Body

A promising new tissue engineering approach may one day improve outcomes for patients who have undergone discectomy - the primary surgical remedy for spinal disc herniations. Tested in live sheep for more than six weeks, the technique is among the first to address damage to both components of intervertebral discs: the tough outer ring, or annulus fibrosus (AF), and the gelatinous inner core, the nucleus pulposus (NP). A spinal disc herniates when the AF ruptures, resulting in a bulbous protrusion of NP tissue that can impinge nearby spinal nerves. This nerve pressure can cause substantial pain and, in extreme cases, loss of sensation and motor control. To relieve this pressure, a surgeon may perform a discectomy to remove the protruding NP tissue. However, there are currently no approved methods to restore lost NP tissue or to repair damage to the ruptured AF, leaving patients at risk of additional herniations and further disc degeneration. Prior tissue engineering work has suggested that repairing the AF or the NP alone is not enough - both components must be restored to ensure a positive outcome. Stephen Sloan and colleagues addressed this using a tissue engineering approach based on biomolecules present in healthy connective tissue, cartilage, muscle and skin. By injecting hyaluronic acid into the NP of live sheep that had undergone lumbar discectomy, the researchers improved the hydration and structural integrity of NP tissue. Then, during the same surgery, the researchers applied a crosslinked collagen patch to locally repair the wounded AF tissue. After six weeks of testing, their combined method substantially improved the structure and function of the sheep's spinal discs. Sloan et al. suggest that, with further development and testing, their method could one day inform strategies to improve outcomes for human discectomy patients.

The use of PET-CT imaging gives doctors the best possible picture of non-small cell lung cancer (NSCLC), and this accurate imaging helps to match patients with the best treatments. Unfortunately, not every NSCLC patient gets the recommended PET-CT imaging. Now a University of Colorado Cancer Center study published in the Journal of the National Cancer Institute shows an important predictor of PET-CT use: African American patients were only about half as likely as non-Hispanic whites to receive this important imaging; Hispanics received this imaging about 70 percent as frequently as non-Hispanic whites.

"We started from the perspective of outcomes: we know that Black and Hispanic lung cancer patients tend to not do as well as non-Hispanic whites. We wondered if there could also be differences in how these groups are imaged at diagnosis," says Rustain Morgan, MD, CU Cancer Center investigator and assistant professor in the CU School of Medicine Department of Radiology.

The study, with co-authors Sana Karam, MD, PhD, and Cathy Bradley, PhD, looked at PET-CT use and outcomes of 28,881 non-Hispanic Whites, 3,123 African Americans, and 1,907 Hispanics diagnosed with NSCLC between 2007 and 2015. To focus on potential ethnic/racial differences, the study controlled for factors including education level and socioeconomics.

"Our study showed a couple things," Morgan says. "First, it reaffirmed that patients who are imaged with PET-CT at diagnosis have better cancer-specific survival. Second, it showed there is a significant difference in who gets the recommended PET-CT at diagnosis. And third, it leads to more questions, like what is driving this difference and are these disparities in adherence to imaging guidelines present in other cancers."

In cancer treatment, more advanced cancers generally require more aggressive treatments. Some earlier imaging strategies including chest radiography may identify a primary lung tumor but may not be sensitive enough to see smaller deposits of the disease, leading doctors and patients to underestimate a cancer's stage. Misidentifying a cancer's stage can lead to under-treating the disease, and possibly to worse outcomes.

"If African Americans and Hispanics aren't getting the best imaging, this could be a piece of the puzzle explaining why these patients with lung cancer tend to have worse outcomes than white patients," Morgan says.

He points to a couple possible explanations for these disparities. First, PET-CT machines are relatively specialized and expensive, meaning that not all hospitals have the capability to offer this imaging.

"For example, our safety net hospital, Denver Health, doesn't have a PET-CT machine. It is also rare for rural hospitals to have this equipment, which means patients would have to travel several hours to have their imaging," Morgan says. In fact, in addition to racial/ethnic disparities, Morgan's study also shows differences in PET-CT use based on the type of treatment facility: Patients treated at NCI-designated cancer centers were more likely than those treated at teaching hospitals and especially those treated at community cancer centers to receive PET-CT imaging.

"Another, and potentially even more problematic factor, could be unconscious bias is a driver of the differences we found," Morgan says.

Future studies hope to answer some of these questions. For example, Morgan is working with CU Cancer Center colleagues to plan a project examining the financial cost of inappropriate cancer staging. And, of course, now that a clearer picture of these disparities is starting to emerge, Morgan and colleagues hope to explore ways to ensure that all NSCLC patients receive the recommended imaging during the process of diagnosis.

"Now that we know more about this problem, we must find ways to address it," Morgan says.

When brains begin developing, there are a lot of moving parts -- and when mutations happen in early neurodevelopment, it can lead to disorders like macrocephaly and autism. But scientists don't know much about the ways that development goes askew, particularly in humans.

That's why Wei Zhang, a postdoctoral scholar and research associate at USC's Center for Craniofacial Molecular Biology, became interested in how specific genes can impact early brain development.

From a previous study, Zhang and his colleagues had already honed in on a particular gene -- RAB39b. They scoured the scientific literature to understand more about this gene and what it does.

RAB39b was reported as an autism spectrum disorder (ASD) risk gene, linked to the X chromosome, Zhang said. When this gene is mutated, it can lead to macrocephaly, ASD, intellectual disability, epilepsy and early onset Parkinson's disease. "However, the functional study of RAB39b is very limited, and the mechanism of RAB39b mutation leading to macrocephaly and ASD is not clear," he added. The researchers were intrigued and decided to investigate.

Macrocephaly/ASD belongs to a subset of autism. The brain surface area of a baby who will develop macrocephaly/autism hyper-expands in the weeks directly before and after birth, and then continues to grow larger than normal after birth, followed by the emergence of autistic social deficits. That makes the study of brain development critical for exploring the mechanism of ASD, Zhang said.

His lab already had a system developed to study brain development using a mouse model and human brain organoids -- miniature brains grown artificially in the lab. These organoids emerged a decade ago as pea-sized blobs, grown from human stem cells that self-organize into brain-like structures with electrically active neurons.

They've been used to make discoveries about Zika-caused microcephaly, schizophrenia and even to test new drugs.

Using those two models, Zhang and his colleagues deleted the RAB39B gene in both the mice and the human brain organoid. The mice showed signs of macrocephaly and autism-like behaviors, and the human brain organoids were enlarged and impaired with the removal of the gene.

Zhang said this shows how a mutation in this gene disrupts growth and differentiation of so-called neural progenitor cells, which go on to become different brain cell types.

Ultimately, that can contribute to macrocephaly and autistic-like behaviors. The research was directed and performed in the laboratory of Jianfu Chen, an assistant professor of USC, and was published last month in the journal Genes and Development. Associate Dean of Research Yang Chai PhD '91, DDS '96 also contributed to the research.

Approximately 1 in 59 children has been identified with autism spectrum disorder, according to estimates from the Centers for Disease Control's Autism and Developmental Disabilities Monitoring Network. Zhang said that this study can provide new insights into neurodevelopmental dysregulation and common pathways associated with macrocephaly and autism disorders across species.

Now that it's clear this gene has an important role in regulating new brain cell growth, Zhang and his colleagues hope to investigate RAB39b's role in regulating neuron activity-dependent signaling networks, for further exploring the mechanism of autism spectrum disorder.

When Gregory Poore was a freshman in college, his otherwise healthy grandmother was shocked to learn that she had late-stage pancreatic cancer. The condition was diagnosed in late December. She died in January.

"She had virtually no warning signs or symptoms," Poore said. "No one could say why her cancer wasn't detected earlier or why it was resistant to the treatment they tried."

As Poore came to learn through his college studies, cancer has traditionally been considered a disease of the human genome -- mutations in our genes allow cells to avoid death, proliferate and form tumors.

But when Poore saw a 2017 study in Science that showed how microbes invaded a majority of pancreatic cancers and were able to break down the main chemotherapy drug given to these patients, he was intrigued by the idea that bacteria and viruses might play a bigger role in cancer than anyone had previously considered.

Poore is currently an MD/PhD student at University of California San Diego School of Medicine, where he's conducting his graduate thesis work in the lab of Rob Knight, PhD, professor and director of the Center for Microbiome Innovation.

Together with an interdisciplinary group of collaborators, Poore and Knight have developed a novel method to identify who has cancer, and often which type, by simply analyzing patterns of microbial DNA -- bacterial and viral -- present in their blood.

The study, published March 11, 2020 in Nature, may change how cancer is viewed, and diagnosed.

"Almost all previous cancer research efforts have assumed tumors are sterile environments, and ignored the complex interplay human cancer cells may have with the bacteria, viruses and other microbes that live in and on our bodies," Knight said.

"The number of microbial genes in our bodies vastly outnumbers the number of human genes, so it shouldn't be surprising that they give us important clues to our health."

Cancer-associated microbial patterns

The researchers first looked at microbial data available from The Cancer Genome Atlas, a database of the National Cancer Institute containing genomic and other information from thousands of patient tumors. To the team's knowledge, it was the largest effort ever undertaken to identify microbial DNA in human sequencing data.

From 18,116 tumor samples, representing 10,481 patients with 33 different cancer types, emerged distinct microbial signatures, or patterns, associated with specific cancer types. Some were expected, such as the association between human papillomavirus (HPV) and cervical, head and neck cancers, and the association between Fusobacterium species and gastrointestinal cancers. But the team also identified previously unknown microbial signatures that strongly discriminated between cancer types. For example, the presence of Faecalibacterium species distinguished colon cancer from other cancers.

Armed with the microbiome profiles of thousands of cancer samples, the researchers then trained and tested hundreds of machine learning models to associate certain microbial patterns with the presence of specific cancers. The machine learning models were able to identify a patient's cancer type using only the microbial data from his or her blood.

The researchers then removed high-grade (stage III and IV) cancers from the dataset and found that many cancer types were still distinguishable at earlier stages when relying solely on blood-derived microbial data. The results held up even when the team performed the most stringent bioinformatics decontamination on the samples, which removed more than 90 percent of the microbial data.

Applying the microbial DNA test

To determine if these microbial patterns could be useful in the real world, Knight, Poore and team analyzed blood-derived plasma samples from 59 consenting patients with prostate cancer, 25 with lung cancer and 16 with melanoma, provided by collaborators at Moores Cancer Center at UC San Diego Health. Employing new tools they developed to minimize contamination, the researchers developed a readout of microbial signatures for each cancer patient sample and compared them to each other and to plasma samples from 69 healthy, HIV-negative volunteers, provided by the HIV Neurobehavioral Research Center at UC San Diego School of Medicine.

The team's machine learning models were able to distinguish most people with cancer from those without. For example, the models could correctly identify a person with lung cancer with 86 percent sensitivity and a person without lung disease with 100 percent specificity. They could often tell which participants had which of the three cancer types. For example, the models could correctly distinguish between a person with prostate cancer and a person with lung cancer with 81 percent sensitivity.

"The ability, in a single tube of blood, to have a comprehensive profile of the tumor's DNA (nature) as well as the DNA of the patient's microbiota (nurture), so to speak, is an important step forward in better understanding host-environment interactions in cancer," said co-author Sandip Pravin Patel, MD, a medical oncologist and co-leader of experimental therapeutics at Moores Cancer Center at UC San Diego Health.

"With this approach, there is the potential to monitor these changes over time, not only as a diagnostic, but for long-term therapeutic monitoring. This could have major implications for the care of cancer patients, and in the early detection of cancer, if these results continue to hold up in further testing."

Comparison to current cancer diagnostics

According to Patel, diagnosis of most cancers currently requires surgical biopsy or removal of a sample from the suspected cancer site and analysis of the sample by experts who look for molecular markers associated with certain cancers. This approach can be invasive, time-consuming and costly.

Several companies are now developing "liquid biopsies"-- methods to quickly diagnose specific cancers using a simple blood draw and technologies that allow them to detect cancer-specific human gene mutations in circulating DNA shed by tumors. This approach can already be used to monitor progression of tumors for some types of already-diagnosed cancers, but is not yet approved by the U.S. Food and Drug Administration (FDA) for diagnostic use.

"While there has been amazing progress in the area of liquid biopsy and early cancer detection, current liquid biopsies aren't yet able to reliably distinguish normal genetic variation from true early cancer, and they can't pick up cancers where human genomic alterations aren't known or aren't detectable," said Patel, who also serves as the deputy director of the San Diego Center for Precision Immunotherapy.

That's why there's often a risk that current liquid biopsies will return false-negative results in the setting of low disease burden. "It's hard to find one very rare human gene mutation in a rare cell shed from a tumor," Patel said. "They're easy to overlook and you might be told you don't have cancer, when you really do."

According to the researchers, one advantage of cancer detection based on microbial DNA, compared to circulating human tumor DNA, is its diversity among different body sites. Human DNA, in contrast, is essentially the same throughout the body. By not relying on rare human DNA changes, the study suggests that blood-based microbial DNA readouts may be able to accurately detect the presence and type of cancers at earlier stages than current liquid biopsy tests, as well as for cancers that lack genetic mutations detectable by those platforms.

Limitations and cautions

The researchers are quick to point out that there's still the possibility blood-based microbial DNA readouts could miss signs of cancer and return a false-negative result. But they expect their new approach will become more accurate as they refine their machine learning models with more data.

And while false negatives may be less common with the microbial DNA approach, false positives -- hearing you have cancer when you don't -- are still a risk.

Patel said that just because a cancer is detected early, it doesn't mean it always requires immediate treatment. Some DNA changes are non-cancerous, changes related to aging, harmless or self-resolve. You would never know about them without the test. That's why more screening and more cancer diagnoses might not always be a good thing, Patel said, and should be determined by expert clinicians.

The team also cautioned that even if a microbial readout indicates cancer, the patient would likely require additional tests to confirm the diagnosis, determine the stage of the tumor and identify its exact location.

Looking ahead

Knight said many challenges still lay ahead as his team further develops these initial observations into an FDA-approved diagnostic test for cancer. Most of all, they need to validate their findings in a much larger and more diverse patient population, an expensive undertaking. They need to define what a "healthy" blood-based microbial readout might look like among many, diverse people. They'd also like to determine whether the microbial signatures they can detect in human blood are coming from live microbes, dead microbes or dead microbes that have burst open, dispersing their contents -- an insight that might help them refine and improve their approach.

To advance blood-based microbial DNA readouts through the next steps toward regulatory approval, commercialization and clinical application of a diagnostic test, Knight and Poore have filed patent applications and they founded a spinout company called Micronoma, with co-author Sandrine Miller-Montgomery, PhD, professor of practice in the Jacobs School of Engineering and executive director of the Center for Microbiome Innovation at UC San Diego.

The latest study may prompt important shifts in the field of cancer biology, Poore said.

"For example, it's common practice for microbiologists to use many contamination controls in their experiments, but these have historically been rarely used in cancer studies," he said. "We hope this study will encourage future cancer researchers to be 'microbially conscious.'"

The researchers also suggest cancer diagnostics may only be the beginning for the newly discovered cancer-associated blood microbiome.

"This new understanding of the way microbial populations shift with cancer could open a completely new therapeutic avenue," Miller-Montgomery said. "We now know the microbes are there, but what are they doing? And could we manipulate or mimic these microbes to treat cancer?"

(Boston)--The longer you lead a healthy lifestyle during midlife, the less likely you are to develop certain diseases in later life.

The more time a person doesn't smoke, eats healthy, exercises regularly, maintains healthy blood pressure, blood sugar and cholesterol levels and maintains a normal weight, the less likely they are to develop diseases such as hypertension, diabetes, chronic kidney disease and cardiovascular disease or to die during early adulthood.

The American Heart Association (AHA) had recommended a renewed focus on prevention to reduce the development of risk factors for cardiovascular disease (CVD) as part of its 2020 Impact Goal to improve population cardiovascular health (CVH) by 20 percent and reduce CVD mortality by 20 percent. While unhealthy lifestyle behaviors are associated with higher risks for certain diseases and death, the association of the duration in which people maintain a healthy lifestyle with the risk of disease and death had not yet been studied.

Using data from the Framingham Heart Study (FHS), researchers from Boston University School of Medicine observed participants for approximately 16 years and assessed the development of disease or death. They found that for each five-year period that participants had intermediate or ideal cardiovascular health, they were 33 percent less likely to develop hypertension, approximately 25 percent less likely to develop diabetes, chronic kidney disease and cardiovascular disease, and 14 percent less likely to die compared to individuals in poor cardiovascular health.

"Our results indicate that living a longer period of time in adulthood with better cardiovascular health may be potentially beneficial, regardless of age. Overall, our findings underscore the importance of promoting healthy behaviors throughout the life-course," explained corresponding author Vanessa Xanthakis, PhD, FAHA, assistant professor of medicine at BUSM and Investigator for FHS.

The researchers hope this study will help people understand the importance of achieving an ideal cardiovascular health early in life and motivate them to maintain a healthy lifestyle. "On the community-level, this will overall help reduce morbidity and mortality associated with diseases such as hypertension, diabetes, chronic kidney disease and death during late adulthood."

These findings appear online in the journal JAMA Cardiology.

A new guide seeks to ensure healthcare providers are ready to help new mothers with the challenging first week of breastfeeding - and to address gaps in knowledge and support created in previous decades when breastfeeding was far less common.

Doctors increasingly have come to appreciate the benefits of breastfeeding, and they now encourage new moms to breastfeed exclusively for the first six months, when possible. But new mothers often face obstacles, and physicians and other care providers need to know the best ways to address those, the guide's authors say. Their article in the journal Pediatrics, based on evidence collected in the last 10 years, seeks to provide useful tools and information so new moms get the support they need.

"In the late '70s, early '80s, as few as 1 in 5 women even tried breastfeeding, so we lost a generation of doctors and nurses as well as family members and support people who had experience with exclusively breastfed babies," said Ann Kellams, MD, a study author and a pediatrician at UVA Children's. "Now that the benefits of exclusive breastfeeding are well-known, it is important for families and the doctors and nurses caring for them to be able to identify those at risk of complications."

Helping Moms With Breastfeeding

The article addresses a variety of important topics, including groups that may encounter difficulty breastfeeding, such as the increasing numbers of women having children later in life. It aims to help care providers better evaluate early breastfeeding, assess mom and infant risks, understand the implications of nutritional supplementation and ensure mom and baby receive the appropriate follow-up care.

The article includes a useful tool to help clinicians determine when moms need to supplement their natural flow of breast milk and if the mothers can do this on their own by expressing [collecting] their milk, or if they need donor human milk or infant formula. The authors note that most mothers can produce enough milk, and most babies are able to breastfeed exclusively. (Current guidelines call for exclusive breastfeeding for the first 6 months, when possible, followed by breastfeeding along with other foods until at least 12 months.)

"This state-of-the-art review highlights these evidence-based solutions and summarizes new tools that can be used to monitor and manage breastfeeding in order to help mothers achieve their personal breastfeeding goals," said the article's lead author, Lori Feldman-Winter, MD, of Cooper University Hospital-Cooper Medical School of Rowan University. "While the incidence of breastfeeding has been on the rise, many infants and mothers encounter difficulties starting out breastfeeding during the first week after delivery. Healthcare practitioners need the appropriate knowledge and skills to identify those at risk for breastfeeding problems to provide evidence-based solutions for breastfeeding management."

Co-author Alison Stuebe, MD, of the University of North Carolina School of Medicine, said care providers need to provide new moms with careful risk assessment, clear guidance and open communication. "Too often, mothers blame themselves when breastfeeding comes undone," she said. "Tailored support in the first week is essential so that every mother has the opportunity to nurture her baby at breast."

The antiretroviral drugs dolutegravir and emtricitabine/tenofovir alafenamide fumarate (DTG+FTC/TAF) may comprise the safest and most effective HIV treatment regimen currently available during pregnancy, researchers announced today. Their findings come from a multinational study of more than 640 pregnant women with HIV across four continents. The study results affirm updated recommendations for HIV treatment in pregnant women set forth by the World Health Organization (WHO). Previous research clearly has demonstrated that antiretroviral therapy (ART) to suppress HIV prevents perinatal HIV transmission and benefits the health of both mother and child. The current study compared three antiretroviral drug regimens and found that regimens containing dolutegravir (DTG) were more effective in suppressing HIV than a commonly used regimen containing efavirenz (EFV).

The Phase 3 clinical trial is called IMPAACT 2010 or VESTED (Virologic Efficacy and Safety of Antiretroviral Therapy Combinations with TAF/TDF, EFV and DTG). It was sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. VESTED was conducted by the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network, which receives support from NIAID, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Institute of Mental Health, all parts of NIH.

Lameck Chinula, M.B.B.S., M.Med., presented the findings today at the 2020 Conference on Retroviruses and Opportunistic Infections (CROI). Dr. Chinula is an assistant professor in the UNC Department of Obstetrics and Gynecology's Division of Global Women's Health at the UNC School of Medicine and Clinical Research Site Leader at UNC Project Malawi, a collaboration between UNC-Chapel Hill and the Malawi Ministry of Health.

"When a woman living with HIV is expecting, she can be confident that the same antiretroviral therapy she takes every day to protect her own health also helps protects her future child from acquiring HIV," said Anthony S. Fauci, M.D., NIAID Director. "Findings from the VESTED study suggest that a drug regimen containing dolutegravir provides the safest, most effective HIV treatment available during this critical time for women and their infants."

An estimated 1.5 million women worldwide living with HIV give birth each year. Since 2013, the WHO has recommended a regimen of three antiretroviral drugs--EFV, lamivudine (3TC) or FTC, and tenofovir disoproxil fumarate (TDF)--to treat HIV in pregnant women in resource-limited settings. In July 2019, the WHO updated their recommendations to include DTG-containing regimens.

Beginning in January 2018, VESTED investigators randomly assigned 643 women to begin HIV treatment 14-28 weeks into their pregnancies with EFV/FTC/TDF or two newer regimens: DTG+FTC/TAF and DTG+FTC/TDF. EFV/FTC/TDF is formulated as a single tablet, while the newer regimens each consist of a DTG tablet taken with a combined FTC/TAF or FTC/TDF tablet. The researchers found that nearly 98% of women who received either of the DTG-containing regimens were virally suppressed at the time of delivery, meaning their viral load (amount of HIV in the blood) was undetectable using standard tests. In contrast, 91% of women who received EFV/FTC/TDF were virally suppressed at delivery. Two infants, one in each of the groups that received DTG-containing regimens, were diagnosed with HIV within 14 days of birth. Researchers are currently investigating data on medication adherence and drug levels at the time of delivery.

The researchers found that 24% of women taking DTG+FTC/TAF had an adverse pregnancy outcome compared with 33% of women taking DTG+FTC/TDF or EFV/FTC/TDF. While these rates are high, they are consistent with adverse pregnancy event rates in low- and middle-income countries, where most participants live. These outcomes included pregnancy complications of preterm delivery, low infant birth weight based on gestational age (a measure of the age of a pregnancy which is taken from the beginning of the woman's last menstrual period), and stillbirth.

Together, these findings show that while all three regimens are safe and effective in pregnancy, HIV is better controlled by DTG-containing regimens, and DTG+FTC/TAF may lead to lower adverse pregnancy outcomes. The findings affirm WHO recommendations for use of DTG in pregnant women.

"A woman's choice of HIV treatment regimen should be based on the best evidence available," said Nahida Chakhtoura, M.D., of the Maternal and Pediatric Infectious Disease Branch at NICHD. "These results from the VESTED study represent the most up-to-date evidence on HIV treatment regimens during pregnancy and childbirth."

VESTED--co-chaired by Dr. Chinula and Shahin Lockman, M.D., M.Sc., of Brigham and Women's Hospital in Boston--enrolled participants at clinical research sites in Botswana, Brazil, India, South Africa, Tanzania, Thailand, Uganda, the United States and Zimbabwe. At enrollment, all participants were living with HIV, 14 to 28 weeks into their pregnancies and not currently on ART. Participants began receiving ART at enrollment during their second trimester of pregnancy. After childbirth, the women's infants received local standard-of-care interventions for HIV prevention after birth. Mothers were counseled on infant feeding options consistent with local standards of care, which included breastfeeding or formula feeding. The investigators are continuing to monitor the health of both mothers and infants up to 50 weeks after delivery.

"These findings include the first of many insights we hope to glean from the VESTED study," said Dr. Chinula. "My fellow researchers and I extend our heartfelt thanks to the study volunteers. Each played a vital role in supporting the wellbeing of women and babies around the world."

The VESTED results build on evidence that DTG is a safe and effective antiretroviral drug for people of childbearing potential. No cases of neural tube defects (serious congenital disorders of the brain and spine) were found in the VESTED study, though with treatment beginning after the first trimester in a moderate sample size, the study cannot accurately assess the risk of neural tube defects.

In 2018, investigators conducting the observational, NIH-funded Tsepamo Study in Botswana reported a 0.9% risk of neural tube defects in infants born to women who were taking DTG at the time of conception. A more recent analysis presented at the 10th International AIDS Society Conference on HIV Science in 2019 dropped that risk to 0.3%, relative to a 0.1% risk of neural tube defects found in newborns in the general Botswana population. At the same scientific conference, two complementary studies of infants born to women who were taking DTG at the time of conception also indicated a lower risk of neural tube defects than the Tsepamo Study had originally reported. Based on this evidence, WHO issued updated HIV treatment guidelines that reconfirmed recommendations to use DTG-containing regimens as the preferred ART option for all populations, including pregnant women and people of childbearing potential.

NIAID and NICHD provided funding to the IMPAACT 2010 (VESTED) clinical research sites. Gilead Sciences, Mylan and ViiV Healthcare Ltd. provided antiretroviral drugs for the study. ViiV also provided funding to IMPAACT for non-participant costs. For more information about the IMPAACT 2010 (VESTED) study, visit ClinicalTrials.gov using identifier NCT03048422.

Attention all family medicine physicians: Identify a computer scientist with expertise in artificial intelligence (AI). Pick up the phone. Make a connection. This is your chance to shape the future of the AI revolution. Dr. Winston Liaw, a researcher at the University of Houston College of Medicine, is encouraging fellow family medicine physicians to actively engage in the development and evolution of AI to open new horizons that make AI more effective, equitable and pervasive.

Liaw collaborated with Ioannis Kakadiaris, a Hugh Roy and Lillie Cranz Cullen University Professor of computer science, to co-author a commentary published in the Annals of Family Medicine. The researchers advocate for a synergistic relationship between AI and family medicine.

The AI revolution in medicine has been underway for decades. Computers already process data to detect disease and predict health outcomes, but the researchers see a unique opportunity to steer the current AI advances so they can deliver on the original promise of electronic health records (EHR). Introduced in 2009 to make health care more efficient and effective, EHRs have created more data entry work while lessening quality time with patients -- a doctor's "most precious resource," according to the authors. About half of family physicians experience symptoms of burnout, and one major reason is the increase in administrative duties, according to studies.

To be fair, said Liaw and Kakadiaris, electronic health records have led to some improvements in population health and quality, but the failures are blamed on a lack of engagement in design and implementation from those who actually use them every day -- the doctors. Liaw wants to make sure the voice of family medicine is "amplified" as AI evolves.

No one questions the power and capability of artificial intelligence. Machines can collate many sources of information-- imaging, labs, data from previous visits -- on a patient's chart much faster than humans. AI chatbots can help facilitate care and monitor patients between office visits. But only with evidence-based recommendations from the physicians on the front lines of patient care can AI truly elevate the practice of family medicine, the researchers contend.

"Computers are not the most important tool in medicine--personal relationships are and always will be," said Liaw and Kakadiaris. At the same time, "Computers can facilitate human interactions and make the time we have with patients more meaningful. But first, we need to recognize that computers are our partners and not our adversaries."

The new UH College of Medicine is focused on improving primary care specialties, and as chair of the Department of Health Systems and Population Health Sciences, Liaw said their innovative curriculum will incorporate informatics, or how to use data to improve patient care. The first class starts this summer.

With a joint appointment in the department, Kakadiaris is learning about the questions that medical school faculty are passionate about answering and is applying computer science methods to critical health problems. He and Liaw hope their partnership will move their respective fields forward and encourage other family medicine and computer science scholars to connect.

"We know that if we don't figure out how to use AI effectively, patient care will suffer, and our students' jobs will be harder because they'll have so much data that they won't know how to process it," said Liaw. "Our specialty has to figure out how to better use tech."

Associate Professor Anthony Leicht was part of an international group led by Professor John Saxton from Northumbria University and the University of East Anglia that studied how exercise might help prostate cancer sufferers who were about to start Androgen Deprivation Therapy (ADT).

The initial treatment for sufferers involves using drugs or surgery to reduce the level of androgen hormones, which prostate cancer cells usually require to multiply.

"The problem is ADT has several side-effects, including increased body fat, decreased cardiopulmonary fitness and increased fatigue. These can increase the risk of a cardiovascular event and reduce health-related quality of life," said Dr Leicht.

The research team tested 50 people to see if supervised exercise sessions could help reduce the side-effects of ADT and how long any benefits lasted after the exercise supervision was withdrawn.

"The exercise group completed three months of supervised aerobic and resistance exercise training involving two sessions a week for 60 minutes, followed by three months of self-directed exercise," said Dr Leicht.

The team found the exercise programs produced sustained benefits in patients' cardiovascular risk profile and quality of life. Differences in cardiopulmonary fitness and fatigue, however, did not continue after the period of supervised exercise ended.

"What was important, and different from most other studies, was that the patients started the exercise program before the ADT treatment began. Other studies have examined patients already undergoing treatment," Dr Leicht said.

"Secondly, we followed up during the period of self-directed exercise and found some of the benefits were ongoing."

Sustaining the exercise program was important because ADT side-effects continue to develop after the first three months of treatment.

"In older people we often see reductions in strength and physical function just three months after halting supervised exercise. They may stop exercising because of cost or other reasons.

"A more pragmatic approach such as home-based exercise or a shorter period of supervision with follow-on remote support could help get around these restrictions and provide measurable benefits to prostate cancer sufferers."

Hip dysplasia, common in both dogs and humans, and associated osteoarthritis are complex disorders influenced by a multitude of genes. Hip dysplasia causes changes to the structure and functioning of the joint, resulting in painful and progressive osteoarthritis that leads to the destruction of the articular surfaces of the hip joint. Additionally, inflammatory factors play a role in the development of osteoarthritis.

A canine study carried out at the University of Helsinki, Finland, uncovered novel loci associated with hip dysplasia and osteoarthritis, as well as those previously identified by the research group, on chromosomes 1, 9 and 28. For gene mapping, blood samples were collected from more than 700 German Shepherds that had relevant hip dysplasia phenotypes (normal hips to severe hip dysplasia) in the breeding database of the Finnish Kennel Club.

"The candidate genes in the associated loci revealed in this study are very interesting in terms of the disease mechanisms in hip dysplasia and osteoarthritis. However, the more specific causality of these genes remains to be shown in future studies," says Lea Mikkola from the Faculty of Veterinary Medicine, University of Helsinki.

The study highlights the hereditary nature and polygenic background of hip dysplasia. Due to the complexity of the disorder, gene tests for it cannot be developed in the same way as for disorders caused by a single gene.

"Nevertheless, understanding the genetic factors of complex diseases and their biological roles is important for the big picture. We may be able to develop better treatment options in the future when we come to understand which genes and related networks drive disease development, and how," Mikkola says.

The study of complex diseases requires extensive and high-quality datasets. In fact, the researchers wish to thank all of their partners for supporting their work, especially the owners of the dogs that took part in the study.

"The collection and categorisation of samples for the genetic analyses took a large effort, requiring versatile cooperation between researchers and dog owners. A particularly meaningful part of this study was that we also determined more specific hip dysplasia and osteoarthritis phenotypes. The Finnish canine DNA biobank founded and maintained by Professor Hannes Lohi was very important for the successful outcome. We have stored all of the samples collected in this project in the biobank", says Professor Antti Iivanainen, the principal investigator of the study.

Life expectancy is influenced not only by the traditional lifestyle-related risk factors but also by factors related to a person's quality of life, such as heavy stress. The biggest causes for shortened life expectancy for 30-year-old men are smoking and diabetes. Smoking takes 6.6 years and diabetes 6.5 years out of their life expectancy. Being under heavy stress shortens their life expectancy by 2.8 years.

These results are based on a study in which researchers from the Finnish Institute for Health and Welfare calculated the effects of multiple risk factors, including lifestyle-related ones, to the life expectancy of men and women.

The study also revealed that a lack of exercise strongly reduced the life expectancy of 30-year-old men - by 2.4 years. On the other hand, things such as the consumption of plenty of fruits and vegetables could increase life expectancy: eating fruit by 1.4 years and eating vegetables by 0.9 years.

The same factors impacted the life expectancy of both men and women. For 30-year-old women, e.g. smoking shortened the life expectancy by 5.5 years, diabetes by 5.3 years, and heavy stress by 2.3 years.

The effects to the life expectancy of older people were similar but smaller than in younger age groups.

The golden middle seemed to have the most positive effect in some factors related to lifestyle. The experience of stress increased the life expectancy if the person felt the amount of stress they had was approximately the same as what other people typically experienced. Having more or less stress than that, on the other hand, reduced their life expectancy.

A new calculation method in use for a large group of risk factors for the first time

The study was based on data collected from men and women aged 25 to 74 in the Finnish National FINRISK Study 1987-2007 through questionnaires and measurements. The rate of mortality was followed until the end of 2014.

The researchers calculated the life expectancies by changing the values of each risk factor at a time and keeping the values of other factors constant. Only the BMI, blood pressure, and cholesterol levels were allowed to be changed when the values related to lifestyle factors were changed.

"Before, life expectancy has usually been assessed based on only a few sociodemographic background factor groups, such as age, sex, and education. In this study, we wanted to assess the impact of several different factors to a person's life expectancy, so we could compare their effects," says Research Manager Tommi Härkänen.

Differences between the life expectancies of men and women largely due to risk factors that can be changed

"What was interesting about the study was how small the difference in the life expectancy of 30-year men and women was based on the same risk factor values - only 1.6 years. According to the statistics from Statistics Finland, the difference between the sexes has been over five years for all 30-year-olds, which comes down to women having healthier lifestyles than men," says Research Professor Seppo Koskinen.

In this study, the differences in the life expectancies of people with different levels of education were fairly small when the other risk factor values were the same. However, earlier studies have discovered large differences between the life expectancies of groups of people with different levels of education.

The lifestyle choices that increase mortality, such as smoking, heavy alcohol use, unhealthy diet, and lack of exercise, are most common in the population groups whose social position is the weakest.

The life expectancy of the whole population could be improved significantly through helping men and people with a lower level of education, in particular, make better lifestyle choices.

In patients with epilepsy, normal neurological activity becomes disrupted, causing debilitating seizures. Now, researchers report in ACS Chemical Neuroscience that they have found a potential new treatment for this disorder by turning to traditional Chinese medicine. Tests of extracts from plants used in these ancient remedies led the team to one compound, derived from a magnolia tree, that could quell drug-resistant seizures in both fish and mice.   

Epilepsy is one of the most common neurological diseases worldwide, and the World Health Organization estimates that about 50 million people have the disorder. Medications are available, but they don't help everyone. Research suggests that about 70% of patients with epilepsy can control it well with medication, leaving many patients without effective treatment. But even when they work, the drugs can cause a range of side effects, from dizziness to mood disruptions. To look for new drug leads that could help even those patients who don't respond to conventional anti-seizure medications, Peter de Witte and colleagues set their sights on plants used in traditional Chinese medicine. 

The team collected 14 plants used in traditional Chinese medicine anti-seizure remedies. They then tested the plants' extracts in two types of zebrafish with epileptic-like seizures, one of which could respond to conventional anti-seizure medications, whereas the other type could not. Only extracts from the bark of Magnolia officinalis, a tree native to China, reduced seizure-like behavior in both types of fish. In tests with mice, the researchers found that the magnolia bark's most potent anti-seizure compound, magnolol, reduced the rodents' otherwise drug-resistant seizures. It and similar compounds in magnolia bark could provide a starting point for the development of treatments for resistant epilepsy, according to the researchers. 

DUARTE, Calif. -- City of Hope scientists have found a toxic fungus previously thought to not be infectious in the sinus tissues of a man with refractory acute lymphocytic leukemia. This is the first time that direct infection of a patient with the black mold Stachybotrys has been recorded. The team's findings published this week in the journal Clinical Infectious Diseases.

Strains of Stachybotrys are typically associated with "sick building syndrome," or black mold infestations in damp buildings that can make people sick by breathing in toxins that the organisms release into the air.

"We have now shown, for the first time, that this black mold can also directly infect immunocompromised people," said Markus Kalkum, Ph.D., corresponding author of the study, professor in the Department of Molecular Imaging & Therapy at the Diabetes & Metabolism Research Institute at City of Hope and director of the Mass Spectrometry and Proteomics Core Facility.

In other words, the actual fugus was found in the patient's tissues as opposed to just the toxins that are usually associated with illness from black mold. It was seen in biopsy specimens from the patient's sinuses after he had complained of facial pain during a hospitalization associated with complications from refractory acute lymphocytic leukemia. Subsequent follow-up tests using modern molecular techniques, including DNA sequencing and species-specific staining methods, confirmed the fungus as Stachybotrys chlorohalonata.

"Even though an infection with a rare fungus, which wasn't previously considered to be infectious, had occurred, City of Hope physicians were able to cure the infection," Kalkum said. "It is notable that the infection with the black mold was resolved by treating with the available antifungal drugs, amphotericin B and micafungin."

Unfortunately, the patient ultimately passed away. However, the likely cause of death was an infection with another species of rare fungi which are known to be difficult to treat. But the findings of the study show that certain cancer patients are at high risk for fungal infections and need to be closely monitored, especially since there has been an observed steady increase in the diversity of emerging invasive fungal pathogens in immunocompromised patients.

"Physicians and scientists, in general, need to drastically improve diagnostics capability to accomplish two things: quickly and correctly identify the microorganisms that cause an infection at the species level and rapidly determine drug sensitivities and resistances for each isolated pathogen," Kalkum said. "Both tasks should be completed within a one to two-day turnaround time. Realization of these objectives is technically feasible, but requires substantial investment in research and the modernization of clinical practice. However, this approach has the potential to treat affected patients effectively with high precision in order to save many lives and prevent a lot of suffering."

The Kalkum laboratory is also working to develop antifungal vaccines. They have previously demonstrated the effectiveness of an anti-aspergillosis vaccine in mice. Aspergillus infections typically happen in the respiratory system of humans and symptoms can be severe for patients with lung disease and/or a compromised immune system. The vaccine is currently being used to treat captive birds (penguins, Inca terns and eider ducks) in zoos. The birds are at high risk of developing fungal infections, similar to the risk seen in some cancer patients.

"Our research goal is to widen the spectrum of the antifungal vaccine, such that it can protect against many different species of fungi, even against Stachybotrys strains," Kalkum added. "Furthermore, we need to find out how to best vaccinate and protect the patients who are most at risk for developing invasive fungal infections."

Squamous cell carcinoma is a very unusual type of cancer. They occur in many tissues - for example in the lungs, esophagus, pancreas, throat and pharynx, and on the skin. Due to the many mutations in this type of cancer, treatment is a particularly challenging task for medicine.

However, all squamous cell carcinoma have a common Achilles' heel: They are dependent on the cancer protein ?NP63. This is a protein that only occurs in this type of tumor and regulates essential biological processes.

An international research team led by Julius-Maximilians-Universität (JMU) Würzburg in Bavaria, Germany, has now found a way to inactivate the cancer protein with the help of another protein and thus curb the growth of squamous cell carcinoma.

Traffic tickets become effective again

The helpful protein is the deubiquitylase USP28, which is particularly common in squamous cell carcinoma. It controls the amount of the cancer protein ?NP63.

"The deubiquitylase belongs to the so-called ubiquitin-proteasome system, which can be imagined as a towing company," explains Dr. Markus Diefenbacher, group leader at the JMU Chair of Biochemistry and Molecular Biology I. His research group was in charge of the study.

"In healthy cells, this towing company marks ‚incorrectly parked' proteins with a kind of parking ticket, namely the protein ubiquitin. "It then towed the parkers away and disposed of them. But the protein can remove the parking ticket and thus prevent the towing. In tumour cells, there is often a loss of traffic wardens/controllers or an accumulation of USP28. Therefore, ?NP63 in a tumour cell behaves in a similar way to an incorrectly parked car where the parking ticket is permanently removed," explains Diefenbacher.

No direct attack possible

The research team has now been able to prove the dependence of squamous cell carcinoma on the protein USP28: Using a preclinical inhibitor, it switched off ?NP63's parking ticket remover in the tumor cells. The tumors then stopped growing.

"Many cancer proteins are constructed in such a way that it is not possible to develop a direct active substance against them with the methods currently available," explains the Würzburg researcher. Also, no direct therapeutic attack on the cancer protein ΔNP63 is possible.

However, by switching off USP28, the cancer protein could be rapidly degraded in human and animal tumor cells and the tumor could be fought. At the same time, there were no side effects in healthy cells. "We have thus discovered a good new way of attacking squamous cell carcinoma," said Diefenbacher.

Searching for other inhibitors

The inhibitor used is not yet suitable for therapeutic use in humans. It still needs further research. This is done in collaboration with the research group of JMU professor Caroline Kisker at the Rudolf Virchow Centre for Experimental Biomedicine. Diefenbacher: "In cancer therapy, inhibitors are already being used that switch off the entire ubiquitin-proteasome system. Our work now shows a possibility of switching off only one component of this system and thus being able to combat the tumour cells even more specifically."

Next, Diefenbacher's team will look for further inhibitors that can also be used against USP28. "In addition, we will also look for other proteins in squamous cell carcinoma which these tumours depend on, and investigate whether the ubiquitin-proteasome system can be used to target these proteins for therapy," says the JMU researcher.

Researchers at the University of Virginia School of Medicine have discovered why obesity causes high blood pressure and identified potential ways of treating that form of high blood pressure.

The researchers have already confirmed their discovery in human tissue samples and used it to reverse high blood pressure in lab mice.

"Our study identifies the cellular mechanisms that increase blood pressure in obesity, and shows that these mechanisms can be targeted for lowering the blood pressure. If we are able to design the appropriate compounds, we might be able to treat hypertension in obese patients," said lead researcher Swapnil K. Sonkusare, PhD, of UVA's Department of Molecular Physiology and Biological Physics and UVA's Robert M. Berne Cardiovascular Research Center.

The Obesity Epidemic

Obesity is a growing problem worldwide. The number of people considered obese has nearly tripled since 1975, and with obesity comes greater risk of cardiovascular disease, high blood pressure (hypertension) and stroke, among other health problems.

Small arteries in our body control blood pressure. Scientists have suspected that hypertension in obesity is related to problems in endothelial cells that line these small arteries. The reasons for this, however, have been unclear - until now.

Sonkusare and colleagues found that a protein on the membranes surrounding endothelial cells allows calcium to enter the cells and maintains normal blood pressure. Obesity, it turns out, affects this protein, called TRPV4, within tiny subsections of the cell membrane. Sonkusare calls these faulty subsections "pathological microdomains."

"Under healthy conditions, TRPV4 at these tiny microdomains helps maintain normal blood pressure. We, for the first time, show the sequence of events that lead to a harmful microenvironment for calcium entry through TRPV4," he said. "I think the concept of pathological microdomains is going to be very important not just for obesity-related studies but for studies of other cardiovascular disorders as well."

A Local Problem

Obesity, the researchers found, increases the levels of peroxynitrite-making enzymes in the microdomains containing TRPV4. Peroxynitrite silences TRPV4 and lowers calcium entry into the cells. Without the proper amount of calcium, blood pressure goes up.

Sonkusare believes that targeting peroxynitrite or the enzymes that make it could be an effective way to treat and prevent high blood pressure in obesity, without the side effects that would come with trying to target TRPV4 itself.

"People asked me, 'Why don't you use a drug to directly activate TRPV4?' But TRPV4 is present in many other tissues, including brain, muscle and bladder," he explained. "So if you directly activate TRPV4, you will likely get undesirable side effects. The better approach would be to target the specific events that reduce TRPV4 function in obesity."

Sonkusare's discovery also may explain why attempts to use antioxidants to lower high blood pressure have not been very effective in clinical trials. This could be due to the lack of specificity of these antioxidants, he said. "We, for the first time, identify peroxynitrite as the precise oxidant molecule that increases blood pressure in obesity. The next step would be to design drugs that specifically target peroxynitrite and provide therapeutic benefit."

The discovery was made possible by innovative techniques developed in Sonkusare's lab. Researchers in his lab can visualize the calcium entry through TRPV4 in real time and use tools that enable the studies of microdomains. "Historically, researchers have studied larger blood vessels that don't control blood pressure," Sonkusare said. "Because of our unique techniques, we are able to study the microdomains in very small arteries that control the blood pressure. So our technical ability allows us to obtain these unique insights."