Body

Starting six-month-old infants on solid food in the amounts recommended by standard feeding guides may lead to overfeeding, according to a study by scientists at the Johns Hopkins Bloomberg School of Public Health.

Solid food feeding guides are produced by infant formula makers, large children's hospitals and other infant health experts. They are meant to guide mothers and other caregivers in starting infants on solid food after initial exclusive milk and/or formula feeding. The new study, published July 25 in the American Journal of Preventive Medicine, found evidence that recommendations in four feeding guides, if followed from age 6 to 12 months, would likely result in overfed, overweight infants.

"It is very important that children aren't overfed during infancy because we know that can lead to weight gain and related health problems later in life, yet the model used in our study showed that following current established guidelines could often lead to overfeeding of the infant," says study first author Marie Ferguson, MSPH, a research associate in the Department of International Health at the Bloomberg School.

The study was based on a model involving computer-simulated infants that were fed certain diets, and their resulting growth was recorded. The study also measured the computer-simulated infants' metabolic rates and activity levels, and documented body size and other attributes that were sampled from normal ranges and tracked day by day from age 6 months to 12 months. The simulation also modeled the fact that mothers normally adjust feeding amounts in response to infant weight gain or weight loss.

Testing the impacts of these feeding guides with real infants in a clinical trial would be a complex undertaking, the authors note, and would involve ethical issues given the risk of over- or under-feeding infants participating in such a trial.

The Virtual Infant computer-simulation model used for the study was developed by a team led by study senior author Bruce Y. Lee, MD, MBA, an associate professor in the Bloomberg School's Department of International Health and executive director of the Global Obesity Prevention Center. "It is important to pay closer attention to what infants are getting fed and how parents are being advised. Overfeeding an infant can make it much tougher for him or her to maintain a healthy weight in the future."

The researchers first validated their model by feeding their virtual infants according to a standard reference guide on infant energy requirements. They found that the resulting growth of the virtual infants was essentially in line with growth curves published by the World Health Organization and other authorities.

The team then simulated feeding of their virtual infants from age 6 to 12 months according to guides published by the Children's Hospital of Philadelphia, Johns Hopkins Medical Institutions, Enfamil and Similac. For every one of these guides, the researchers ran four simulations. Each modeled 1,000 infants, assumed standard breastmilk intake and assumed solid food intake according to the guide, but included a different rule about caregiver adjustments to solid food portions.

Ferguson and her colleagues found, in their initial analysis, that following each of the four guides for just a few months would drive the average body mass index (BMI) for the virtual infants into the "overweight" category--above the 85th percentile for BMIs. This finding applied even for the scenario in which solid food portions were kept to the lowest 25 percent (quartile) of the guide's recommended range.

The solid food feeding guide that seemed to produce the healthiest results was the Similac guide. In the most favorable scenario, with feeding portions kept to the lowest quartile, following the Similac guidelines did not move infants into the overweight category until age 10 months for girls and 11 months for boys.

Even when the team ran further simulations assuming that breastmilk portions were halved, all guides except Similac led to overweight BMIs between 9 and 11 months.

The results, Ferguson says, suggest that although current standard solid food guidelines may have been based on the best available evidence, that evidence may not have been good enough.

"Our study shows what could happen when parents follow standard feeding guidelines and suggests that these guidelines may need to be revisited and revised," Ferguson says. "Feeding guidelines may also need to be adjusted and personalized to better match an individual infant's body type and metabolism."

Phoenix, Ariz. (July 25, 2019) - The Ivy Brain Tumor Center at the Barrow Neurological Institute, has released the results of its recent Phase 0 clinical trial of the breast cancer drug ribociclib (Kisqali®) for the treatment of recurrent glioblastoma. The agent, recently approved by the FDA for advanced breast cancer, is part of a newly-discovered class of targeted therapy that undermines cancer cell division and could form the backbone of a new drug cocktail for patients with malignant brain tumors like glioblastoma.

"Glioblastoma presents singular, complex challenges as compared to other types of cancer," said Dr. Nader Sanai, director of the Ivy Brain Tumor Center. "You are not dealing with a single entity, but rather a collection of genetic variants that differ from patient to patient. This Phase 0 clinical trial used a precision medicine approach to uncover which subtypes of glioblastoma may respond to ribociclib and how our patients' tumors developed resistance to the new therapy."

Results from the trial show that ribociclib is uniquely capable of breaking through the blood-brain barrier, a critical obstacle that for years has stalled drug development in brain tumor patients, and that the drug effectively hits its molecular target in cancer cells. The experimental Phase 0 clinical trial design also identifies a potential mechanism of drug resistance, which the Ivy Brain Tumor Center clinical trials team is now exploiting as part of an ongoing drug cocktail trial for recurrent glioblastoma patients.

"This comprehensive study has helped us to identify a potent combined-drug regimen to undermine a glioblastoma resistance mechanism to ribociclib. In less than a year, we have made tremendous progress in moving towards creating a new drug cocktail, which is significant given how precious time is for both patients and physicians fighting this disease," said Dr. Sanai.

Study results were released in Clinical Cancer Research, a journal published by the American Association of Cancer Research.

BOSTON - Scientists at Dana-Farber Cancer Institute have demonstrated that an artificial intelligence tool can perform as well as human reviewers - and much more rapidly - in extracting clinical information regarding changes in tumors from unstructured radiology reports for patients with lung cancer.

The AI tool performed comparably to trained human "curators" in detecting the presence of cancer; and whether it was responding to treatment interventions, stable or worsening.

The goal of the study, said corresponding author Kenneth Kehl, MD, MPH, a medical oncologist and faculty member of the Population Sciences Department at Dana-Faber, was to determine whether artificial intelligence tools can extract the most high-value cancer outcomes from radiology reports, which are a ubiquitous but unstructured data source.

Kehl noted that electronic health records now collect vast amounts of information on thousands of patients seen at a center like Dana-Farber. However, unless the patients are enrolled in clinical trials, information about their outcomes, such as whether their cancers grow or shrink in response to treatment, is recorded only in the text of the medical record. Historically, this unstructured information is not amenable to computational analysis and therefore could not be used for research into the effectiveness of treatment.

Because of studies like the Profile initiative at Dana-Farber/Brigham and Women's Cancer Center, which analyzes patient tumor samples and creates profiles that reveal genomic variants that may predict responsiveness to treatments, Dana-Farber researchers have accumulated a wealth of molecular information about patients' cancers. "But it can be difficult to apply this information to understand what molecular patterns predict benefit from treatments without intensive review of patients' medical records to measure their outcomes. This is a critical barrier to realizing the full potential of precision medicine," said Kehl.

For the current study, Kehl and colleagues obtained over 14,000 imaging reports for 1,112 patients and manually reviewed records using the "PRISSMM" framework. PRISSMM is a phenomic data standard developed at Dana-Farber that takes unstructured data from text reports in electronic health records and structures them so that they can be readily analyzed. PRISSMM structures data pertaining to a patient's pathology, radiology/imaging, signs/symptoms, molecular markers, and a medical oncologist's assessment to create a portrait of the cancer patient journey.

Human reviewers analyzed the imaging text reports and noted whether cancer was present and, if so, whether it was worsening or improving, and if the cancer had spread to specific body sites. These reports were then used to train a computational "deep learning" model to recognize these outcomes from the text reports. "Our hypothesis was that deep learning algorithms could use routinely generated radiology text reports to identify the presence of cancer and changes in its extent over time," the authors wrote.

The researchers compared human and computer measurements of outcomes such as disease-free survival, progression-free survival, and time to improvement or response, and found that the AI algorithm could replicate human assessment of these outcomes. The deep learning algorithms were then applied to annotate another 15,000 reports for 1,294 patients whose records had not been manually reviewed. The authors found that computer outcome measurements among these patients predicted survival with similar accuracy to human assessments among the manually reviewed patients.

The human curators were able to annotate imaging reports for about three patients per hour, a rate at which one curator would need about six months to annotate all of the nearly 30,000 imaging reports for the patients in the cohort. By contrast, the artificial intelligence model that the researchers developed could annotate the imaging reports for the cohort in about 10 minutes, the researchers said in a report in JAMA Oncology.

"To create a true learning health system for oncology and to facilitate delivery of precision medicine at scale, methods are needed to accelerate curation of cancer-related outcomes from electronic health records," said the authors of the publication. If applied widely, the investigators said, "this technique could substantially accelerate efforts to use real-world data from all patients with cancer to generate evidence regarding effectiveness of treatment approaches." Next steps will include testing this approach on EHR data from other cancer centers and using the data to discover which treatments work best for which patients.

Women and minority groups are underrepresented in Emergency Medical Services (EMS) in the US and workforce diversity is not likely undergo big changes anytime soon, according to a new ten-year study of almost 700,000 newly certified emergency medical technicians (EMTs) and paramedics, published in Prehospital Emergency Care.

"A diverse healthcare workforce can reduce health disparities and inequities in the delivery of care to minority patient populations", said Dr. Remle Crowe, a Research Scientist at ESO in Austin Texas and lead author of the study. EMS serves as an important entry point to the healthcare system for diverse populations. However, few studies have focused on the gender and racial/ethnic diversity of those entering the EMS workforce.

Dr. Crowe and colleagues at The Ohio State University and the National Registry of EMTs, examined the gender and racial/ethnic composition of the 588,337 EMTs and 105,356 paramedics who earned initial National EMS Certification from 2008 to 2017.

Throughout this period, less than a quarter of newly certified paramedics were female (range: 20%-23%). The proportion of newly certified EMS professionals identifying as black remained near 5% among EMTs and 3% among paramedics; and for Hispanics, the proportion rose from 10% to 13% among EMTs and from 6% to 10% among paramedics.

Compared to the US population in 2017, women and racial/ethnic minorities remained underrepresented among newly certified EMS professionals, and these representation differences varied across geographic regions. For example, in the Northeast there were 93% fewer newly certified EMTs who identified as black compared to the US population (4% vs. 11%) and the difference was 138% for new paramedics (4% vs. 11%).

While efforts to increase diversity among healthcare professionals are increasing on a national scale, few have specifically targeted EMS, the authors note.

"Diversity among EMS professionals is important for fomenting multicultural awareness, enhancing patient-provider communication, and improving equality in the delivery of care," said Dr. Crowe. "However, we're unlikely to see substantial changes in the diversity of the EMS workforce in the near future. Women and racial/ethnic minority groups remain underrepresented among recent graduates, and the gaps are more pronounced among paramedics. This is particularly concerning as paramedics provide more critical invasive interventions and make complex, time-sensitive decisions regarding care.

"Improving diversity in the EMS workforce will require coordinated national recruitment efforts to encourage underrepresented groups to pursue careers in EMS, the authors conclude. Examples of direct and indirect practices that could lead to increased recruitment include partnerships with schools, particularly elementary and middle schools, and community engagement initiatives that involve youth activities and classes.

WASHINGTON, DC (July 25, 2019) - Resources are limited on an airplane during an in-flight emergency and access to care is not always immediate. A new study published in Annals of Emergency Medicine reveals that 15.5 percent of in-flight emergencies involve children and that one in six cases require additional care.

"While traveling on a plane, it's important to make sure our most vulnerable and precious cargo -- our children -- are as safe as possible, especially if a medical emergency should occur," said Alexandre T. Rotta, MD, chief, Division of Pediatric Critical Care Medicine at Duke University Medical Center and lead study author. "We hope this study informs opportunities to improve in-flight safety equipment and highlights the importance of coordination between in-air and ground-level emergency response. It is also important for parents to be mindful of steps they can take to avoid emergencies while traveling."

The most common medical incidents involved nausea and vomiting (33.9 percent), fever or chills (22.2 percent), or acute allergic reaction (5.5 percent). Other common incidents were abdominal pain (4.7 percent), stomach flu (4.5 percent), syncope (3.5 percent) and seizure (2.6 percent). There were 11 in-flight deaths.

Lap infants comprised 14 percent of the global sample of in-flight pediatric emergencies. The most common emergencies for these tiny travelers included fever (33 percent), vomiting (18.3 percent), blunt trauma (6.9 percent), respiratory distress (5.7 percent) or seizures (4.8 percent).

"Parents should take precautions to avoid in-flight medical events when possible," said Dr. Rotta. "For example, remember to carry your child's medicine onto the plane rather than leaving it in checked baggage, since on-board emergency medical kits currently are not tailored to address issues most commonly experienced by pediatric travelers."

The study found that crewmembers provided the vast majority of pediatric in-flight emergency care (86.6 percent), with physician and nurse passenger volunteers providing 8.7 percent and 2.1 percent of the care, respectively. While most incidents were resolved in-flight (82.9 percent), one in six (16.5 percent) required additional care upon landing and only 0.5 percent required airplane diversion.

"Certain types of pediatric in-flight medical events, like seizures or cases requiring the involvement of an onboard nurse or physician medical volunteer, are significantly more likely to result in aircraft diversion," added Dr. Rotta. "However, not every serious in-flight emergency leads to diversion. Although input from the onboard medical volunteer is considered, the decision to divert rests ultimately with the pilot in command and must weigh multiple factors, including the safety of all passengers and crew, fuel load, and the availability of suitable diversion points."

Study authors examined in-flight medical emergency records from January 2015 through October 2016 involving children under the age of 19. A total of 75,587 unique calls were analyzed and 11,719 (15.5 percent) involved children. The calls originated from flights involving 77 airlines on six continents.

Delivering two federally approved immunity-altering drugs together significantly extended the lives of mice injected with human ovarian cancer cells, an early proof-of-concept experiment that may advance treatment for the most deadly -- although rare -- gynecologic malignancy in humans, according to scientists at the Johns Hopkins Kimmel Cancer Center who performed the research.

The combination treatment appears to improve survival by changing the natural ratio of different types of immune system "clean up" cells called macrophages, a therapy target that's received less attention than other immune system components but could hold promise for patients with various types of malignancies, the investigators say.

"Together these drugs could one day make some headway where other therapies have failed," says study leader Cynthia Zahnow, Ph.D., associate professor of oncology at the Johns Hopkins Kimmel Cancer Center.

A report on the findings was published online in the July issue of Cancer Research.

Over the past decade, Zahnow notes, several cancer clinical trials have shown promise for a class of drugs known as epigenetic therapies, which remove chemical groups on DNA and proteins that affect the activity of cancer-related genes. Although the drugs mainly battle cancer by returning the function of cancer-fighting genes that have become suppressed by the disease itself, researchers have also discovered that the drugs may trigger an anti-viral, immune response that may help the body attack tumors.

A different class of drugs, known as polyamine-blocking therapies, has also shown potential in inhibiting tumor growth in animal models by preventing the synthesis and/or transport of molecules necessary for cancer cells to thrive. These agents also affect the immune system, with studies showing that they alter the makeup of immune cell populations in tumor microenvironments.

However, Zahnow says neither class of drugs alone has been shown effective against ovarian cancer, a disease that kills about 20,000 women per year in the U.S. even though it accounts for only 3% of cancers in women.

Because both drug classes alter immune cell behavior, Zahnow, co-study leader Robert Casero Jr., Ph.D., professor of oncology, and their colleagues reasoned that they could be more effective at fighting ovarian cancer when combined.

The researchers tested this idea in a mouse model in which the animals' abdominal cavities were injected with human ovarian cancer cells to generate disseminated disease often seen in women with ovarian cancer. Over the course of several weeks, the rodents developed ascites, or fluid collections in their abdomens full of cancer and immune cells, as a consequence of cancer progression. By sampling the fluid weekly, the researchers obtained a window on tumor growth and immune activity simultaneously over time.

In a set of experiments, three days after the mice were injected with cancer cells, the researchers put the mice on one of four treatment regimens: injections of saline (as a "control" treatment); an epigenetic drug known as 5-azacytidine (AZA); a polyamine-blocking drug known as 2-difluoromethylornithine (DFMO); or a combination of AZA and DFMO. Currently, AZA is FDA approved to treat a bone marrow disorder known as myelodysplastic syndrome, and DFMO is FDA-approved for African sleeping sickness.

Their results showed that mice that received the single agents lived slightly longer compared with mice that received just saline -- an average of 44 days after they were injected with cancer cells. However, mice treated with the combination therapy lived about 25% longer, to 59 days.

Examining cancer and immune system cells present in the animals' ascites showed that the drug combination had no effect on most immune cell types compared with treatment with the single agents. However, there were two exceptions.

They found increases in cytotoxic lymphocytes, a type of white blood cell, including both T cells and natural killer cells, which are tumor-fighting immune system cells, but Zahnow said the effect didn't seem large enough to explain the significant increase in survival of the treated mice.

More importantly, they said, they found a greater change in the ratio of two types of macrophages, immune cells that digest foreign material and cell debris while regulating other immune processes. Previous studies have shown that M1 macrophages can protect against tumor growth and progression, while M2 macrophages promote tumor growth.

While the combined treatment greatly reduced the total number of macrophages, it left more M1 macrophages than M2. When the researchers blocked the activity of all macrophages with an antibody that inhibits them, the combination therapy lost its survival effect, demonstrating the importance of this M1 population of immune cells to fight the cancer.

Zahnow says the combination therapy is especially promising because of the significant boost it gave to the animals' survival, but also because both agents are already approved for use to treat other conditions. "DFMO is so nontoxic that it also could provide a buffer in patients' drug regimens that would help them add other potent medications with more significant side effects," says Zahnow. Such regimens might include medications that could further offset the balance between M1 and M2 macrophages as a patient's disease returns or progresses, hallmarks of ovarian cancer.

The team is currently testing combined AZA and DFMO therapy in other animal models of cancer in which macrophages play a prominent role, including breast and pancreatic cancers.

To successfully set off disease, rotavirus, a virus that causes severe diarrhea and vomiting in children around the world, must invade cells of the gastrointestinal track and trigger a surge of calcium inside the cells. How this surge occurs has not been clarified, but a report in the journal Scientific Reports released today shows in cinematic detail the dynamic changes in calcium that follow rotavirus invasion.

Using time-lapsing imaging and other experimental approaches, researchers at Baylor College of Medicine and Indiana University reveal that rotavirus induces hundreds of discrete and highly dynamic calcium spikes that increase during peak infection. The calcium spikes can be attenuated by genetically knocking down rotavirus protein NSP4, which is known to disturb calcium balance within cells. The spikes originate from calcium released from the endoplasmic reticulum, a specialized structure within cells, into the cytoplasm of the cell.

The study's findings open new ways to better understand what the virus does to cause disease.

MINNEAPOLIS - Having a bigger waistline and a high body mass index (BMI) in your 60s may be linked with greater signs of brain aging years later, according to a study published in the July 24, 2019, online issue of Neurology®, the medical journal of the American Academy of Neurology. The study suggests that these factors may accelerate brain aging by at least a decade.

"People with bigger waists and higher BMI were more likely to have thinning in the cortex area of the brain, which implies that obesity is associated with reduced gray matter of the brain," said study author Tatjana Rundek, MD, PhD, of University of Miami Miller School of Medicine and a member of the American Academy of Neurology. "These associations were especially strong in those who were younger than 65, which adds weight to the theory that having poor health indicators in mid-life may increase the risk for brain aging and problems with memory and thinking skills in later life."

The study involved 1,289 people with an average age of 64. Two-thirds of the participants were Latino. Participants' BMI and waist circumference were measured at the beginning of the study. An average of six years later, participants had MRI brain scans to measure the thickness of the cortex area of the brain, overall brain volume and other factors.

A total of 346 of the participants had a BMI of less than 25, which is considered normal weight; 571 people had a BMI of 25 to 30, which is considered overweight; and 372 people had a BMI of 30 or higher, which is considered obese.

For waist circumference, which can be different for men and women, the normal weight group, which was 54 percent women, had an average of 33 inches. The overweight group, which was 56 percent women, had an average of 36 inches, and the obese group, which was 73 percent women, had an average of 41 inches.

Having a higher BMI was associated with having a thinner cortex, even after researchers adjusted for other factors that could affect the cortex, such as high blood pressure, alcohol use and smoking. In overweight people, every unit increase in BMI was associated with a 0.098 millimeter (mm) thinner cortex and in obese people with a 0.207 mm thinner cortex. Having a thinner cortex has been tied to an increased risk of Alzheimer's disease.

Having a bigger waist was also associated with a thinner cortex after adjusting for other factors.

Rundek said, "In normal aging adults, the overall thinning rate of the cortical mantle is between 0.01 and 0.10 mm per decade, and our results would indicate that being overweight or obese may accelerate aging in the brain by at least a decade."

"These results are exciting because they raise the possibility that by losing weight, people may be able to stave off aging of their brains and potentially the memory and thinking problems that can come along with brain aging," Rundek said. "However, with the rising number of people globally who are overweight or obese and the difficulty many experience with losing weight, obviously this is a concern for public health in the future as these people age."

Rundek noted that the study does not prove that extra weight causes the cortex to get thinner; it only shows an association.

A limitation of the study was that, like many studies of older people, it is possible that the healthiest people are more likely to live longer and take part in studies, so that may affect the results.

Treatment with the FGFR inhibitor erdafitinib in patients with metastatic bladder cancers marked by mutations in the FGFR3 gene resulted in a 40% overall response rate (ORR) and was well-tolerated, according to an international Phase II trial led by The University of Texas MD Anderson Cancer Center.

The trial results, published today in the New England Journal of Medicine, led to approval of erdafitinib in April by the Food and Drug Administration (FDA), making it the first targeted therapy approved for treating patients with advanced bladder cancer.

The oral targeted therapy also achieved a 59% ORR in patients for whom immunotherapy had previously failed, indicating this may be a viable option for these patients in need of alternative treatments. The findings were first reported at the 2018 American Society of Clinical Oncology Annual Meeting by principal investigator Arlene Siefker-Radtke, M.D., professor of Genitourinary Medical Oncology.

"Patients have been in desperate need for alternative strategies, especially when a large number of patients cannot tolerate the current standards of care," said Siefker-Radtke. "We were very gratified to see a 40% response rate in patients treated on this clinical trial. Not only did it work well in patients with lymph node metastases, but also in patients with high volume and very aggressive disease."

Standard of care for these cancers is cisplatin-based chemotherapy, an aggressive regimen with significant side effects, and this has largely remained unchanged for several decades, explained Siefker-Radtke. Recently, immune checkpoint inhibitors have been approved for the treatment of advanced bladder cancer, but only 15 to 20% of patients see any benefit from these therapies, she said.

"I noticed that I wasn't seeing a great response to immune checkpoint inhibitors in my patients with FGFR3 mutations, which led me to wonder whether this would reflect a group of patients with an unmet need," said Siefker-Radtke. "When we heard about novel agents targeting this pathway, I became quite interested in exploring them in our bladder cancer patients."

Mutations in FGFR3 are present in approximately 15 to 20% of patients with metastatic bladder cancer and up to 35% of patients with other urothelial cancers, such as those of the renal pelvis and ureter. The international trial enrolled 99 patients with metastatic or surgically unresectable urothelial cancer and verified alterations in the FGFR3 gene.

Three patients in the trial had complete responses, or tumor disappearance, and 39 had percent stable disease. Median PFS was 5.5 months and median OS was 13.8 months. Among 22 patients previously treated with immunotherapy, 59% (13) had a partial or complete response.

"With a response rate of over 50% in patients previously treated with immunotherapy, the data suggest treatment with erdafitinib may be preferential for patients with FGFR3 mutations. However, this is preliminary evidence, so we need additional data to confirm this finding," said Siefker-Radtke.

All patients on the trial reported side effects from the therapy, with 21% discontinuing treatment due to adverse events and 67% reporting grade 3 or 4 adverse events. The most common treatment-related side effects were stomatitis (9%), nail dystrophy (6%), and hand-foot syndrome (5%).

Based on the results of the trial, the FDA granted a breakthrough therapy designation to erdafitinib in 2018 and approved the drug in April 2019 for treating patients with locally advanced or metastatic urothelial cancers with mutations in the FGFR2 or FGFR3 genes.

"With the recent approval of erdafitinib for the treatment of patients with FGFR3-mutant urothelial cancers, we now have an additional agent to add to our armamentarium," said Siefker-Radtke. "My hope is we will be able to add this to our treatment strategy, learn how it combines with immunotherapy and how we can use the effects of this drug to improve the survival for all of our bladder cancer patients."

A Phase III trial currently is underway to evaluate the efficacy of erdafitinib relative to chemotherapy or the checkpoint blockade inhibitor pembrolizumab in patients with metastatic urothelial cancer and FGFR3 mutations.

Having a bigger waistline and a high body mass index (BMI) in your 60s may be linked with greater signs of brain aging years later, according to a study published by a leading University of Miami neurologist researcher in the July 24, 2019, online issue of Neurology®, the medical journal of the American Academy of Neurology. The study suggests that these factors may accelerate brain aging by at least a decade.

"People with bigger waists and higher BMI were more likely to have thinning in the cortex area of the brain, which implies that obesity is associated with reduced gray matter of the brain," said study author Tatjana Rundek, M.D., Ph.D., a UHealth neurologist, professor of neurology, epidemiology, and public health and scientific director of the Evelyn F. McKnight Brain Research Institute.

"These associations were especially strong in those who were younger than 65, which adds weight to the theory that having poor health indicators in mid-life may increase the risk for brain aging and problems with memory and thinking skills in later life," said Dr. Rundek,

The study involved 1,289 people with an average age of 64. Two-thirds of the participants were Latino. Participants' BMI and waist circumference were measured at the beginning of the study. An average of six years later, participants had MRI brain scans to measure the thickness of the cortex area of the brain, overall brain volume and other factors.

A total of 346 of the participants had a BMI of less than 25, which is considered normal weight; 571 people had a BMI of 25 to 30, which is considered overweight; and 372 people had a BMI of 30 or higher, which is considered obese.

For waist circumference, which can be different for men and women, the normal weight group, which was 54 percent women, had an average of 33 inches, the overweight group, which was 56 percent women, had an average of 36 inches, and the obese group, which was 73 percent women, had an average of 41 inches.

Having a higher BMI was associated with having a thinner cortex, even after researchers adjusted for other factors that could affect the cortex, such as high blood pressure, alcohol use and smoking. In overweight people, every unit increase in BMI was associated with a 0.098 millimeter (mm) thinner cortex and in obese people with a 0.207 mm thinner cortex. Having a thinner cortex has been tied to an increased risk of Alzheimer's disease.

Having a bigger waist was also associated with a thinner cortex after adjusting for other factors.

Rundek said, "In normal aging adults, the overall thinning rate of the cortical mantle is between 0.01 and 0.10 mm per decade, and our results would indicate that being overweight or obese may accelerate aging in the brain by at least a decade."

"These results are exciting because they raise the possibility that by losing weight, people may be able to stave off aging of their brains and potentially the memory and thinking problems that can come along with brain aging," Rundek said. "However, with the rising number of people globally who are overweight or obese and the difficulty many experience with losing weight, obviously this is a concern for public health in the future as these people age."

Rundek noted that the study does not prove that extra weight causes the cortex to get thinner; it only shows an association.

A limitation of the study was that, like many studies of older people, it is possible that the healthiest people are more likely to live longer and take part in studies, so that may affect the results.

JUPITER, Fla.--July 24, 2019--Among HIV researchers, one seemingly indestructible HIV-like strain has earned the nickname "death star." That's due to the strain's reputation for killing off hopes for potential vaccines and immunotherapies that could prevent the disease.

A team at the Scripps Research Florida campus reports successfully beating that challenge. In a paper published in the journal Science Translational Medicine today, lead authors Michael Farzan, PhD, and Mathew Gardner, PhD, describe their destruction of the "death star" strain and another especially hard-to-fight strain, suggesting it may be possible to protect uninfected individuals from multiple forms of HIV.

Their nontraditional vaccine achieved another critical goal: durability. This means it protected the research animals from infection long-term, with a single inoculation, Farzan says.

"We have solved two problems that have plagued HIV vaccine studies to date--namely, the absence of duration of response and the absence of breadth of response," Farzan says. "No other vaccine, antibody or biologic protects against the two viruses for which we have demonstrated robust protection."

Globally, about 180,000 new HIV infections occur in children annually, according to UNAIDS, and about 1 million people a year die of HIV/AIDS-related illnesses. Developing an HIV vaccine that protects long-term with a single dose is an important goal, especially in places where medical resources can be scarce, anti-retroviral drugs may be unavailable, and the risk of mother-to-infant transmission of HIV can be high.

The Farzan group's work adds to the significant mark that Scripps Research is making in the fight against HIV. On July 10, the institute announced that the Scripps Consortium for HIV/AIDS Vaccine Development (CHAVD), an international collaboration led by Scripps Research, been awarded a $129 million, seven-year award from the National Institutes of Health to advance next-generation vaccines.

Conventional vaccine approaches typically use a piece of virus or other immunogen to activate an immune system response. Because HIV replicates and changes so quickly, that approach has proven challenging. Farzan's approach uses a safe virus to fight the dangerous one, and relies on muscle cells rather than immune cells to generate protective agents. Here's how: A harmless, lab-made adeno-associated virus (AAV) carries within it a protective protein designed by Farzan and colleagues to stop HIV infectivity.

Called eCD4-Ig, the protective protein features two HIV co-receptors, CD4 and CCR5. The latter was discovered by Farzan and his team over a decade ago. Farzan's viral vaccine is injected into muscle. It "infects" the muscle cells, which causes them to produce the protective eCD4-Ig. During exposure to HIV, the HIV virus is attracted to eCD4-Ig. It binds, and then "undergoes conformational change prematurely, and it's no longer able to infect," Farzan says.

The tough-to-stop research strain is SIVmac239, dubbed the "death star" because it has proven nearly impossible to defend against. It's a type of simian immunodeficiency virus, which is an HIV-like virus that can infect primates. Primates are the only animals, other than humans, that support replication of these viruses. There's much more work to be done, notes first author Gardner. The study showed that the research animals could eventually become infected when exposed to atypically large loads of HIV. It also showed that HIV is capable of developing resistance to eCD4-Ig, albeit in a much-weakened state.

Encouragingly, the research animals did not develop serious immune reactions to the adeno-associated viral vector or the eCD4-Ig. Farzan said they had made concerted efforts to minimize that risk.

The use of AAV as a gene therapy tool has generated considerable excitement recently, gaining FDA approval for genetic diseases including inherited retinal disease and spinal muscular atrophy. This study shows it also has the potential save lives used as a protective vaccine, Farzan says.

"The results of our paper are encouraging for the potential of AAV as a platform for prevention of disease generally, and in concert with eCD4 as an agent for stopping HIV infection," Farzan says. "We hope ultimately to prove that our approach is safe for both infected and at-risk persons at a cost that makes it useable everywhere."

Cellular soldiers created using the body's own defenses can track down and kill escaping cancer cells during surgeries, preventing metastasis and saving lives, a Vanderbilt University biomedical engineer has discovered, particularly in cases of triple negative breast cancer.

Michael King, J. Lawrence Wilson Professor of Engineering and chair of the biomedical engineering department, and his team attached two proteins to the surface of lipid nanoparticles: TNF-related apoptosis-inducing ligand - or TRAIL - and the adhesion receptor E-selectin. The injected nanoparticles then adhere to white blood cells, and the introduction of these TRAIL-coated leukocytes into the bloodstream before, during and after tumor removal kills all cancer cells loosed as a result.

"Collisions between the TRAIL-coated leukocytes and cancer cells in the bloodstream are happening constantly," King said. "We've tested this both in the bloodstream and in hundreds of blood samples from cancer patients being treated in clinics across the country. In all cases, within two hours, the viable cancer cells are cleared out. This has worked with breast, prostate, ovarian, colorectal and lung cancer cells."

Not only can the method work during surgeries, King said, but potentially with patients who already suffer metastatic cancer in multiple sites and who have no worthwhile treatment options. Because all the components of the TRAIL-coated leukocytes occur naturally in the body, it increases the potential for a quicker path from the bloodstreams of mouse models to human trials.

Surgical intervention in breast cancer is a known cause of metastatic growth and accelerated tumor relapse, either because of cancer cells shed during the process, inflammation at the wound site or a combination of the two factors. Chemotherapy is the most widely used treatment for the resulting metastasis, but still, the five-year survival rate for triple negative breast cancer sits well below 30 percent.

The group's past experiments with TRAIL-coated leukocytes were effective in blocking metastasis, but required multiple repeated injections to sustain their beneficial effect. King said this new breakthrough overcomes those issues by designing three simple doses to coincide with the surgical procedure.

Lina Colucci and colleagues have created a portable device that within 45 seconds accurately detected excess fluid buildup in the legs of seven participants with end-stage kidney failure. Their device is based on the same technology as that of larger MRI machines, but can take measurements at a fraction of the time and cost, indicating it could help prevent complications in patients with excess fluid levels. Treating patients with fluid buildup requires striking a delicate balance; removing too little fluid leaves them at risk of hypertension and heart failure, while removing too much leads to muscle cramps and low blood pressure. Fluid buildup, which impacts over six million people in the U.S., occurs in conditions such as kidney and congestive heart failure and costs the U.S. more than $35 billion annually, but current imaging techniques such as MRI machines are expensive and can only be used in hospitals, making them impractical for routine use. Lina Colucci and colleagues created an alternative, non-imaging tool based on portable nuclear magnetic resonance (NMR) sensors, which can noninvasively assess fluids and their environment. Their platform contains a single-sided NMR sensor harboring 180 individual magnets, and was found to provide accurate measurements of leg fluid buildup when applied to seven participants with end-stage kidney disease, which were matched by results from an MRI machine and an FDA-approved device that estimates body fat and muscle mass. The authors believe their platform's portability and ease-of-use could allow clinicians to track fluid buildup at the bedside in a manner not possible with larger machines.

Use of medical imaging during pregnancy increased significantly in the United States, a new study has found, with nearly a four-fold rise over the last two decades in the number of women undergoing computed tomography (CT) scans, which expose mothers and fetuses to radiation. Pregnant women are warned to minimize radiation exposure.

This is the first large, multi-center study to assess the amount of advanced imaging occurring during pregnancy. The study, which included authors from UC San Francisco, UC Davis and Kaiser Permanente, published July 24, 2019, in JAMA Network Open.

Over the 21-year study period, rates of CT increased nearly four-fold in the United States, and doubled in Ontario, Canada.

"Most pregnant women get routine ultrasound to monitor fetal growth, which delivers no ionizing radiation," said co-lead author Diana L. Miglioretti, PhD, biostatistics professor at the UC Davis Department of Public Health Sciences and senior investigator with Kaiser Permanente Washington Health Research. "But occasionally, doctors may want to use advanced imaging to detect or rule out a serious medical condition of the expectant mother, most often pulmonary embolism, brain trauma or aneurysm, or appendicitis."

That imaging could include CT, which involves a large dose of ionizing radiation -- many times more than a chest X-ray. Ionizing radiation carries potential health risks to the developing fetus, including congenital abnormalities, developmental delays, or cancer.

"Imaging can be helpful, but it can be overused," said senior author Rebecca Smith-Bindman, MD, a UCSF professor of radiology, epidemiology and biostatistics, and of obstetrics, gynecology and reproductive medicine. "Always, but especially if you're pregnant, you should ask whether it is really medically necessary to have any imaging test that involves ionizing radiation."

The researchers said alternative methods that do not use radiation should be considered whenever possible to avoid unnecessary exposure of women and fetuses to imaging radiation.

"There's a tradeoff," Smith-Bindman said. "CT scans provide the clearest images, they can be done quickly, and are less expensive and more widely available. However, CT scans have the most ionizing radiation and they are commonly done in places of the body where the fetus is exposed to the radiation."

The authors said that professional organizations have not consistently recommended minimizing medical imaging during pregnancy. Their research opens a new avenue of inquiry into the potential risks involved.

"This study has given us a chance to look more closely at the use of advanced imaging in pregnancy," said Marilyn L. Kwan, co-lead author and senior research scientist in the Kaiser Permanente Northern California Division of Research. "It's important to quantify exposure to ionizing radiation because it can cause cancer and birth defects, and should be kept to a minimum, especially during pregnancy."

For their study, which tracked the combined use of advanced medical imaging during pregnancy, the researchers analyzed more than 3.5 million pregnancies at six U.S. health systems and the provincial health system of Ontario, Canada, between January 1, 1996, and December 31, 2016. They reviewed the use of advanced imaging, including CT, magnetic resonance imaging (MRI), conventional radiography, angiography and nuclear medicine.

During the 21-year study, 5.3 percent of pregnant women at U.S. sites and 3.6 percent in Ontario underwent imaging with ionizing radiation, the authors said. Rates of CT scanning during pregnancy in the U.S. started leveling off in 2007 and have been trending downward since 2010, the study found. Meanwhile, overall rates continued to climb in Ontario, but in 2016, they were nonetheless 33 percent lower than in the U.S. They also found that Ontario utilized MRI, which doesn't use radiation, more often than CT, which does.

Altogether, nearly one in 100 pregnancies in the United States and approximately two-thirds in Canada involved CT in 2016, researchers found. Imaging rates during the course of the study were highest in women under 20 and over 40 years old, as well as those who delivered preterm or were black, Native American or Hispanic.

The South African study shows that dolutegravir-containing regimens perform as well as the current efavirenz-containing one used for first-line antiretroviral treatment (ART) in South Africa and most of Africa.

These data are important in showing how dolutegravir and a new form of tenofovir (called tenofovir alafenamide - or TAF) perform in African populations, and in providing the scientific backing for the move to dolutegravir-containing regimens from efavirenz-containing ones worldwide.

The initial study results are also published today in the prestigious New England Journal of Medicine (NEJM).

Professor Francois Venter of Ezintsha, a sub-syndicate of the Wits Reproductive Health and HIV Institute (Wits RHI) at Wits University, today presented 48-week results from the ADVANCE study at the International AIDS Society scientific conference in Mexico City.

ALL REGIMENS - DOLUTEGRAVIR, TAF AND EFAVIRENZ - RAPIDLY AND EFFECTIVELY SUPPRESSED HIV

The ADVANCE study showed that at the 48-week mark, dolutegravir-containing regimens perform as well as the current efavirenz-containing regimens used for first-line antiretroviral treatment (ART) in South Africa and many other African countries.

ADVANCE is a 96-week study comparing two alternative antiretroviral drugs to the current first-line regimen of tenofovir disoproxil fumarate, emtricitabine and efavirenz, replacing tenofovir with TAF, replacing tenofovir with TAF, and replacing efavirenz with dolutegravir.

All three regimens were safe, with few side effects reported, other than weight gain. Discontinuations from treatment were mainly related to social and personal factors (people who were employed or older tended to be able to stay on treatment more), and not the drug regimens.

"These two new drugs are really important for our region - they will improve patients' lives, decrease the use of more toxic second-line drugs, and save money. In summary, all regimens, the new ones studied [dolutegravir and TAF] and the one South Africa uses currently [efavirenz], rapidly and effectively suppressed HIV. The regimens were also all very safe, with minimal side effects that we generally worry about - to bone, kidneys, liver and neuropsychiatric side effects. The one surprising side effect was weight gain, especially among women. To better understand the weight gain, and its longer-term consequences, more follow-up is needed, and this is being explored in the study in more detail," says Venter.

KEEPING AN EYE ON WEIGHT GAIN

The issue of weight gain in patients on integrase inhibitors (dolutegravir is an integrase inhibitor) received significant attention in March 2019 during the Conference on Retroviruses and Opportunistic Infections (CROI) held in Seattle, USA. There were several reports from studies, mainly in the US and Europe, that showed greater weight gain for those on integrase inhibitor-containing ART regimens.

ADVANCE is one of two studies on the African continent that provides an opportunity to investigate this issue. The other is a study called NAMSAL, conducted in Cameroon. More information on the weight gain seen in ADVANCE and NAMSAL was presented at IAS on Monday, 22 July 2019.

ADVANCE, similarly to those early reports at CROI 2019, found a steady rise in weight with the new drug regimens containing dolutegravir, especially among women and people who had more advanced HIV (low CD4 counts, higher viral loads), of around 5-6 kg on average at 48 weeks. The effect was worse when dolutegravir was combined with TAF. As the study is continuing to 96 weeks, this is an issue the study team continues to monitor, and further analysis on the weight gain will be forthcoming. As yet, there is no impact clearly evident on weight-linked health problems, including diabetes, lipids and blood pressure, but it may still be too early to see these.

DOLUTEGRAVIR-CONTAINING REGIMENS FOR SOUTH AFRICAN PUBLIC IN SEPTEMBER 2019

The data generated from ADVANCE have been shared with the South African Department of Health, the South African Health Products Regulatory Authority, the Food and Drug Administration and European regulators, as well as the World Health Organization to inform both local and international ART guidelines. The study team has been actively involved in assisting with the development of the new 2019 ART guidelines for South Africa.

South Africa will be introducing dolutegravir-containing regimens in September 2019 in the public sector (it is now available in private), a change that will affect millions of people living with HIV.

Dolutegravir-containing regimens are cheaper than efavirenz-containing ones, with fewer side effects and a greater resistance barrier. This study confirms the results in other studies in Europe and North America, and will revolutionise ART in South Africa and beyond, although the weight gain side effect has only been recently recognised.

TOWARDS 90-90-90 TARGETS

The savings in drug cost - as well as its robust resistance barrier stopping people from moving to more toxic and more expensive drugs - would allow South Africa to continue to scale up access to ART in order to meet the UNAIDS/WHO/SA Department of Health 90-90-90 targets. This refers to the goal of 90% of people living with HIV knowing their status, 90% of those being on ART, and 90% of those being virally supressed.

It was proposed that the new drugs investigated in ADVANCE might have benefits relating to cost to the public sector, resistance and side effects that would significantly impact the well-being of people living with HIV. To investigate if a new ART drug regimen could mitigate the side effects and low barrier to resistance of the current first-line of treatment, the ADVANCE study was designed with input from local and international collaborators, and funded by USAID, Unitaid, the South African Medical Research Council. ViiV Healthcare and Gilead Sciences donated the drugs.

ABOUT THE ADVANCE STUDY

The study enrolled 1053 ART naïve people living with HIV, of which around 60% were female, at two sites in Yeoville and Hillbrow, Johannesburg, South Africa. At 48 weeks, the virological suppression rates in all three study arms were very similar. This finding is important, as there has long been concern about rising transmitted drug resistance in South Africa. Additional analysis on pre-treatment drug resistance is ongoing.

The ADVANCE study was conceived by a team of research collaborators from Ezintsha (a subdivision of Wits RHI), the Clinton Health Access Initiative, the Bill and Melinda Gates Foundation, ViiV Healthcare, HIV i-Base, Mylan, the University of Liverpool, and Chelsea and Westminster Hospital, with subsequent input from ViiV Healthcare and Gilead Sciences, as well as the Department of Health, Treatment Action Campaign, WHO and others.

South African researchers from Wits University lead the study in an international alliance with public health and clinical researchers, the South African government, activist groups, and pharmaceutical manufacturers in a programme linked to community education programmes about the new drugs across the region.

The study was funded in 2015 through a grant from USAID (AID-OAA-A-15-00069), and in 2016 through a grant from Unitaid (2016-07-Wits RHI), with additional financial support from the South African Medical Research Council, and investigational study drugs donated by ViiV Healthcare and Gilead Sciences.

The study commenced in January 2017, and by May 2018 the recruitment of 1053 participants, mainly from inner-city Johannesburg, was finalised. Participants were randomised into three arms of 351 participants each: arm 1 receiving TAF (25mg), FTC (200mg) and DTG (50mg); arm 2 receiving TDF (300mg), FTC (200mg) and DTG (50mg); and arm 3 receiving TDF (300mg), FTC (200mg) and EFV (600MG).

In April 2019 all participants had completed their 48-week study visit, and it is this primary outcome that was reported at the 10th International AIDS Society Conference on HIV Science (IAS 2019), held in Mexico City from 21-24 July.

The study continues to provide valuable insights into antiretroviral treatment in a local cohort (with around 40% of the study population being from other African countries, reflecting the demography of inner-city Johannesburg). The study will complete 96 weeks in mid-2020, and additional analyses will be forthcoming.

This study shows the value of investing in local research, and aside from the funders listed, has had strong support from the South African government, through the Departments of Health, as well Science and Technology.