subsequent cancer according to survivor characteristics highlights that more targeted approaches for cancer prevention and early-detection strategies are needed in survivorship care planning to mitigate the burden of subsequent cancers in the growing population of survivors," said the authors.

An international research team headed by Michal Hocek of the Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences (IOCB Prague) and Charles University and Ciara K. O'Sullivan of Universitat Rovira i Virgili (URV) in Spain have developed a novel method for labeling DNA, which in the future can be used for sequencing DNA by means of electrochemical detection. The researchers presented their results in the Journal of the American Chemical Society.

A DNA molecule comprises four basic building blocks, nucleotides. The genetic information carried within the molecule is determined by the order of the nucleotides. Knowledge of the order of these building blocks, which is known as the DNA sequence, is necessary for disease diagnostics and forensic DNA analysis, for example. Despite the great progress in recent years, the current DNA sequencing methods, typically based on fluorescent labelling, are still time-consuming and relatively expensive techniques, which have some limitations. Therefore, scientists are intensively searching for new approaches to simplify and accelerate sequencing.

One promising approach is the use of electrochemical detection and so-called redox labels, which are compounds that can be oxidized or reduced on electrodes. A multidisciplinary team of researchers from IOCB Prague, URV, the Faculty of Science of Charles University, the Polish Academy of Sciences, and the Institute of Biophysics of the Czech Academy of Sciences, with students David Kodr and Cansu Pinar Yenice as first authors, has now succeeded in designing and synthesizing artificial nucleotides with special attached redox labels that can be oxidized on a gold or carbon electrode at a specific potential to produce a measurable and analytically useful signal. These labels are carboranes, cage structures composed of boron and carbon atoms, into which other metal atoms can be incorporated, such as iron or cobalt, affecting their resulting electrochemical properties.

The modified nucleotides have been engineered so that the enzyme DNA polymerase, which uses available nucleotide building blocks to build DNA within a cell, can incorporate them into a newly synthesized DNA strand. Thus, the researchers have succeeded in preparing a strand of DNA comprising modified nucleotides. At the same time, each of the four types of nucleotide carries its own unique label allowing for its subsequent identification. And therein lay the primary pitfall of the project; until now, researchers had always only managed to label and measure one, at most two, types of redox-labelled nucleotides in a single strand of DNA.

Because each of the modified nucleotides carries its own label, which during electrochemical detection gives a specific oxidation signal at varying potentials, the individual types of nucleotides can be distinguished. Moreover, the size of each signal is dependent on the number of copies of the given nucleotide in the DNA, which then makes it possible to quickly determine the relative representation of individual nucleotides in the measured DNA.

The newly developed electrochemical coding of DNA bases offers a range of advantages, such as simpler and more affordable instrumentation and faster analysis. The method holds promise for DNA sequencing and diagnostic applications as well as for development of new DNA chips.

A rigorous meta-analysis of randomized clinical trials (RCTs) that compared the effects of medical therapies alone with medical therapies plus revascularization in patients with stable ischemic heart disease (SIHD) was presented at EuroPCR on May 18, 2021. The study concluded that adding revascularization was associated with a statistically important reduction in cardiovascular death associated with a statistically important reduction in spontaneous myocardial infarction (MI), providing a biologically plausible explanation for the observed benefit.

An international group of investigators performed a meta-analysis of RCTs conducted between 1979 and 2020. Strict entry criteria were established to assure the analysis was restricted to studies involving elective, deferrable treatments of patient with SIHD. This produced 25 RCTs with an enrolment of 19,806 patients. Event rates at the latest reported time point were studied. The analysis found that use of revascularization with percutaneous coronary intervention (PCI) or coronary artery bypass grafting surgery (CABG) was linked to a statistically important 21% reduction in late cardiovascular death. Furthermore, the magnitude of benefit appeared to increase over time. The rigorous statistical assessment concluded that an initial strategy of invasive care was superior to an initial strategy of conservative care and that this benefit became more evident with longer follow up. In fact, meta-regression techniques indicated that prior studies may have missed this finding principally because follow up wasn't long enough.

The research team performed multiple sensitivity analyses to determine how certain conditions influenced the results of the meta-analysis such as treatment in the context of a recent acute coronary syndrome, inclusion of patients requiring treatment of chronic total occlusions, or studies in which >30% of patients received CABG. Also, a few studies were judged to have a meaningful risk of bias. Exclusion of these studies did not alter the significance of the cardiovascular mortality risk reduction with an initial invasive strategy.

The meta-analysis also found that an initial invasive approach was associated with a 24% reduction in spontaneous MI which had a larger impact on survival than peri-procedural MI; in fact, the meta-analysis found that peri-procedural MI in the RCTs did not impact reported cardiac death rates. Furthermore, the meta-analysis linked a survival advantage to lower spontaneous MI rates especially among patients with extensive disease. "This comprehensive analysis clearly defines a risk-reduction in cardiovascular mortality following coronary revascularization in patients with stable coronary artery disease that is directly related to both duration of follow-up and magnitude of risk reduction in spontaneous myocardial infarction. This mechanistically plausible benefit of revascularization is evident through multiple sensitivity analyses," said Dean Kereiakes, MD, FSCAI, medical director of the Christ Hospital Research Institute in Cincinnati, OH, and a co-author of the study.

An especially important observation from this report evolved from a meta-regression analysis which found that longer follow up was associated with increased observed benefit with an invasive strategy, and that differences in conclusions between RCTs could be explained largely by differences in follow up duration. While total MI rates may not appear to be different between treatment strategies in the short run, revascularization helps over a long timeline by more effectively lowering the risk of spontaneous MI; this observation may be overwhelmed by the effects of peri-procedural MI associated with undergoing revascularization if follow up is relatively short. According to Alexandra Lansky MD, FSCAI, director of the Heart and Vascular Clinical Research Program and the Cardiovascular Research Center at Yale and a co-author of the study. "For our patients with stable coronary artery disease on medical therapy, this means that 1 in 5 will realize a survival benefit about 5.5 years after revascularization and 1 in 4 will avoid a spontaneous heart attack. The two are related, and the survival benefit of revascularization increases with time. For our studies, this means we need long-term follow-up focused on cardiac death to see the benefit of revascularization," Dr. Lansky continued.

This meta-analysis indicates that coronary revascularization with PCI or CABG provides a long-term cardiovascular survival advantage over an initial conservative approach in patients with stable ischemic heart disease by lowering rates of spontaneous MI, a new and exciting finding related to coronary revascularization including PCI. Prior studies may have missed this relationship primarily because patients were not followed long enough for the benefit to be seen.

A new technology developed by UZH researchers enables the body to produce therapeutic agents on demand at the exact location where they are needed. The innovation could reduce the side effects of cancer therapy and may hold the solution to better delivery of Covid-related therapies directly to the lungs.

Scientists at the University of Zurich have modified a common respiratory virus, called adenovirus, to act like a Trojan horse to deliver genes for cancer therapeutics directly into tumor cells. Unlike chemotherapy or radiotherapy, this approach does no harm to normal healthy cells. Once inside tumor cells, the delivered genes serve as a blueprint for therapeutic antibodies, cytokines and other signaling substances, which are produced by the cancer cells themselves and act to eliminate tumors from the inside out.

Sneaking adenoviruses past the immune system undetected

"We trick the tumor into eliminating itself through the production of anti-cancer agents by its own cells," says postdoctoral fellow Sheena Smith, who led the development of the delivery approach. Research group leader Andreas Plueckthun explains: "The therapeutic agents, such as therapeutic antibodies or signaling substances, mostly stay at the place in the body where they're needed instead of spreading throughout the bloodstream where they can damage healthy organs and tissues."

The UZH researchers call their technology SHREAD: for SHielded, REtargetted ADenovirus. It builds on key technologies previously engineered by the Plueckthun team, including to direct adenoviruses to specified parts of the body to hide them from the immune system.

High amount of drugs in the tumor, low concentration in other tissues

With the SHREAD system, the scientists made the tumor itself produce a clinically approved breast cancer antibody, called trastuzumab, in the mammary of a mouse. They found that, after a few days, SHREAD produced more of the antibody in the tumor than when the drug was injected directly. Moreover, the concentration in the bloodstream and in other tissues where side effects could occur were significantly lower with SHREAD. The scientists used a very sophisticated, high-resolution 3D imaging method and tissues rendered totally transparent to show how the therapeutic antibody, produced in the body, creates pores in blood vessels of the tumor and destroys tumor cells, and thus treats it from the inside.

Use to combat Covid-19 being investigated

Plueckthun, Smith and colleagues emphasize that SHREAD is applicable not only for the fight against breast cancer. As healthy tissues no longer come into contact with significant levels of the therapeutic agent, it is also applicable for delivery of a wide range of so-called biologics - powerful protein-based drugs that would otherwise be too toxic.

In fact, members of the Plueckthun group are currently applying their technology in a project aimed as a therapy for Covid-19. Adenoviral vectors are already being used in several of the COVID vaccines, including the Johnson & Johnson, AstraZeneca, China's CanSino Biologics and Russia's Sputnik V vaccines - but without the innovative SHREAD technology. "By delivering the SHREAD treatment to patients via an inhaled aerosol, our approach could allow targeted production of Covid antibody therapies in lung cells, where they are needed most," Smith explains. "This would reduce costs, increase accessibility of Covid therapies and also improve vaccine delivery with the inhalation approach."

BOSTON - Peripheral artery disease (PAD), or blockages in the arteries outside of the heart, affects more than 200 million people worldwide and 12.5 million people in the United States. Patients with this circulatory disorder may develop severe leg pain or unhealing wounds that require a minimally invasive revascularization procedure to open the blood vessels to improve blood flow.

For nearly a decade, proceduralists and surgeons have depended on devices coated with a drug called paclitaxel -- which reduces the need for another procedure by up to 50 percent -- during procedures to open the arteries of the leg. However, in the wake of a 2018 study that found a potential link between these drug-coated peripheral devices and death after two years post procedure, the FDA restricted the use of these devices for the treatment of PAD out of an abundance of caution.

At the behest of the FDA, cardiologists Eric Secemsky, MD, and Robert Yeh, MD, both of the Richard A. and Susan F. Smith Center for Outcomes Research in Cardiology at Beth Israel Deaconess Medical Center (BIDMC), designed the Safety Assessment of Femoropopliteal Endovascular Treatment With Paclitaxel-coated Devices (SAFE-PAD) study to provide the information necessary to make scientifically-sound regulatory decisions about the safety of these devices. Using claims data from the Centers for Medicare & Medicaid Services (CMS), the researchers evaluated survival following treatment with these drug-coated devices in more than 160,000 leg artery revascularization procedures conducted between 2015 and 2018.

The team found no statistically significant difference in mortality between patients treated with drug-coated devices and non-drug-coated devices. The report was presented as a late-breaking study at the American College of Cardiology's Scientific Sessions May 16 and published simultaneously in JAMA Internal Medicine.

"Our study of Medicare beneficiaries includes more than 160,000 patients, including more than 30,000 patients with survival data extending past four years, making it one of the largest and most comprehensive evaluations of the safety of drug-coated devices to be published since the initial analysis," said Secemsky, Director of Vascular Intervention at BIDMC and Assistant Professor of Medicine at Harvard Medical School. "Although the 2018 findings raised concerns about the safety of these drug-coated devices, there were many issues with that analysis -- including the study's small size and a lack of complete patient follow-up."

Secemsky and colleagues' study included Medicare patients treated with either a drug-coated or non-drug coated peripheral device between 2015-2018 at nearly 3000 hospitals across the United States. Deaths were evaluated through May 2020, and after accounting for any differences in demographics and co-morbidities between the two groups, the investigators found no evidence that drug-coated devices were associated with higher mortality rates through an average 2.7 years of follow-up, with some patients having follow-up through 5 years.

"We used a number of novel statistical methods to assure these results were accurate, and found consistent results across a number of different patient groups -- including among those of lower overall risk, those with more severe disease, and those treated in outpatient centers," Secemsky said. "We've provided these results to the FDA to make decisions on whether to continue to restrict these drug-coated devices to only those at high risk of needing another leg procedure, or to return to the previous indications where these were used without restriction."

The current publication is the first report of seven planned biannual reports as part of the SAFE-PAD study, which was designed to continue until all patients in the study had follow-up exceeding 5 years. As such, Secemsky and colleagues will continue to analyze these Medicare beneficiaries and update their findings until this study completes in late 2023.

“The SAFE PAD study is a model example for collaboration between industry, academia and the FDA to carry out rigorously designed real world studies to evaluate important medical device safety signals,” said Yeh, Director of the Richard A. and Susan F. Smith Center for Outcomes Research in Cardiology at BIDMC and Katz-Silver Family Associate Professor of Medicine Harvard Medical School. “We believe that applying stringent scientific standards to observational studies can create greater confidence in validity of these ‘big data’ approaches to the evaluation of medical therapies.”

Early preterm births may be dramatically decreased with docosahexaenoic acid (DHA) supplements, with a dose of 1000 mg more effective for pregnant women with low DHA levels than the 200 mg found in some prenatal supplements, according to a study led by researchers from the University of Kansas and the University of Cincinnati and published today in EClinicalMedicine, a clinical journal of The Lancet. Early preterm birth, defined as birth before 34 weeks gestation, is a serious public health issue because these births result in the highest risk of infant mortality and child disability.

"This study tells us that pregnant women should be taking DHA," said Susan E. Carlson, Ph.D., professor of nutrition in the Department of Dietetics and Nutrition in the KU School of Health Professions, co-principal investigator and first author on the study. "And many would benefit from a higher amount than in some prenatal supplements, particularly if they are not already taking a prenatal vitamin with at least 200 mg DHA or eating seafood or eggs regularly," Carlson said. "Many pregnant women take DHA, but we wanted to see if the amount in most prenatal supplements was enough to prevent early preterm birth."

Overall, women who received the higher dose had fewer early preterm birth, however, participants with low DHA levels at enrollment had half the rate of early preterm birth (2.0% compared to 4.1%) when they were given a supplement of 1000 mg compared with those given a 200 mg supplement during the last half of pregnancy. For women who began the study with high DHA levels, many of whom were already taking prenatal DHA, the rate of early preterm birth was 1.3%, and there was no benefit of the higher dose.

"We knew from our previous work that women in the United States eat very little food sources of DHA, and we thought a higher dose might be needed to boost intake," said Christina J. Valentine, M.D., a neonatologist and registered dietitian at the University of Cincinnati and one of three principal investigators for the study.

Because preterm birth is associated with such negative outcomes and high health care costs, having an option for women to prevent preterm birth reliably and inexpensively is significant.

"This study is a potential game changer for obstetricians and their patients," said co-author Carl P. Weiner, M.D., professor of obstetrics and gynecology and professor of integrative and molecular physiology at the University of Kansas School of Medicine and professor of pharmaceutical sciences at the University of Kansas School of Pharmacy. "The dramatic decrease in early preterm birth with DHA supplementation will improve short- and long -term outcomes for children, families and society in a cost-effective fashion."

Carlson notes that this information should be widely shared with women who are pregnant and those planning to become pregnant. "Women should be consulting with their doctor and getting their DHA levels tested to ensure they are taking the proper dose to prevent preterm birth," she said.

The multi-center, double-blind, randomized, superiority trial recruited participants at three large academic medical centers in the United States (the University of Kansas Medical Center, Ohio State University and the University of Cincinnati).

The study used an innovative Bayesian response adaptive randomization design developed by Byron J Gajewski Ph.D., a professor in the department of Biostatistics & Data Science in the KU School of Medicine and one of three principal investigators on the study. "The study design allowed us to preserve the rigor of the study while allowing us to more efficiently work to accomplish the study goals," he said. One example of that, Gajewski said, is that once one arm of the study showed more success, future enrollees were more likely to be placed into that arm. "People enrolling the participants don't see behind the scenes, but the statisticians are able to use this technique to more efficiently get to the answers the study is seeking."

What The Study Did: Online search data were used to assess changes in home birth information seeking across the United States and United Kingdom during the COVID-19 pandemic.

Authors: Christina N. Schmidt, B.S., of the University of California, San Francisco, 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.2021.10310)

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.