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In the current issue of Cardiovascular Innovations and Applications volume 4, issue 2, pp. 85-98 ; DOI https://doi.org/10.15212/CVIA.2017.0060, Jayasheel O. Eshcol and Adnan K. Chhatriwalla from Saint Luke's Hospital Mid America Heart Institute, and University of Missouri-Kansas City, School of Medicine, Kansas City, MO, USA consider selective coronary angiography following cardiac arrest.

Sudden cardiac arrest is a major cause of death predominantly caused by ventricular tachyarrhythmia in patients with coronary artery disease. Despite advancements in resuscitation care, the rate of survival after cardiac arrest remains low. There is a growing body of observational data suggesting early coronary angiography reduces delay to revascularization and may improve outcomes. Most survivors present comatose, and neurologic outcome is uncertain; therefore it is often challenging to identify patients who will benefit from early coronary angiography. Several variables and risk scores that predict a favorable neurologic outcome have been identified. The authors review rationale and current evidence for early angiography and suggest an approach to the selection of patients.

What to Do with Epicardial Coronary Artery Abnormalities That do not Result in Myocardial Ischemia?

In the current issue of Cardiovascular Innovations and Applications volume 4, issue 2, pp. 109-111 ; DOI https://doi.org/10.15212/CVIA.2017.0067 C. Richard Conti from the University of Florida Medical School, Gainesville, FL, USA considers epicardial coronary artery abnormalities that do not result in myocardial ischemia.

When epicardial arteries with minimal CAD do not limit flow are found at coronary angiography, all cardiologists agree that aggressive risk factor modification and use of appropriate drugs are warranted. Some consider plaque sealing of minor coronary lesions with balloon angioplasty to prevent future infarction. Others believe that a coronary lesion that does not cause ischemia should not have the plaque sealed but should have FFR and the non-ischemia producing steno-sis should be treated with aggressive risk factor modification (DEFER study). Evidence based data e.g. DEFER, relates to populations, not the individual. Thus these data provide guidelines, which are suggestions for decision making. The weight of evidence favors angioplasty/stent for epicardial vessels that result in myocardial ischemia. Sealing of non-flow limiting plaques with angioplasty must await further information derived from invasive and non invasive studies.

A new Pharmacology Research & Perspectives study found no harm to newborns from opioid maintenance treatment (OMT) during pregnancy compared with no treatment.

Because little is known about the safety of treatment with methadone and buprenorphine as part of OMT in pregnant women with opioid use disorders, researchers compared prenatally OMT-exposed newborns with two other newborn groups: newborns of women hospitalized with opioid use disorder during pregnancy who were not receiving OMT and newborns with neonatal abstinence syndrome (which a baby experiences when withdrawing from exposure to opioids).

The growth parameters (birth weight, length, and head circumference) in newborns were similar in the OMT and the comparison groups. Due to the benefits of OMT for individuals with drug addiction, the findings support the prescription of OMT drugs to pregnant women with opioid use disorders.

"The growth parameters were similar for all newborns born of drug-dependent women irrespective of if the women received OMT treatment or not during pregnancy, and even if the women used OMT outside of pregnancy, but not during pregnancy. However, when compared with the general population, all the newborns of women who had any indications of opioid abuse before, during or after pregnancy, seem to have worse neonatal outcomes--regardless of whether the woman received OMT during pregnancy or not," said lead author Marte Handal, PhD, of the Norwegian Institute of Public Health. "Taken together, this might suggest that it is not the OMT drugs themselves that are associated with worse neonatal outcomes, but other factors related to opioid use, such as comorbidity, socio-economic, and lifestyle factors."

A breakthrough in monkey malaria research by two University of Otago scientists could help scientists diagnose and treat a relapsing form of human malaria.

Malaria is a mosquito-borne infectious disease that affects humans and other animals with more than 200 million cases annually, particularly in Asia, the Pacific and South America. Symptoms include fever, tiredness, vomiting and headaches and in severe cases it can cause seizures, coma or death.

Relapsing malaria is caused by the vivax malaria parasite, which is also the most widely distributed and difficult to treat cause of human malaria. Current efforts to develop new drugs and vaccines against vivax have been stymied by lack of a test tube (in vitro) cultured method.

However, in a world-first discovery, Dr Adelina Chua and Jessica Ong have cracked an in vitro method for culturing a monkey malaria parasite which is closely related to the relapsing vivax parasite.

"We can't culture vivax malaria, but now we can culture its almost identical sister species which gives us an unprecedented opportunity to develop and rapidly test new antimalarials," Ms Ong, a doctoral candidate from the Department of Microbiology and Immunology, explains.

An interesting spinoff from this research is that the drugs developed against human relapsing malaria also have a good chance of working against bird malaria, which has been killing the endangered yellow-eyed penguin on the New Zealand mainland.

"Before our model there was no high throughput model to screen new antimalarials targeting relapsing malaria," Ms Ong says.

"Our model will play a significant part in not only drug development, but also vaccine and diagnostic research."

The publication of this new malaria culture method in Nature Communications, follows an international conference in Dunedin last September which brought together a range of industry, government and academic interest groups, keen to utilise this culture method.

Dr Chua says since the discovery, the special malaria culture has been exported to Japan, France, the USA and the Netherlands.

"These various industry and academic groups are using the model to conduct mass screenings of drugs that target the dormant liver stages which are responsible for the relapsing nature of malaria."

While the parasite used was originally isolated from old world monkeys from Malaysia, Ms Ong says it is important to note that because this new method is in vitro, it reduces the need for animal research models.

The finding is also significant for the penguin population.

"Bird malaria has a relapsing form in its tissues, very similar to vivax malaria, so treating the penguins with regular antimalarials doesn't flush out the hidden tissue forms," Ms Ong says.

"The new method will not only help develop anti-relapse antimalarials for drug-resistant human malaria, but also help target the growing problem of penguin malaria."

The manager of Penguin Rescue Rosalie Goldsworthy says she is excited to learn of the new development which will benefit both penguins and humans.

"Research has shown human drugs to be effective in treating avian malaria, so the critically threatened yellow-eyed penguins will have a better chance of surviving when this model is developed."

ROCHESTER, Minn. -- For people with diabetes, taking medications and monitoring their blood sugar is part of the rhythm of their daily lives. However, according to new research from Mayo Clinic, more than 2.3 million adult patients in the U.S. are likely treated too intensively. This has caused thousands of potentially preventable emergency department visits and hospitalizations for hypoglycemia (low blood sugar).

The study team, led by Rozalina McCoy, M.D., an endocrinologist and primary care physician at Mayo Clinic, sought to identify the real-world implications of intensive glucose-lowering therapy across the U.S. The team showed that overly intensive glucose-lowering therapy -- when patients receive more medication than is required based on their hemoglobin A1C level -- was not only common across the U.S., but also directly contributed to 4,774 hospitalizations and 4,804 emergency department visits in a two-year period. Their findings were published online Aug. 15 in Mayo Clinic Proceedings.

"Importantly, these numbers are a large underestimation of the true scope of overtreatment-induced hypoglycemic events," says Dr. McCoy.

There are many reasons why people with diabetes may experience hypoglycemia. Dr. McCoy says that people who have multiple chronic health conditions, are older, have Type 1 diabetes, or are treated with medications such as insulin or sulfonylureas are at highest risk.

"While some episodes of hypoglycemia may be unavoidable, especially if caused by unmodifiable risk factors such as need for insulin therapy, others may be preventable, as in the case of overtreatment," she states.

"In an earlier study, we separated out the effect of overtreatment from other high risk factors and showed it was a significant independent contributor to hypoglycemic events," says Dr. McCoy. "In this study, we wanted to learn more about national scope of those overtreatment-related events."

"Because there is no U.S.-wide data about how many hypoglycemic events may be avoided if patients were treated less intensively, we had to separately calculate how many Americans are overtreated," continues Dr. McCoy. "We then used data from the earlier study, combined with this new data, to estimate the number of hypoglycemia-related emergency department visits and hospitalizations likely caused by overtreatment."

Persistent elevation in blood glucose levels increases the risk of diabetes complications, such as cardiovascular disease, retinopathy (eye disease), nephropathy (kidney disease) and neuropathy. Glucose-lowering medications reduce these risks, but treatment plans must be evidence-based and individualized, says Dr. McCoy.

"It is important not only to ensure that we do not undertreat our patients with diabetes, but also that we do not overtreat them because both undertreatment and overtreatment can harm our patients," she says.

Patients and research methods

Dr. McCoy and her team used patient data from the National Health and Nutrition Examination Survey (2011-2014) and the OptumLabs Data Warehouse to conduct this study. They first estimated the prevalence of intensive glucose-lowering therapy among U.S. adults using the most recently available National Health and Nutrition Examination Survey. Then the researchers determined the approximate number of hypoglycemia-related emergency department visits and hospitalizations attributable to such intensive therapy using OptumLabs data obtained in the earlier study.

The National Health and Nutrition Examination Survey data identified more than 10.7 million nonpregnant adults with diabetes whose hemoglobin A1C was in the range recommended by clinical guidelines (less than 7%). The researchers found that almost 22% of these individuals were intensively treated. Individuals were considered to be receiving intensive treatment if they were taking a medication to achieve HbA1C levels of 5.6% or less, or were taking two or more medications to achieve HbA1C levels of 5.7-6.4%.

"Hypoglycemia, or low blood glucose, is one of the most common serious adverse effects of diabetes therapy, causing both immediate and long-term harm to patients who experience it," says Dr. McCoy. "Severe hypoglycemia, defined by the need for another person to help the patient treat and terminate their hypoglycemic event, is associated with increased risk of death, cardiovascular disease, cognitive impairment, falls and fractures, and poor quality of life."

To gain further insight, the investigators also subcategorized patients as clinically complex if the patient:

Was age 75 or older

Had two or more limitations on daily living activities, such as the inability to dress, feed, walk from room to room, or get in or out of bed

Had end-stage kidney disease

Had three or more chronic conditions

Of the 10.7 million patients, 32.3% were clinically complex. Although this did not appear to be a factor in whether a person was intensively treated, Dr. McCoy notes that it would have been ideal if it had been.

"Older people and others we consider clinically complex are more at risk to develop hypoglycemia, as well as experience other adverse events because of intensive or overtreatment. However, at the same time, these patients are unlikely to benefit from intensive therapy rather than moderate glycemic control," says Dr. McCoy. "When we develop a diabetes treatment plan, our goal should be to maximize benefit while reducing harm and burden of treatment."

Dr. McCoy says that the researchers found the study results alarming, with as many as 2.3 million Americans overtreated between 2011 and 2014. Moreover, clinically complex patients were intensively treated at a similar rate as patients who were not complex.

Next steps

Historically, professional societies and regulatory bodies largely focused on reducing undertreatment and controlling hyperglycemia (high blood sugar). Dr. McCoy hopes to see a shift to also include addressing and preventing overtreatment and hypoglycemia.

"We need to align treatment regimens and goals with each patient's clinical situation, health status, psychosocial situation, and reality of everyday life to ensure that care is consistent with their goals, preferences and values," she says.

If the health care system shifts from being disease-focused -- and for diabetes, specifically, glucose-focused -- to being more person-focused, she believes that will be less harmful, and lead to better outcomes for patients and less treatment burden.

For patients with diabetes, she says, "this includes treatment de-intensification and simplification as a means of reducing hypoglycemia, polypharmacy and treatment burden."

Transgender men who become pregnant are at increased risk for depression and difficulty getting medical care due to a lack of knowledge among health care providers, a Rutgers study reports.

The study, published in the journal Maturitas, examined health care research on transgender men who become pregnant at or after age 35 to determine their medical and mental health needs.

"Despite the increased visibility of transgender people -- there are about 1.4 million who have transitioned in the United States -- medical providers are largely unprepared to care for them and most have had limited educational opportunities," said lead author Justin Brandt, an assistant clinical professor in the Department of Obstetrics, Gynecology and Reproductive Sciences at Rutgers Robert Wood Johnson Medical School.

Transgender men who have transitioned hormonally and are taking testosterone but retain their female reproductive organs have the potential to become pregnant. Since the U.S. medical system has been tracking these patients as female, no data exists on how many transgender men give birth each year, but Brandt said the number is likely higher than people realize. While some plan to become pregnant, the research suggests that unintended pregnancies occur in up to 30 percent of transgender men.

According to the U.S. Transgender Survey, nearly 40 percent of its 28,000 respondents reported attempting suicide -- nearly nine times the national average. That risk can be increased in transgender men with the unwanted physical changes resulting from pregnancy, according to Brandt. "The process of transitioning is long and arduous, and pregnancy, which is regarded as a feminine condition, forces these men to almost fully transition back to their sex assigned at birth, which can worsen gender dysphoria," he said.

Surveys used to screen pregnant and postpartum females for depression are not designed to assess the impact of pregnancy on gender dysphoria in transgender men.

The study also found that nearly 25 percent of transgender people reported negative health care experiences in the last year. This correlates with the finding that about 44 percent of pregnant transgender men seek medical care outside of traditional care with an obstetrician. Rather, they may seek out non-physician providers, such as nurse midwives, with 17 percent delivering outside of hospitals -- a higher rate than with women.

Although data is limited on how transgender men give birth, the review found that 64 percent had vaginal births and 25 percent requested cesarean delivery.

The report also noted that transgender men who requested cesarean deliveries reported feeling uncomfortable with their genitalia being exposed for long periods of time while those who went through labor reported that the process of giving birth vaginally overcame any negative feelings that they had with the female gender that they had been assigned at birth.

"Although Rutgers physicians have not yet had a pregnant transgender male patient, our healthcare professionals are trained and ready," Brandt said.

The researchers also found that about 51 percent of transgender men breast or chest fed their infants even if they had breast surgery.

Brandt recommended that transgender men planning to conceive should visit their doctor before becoming pregnant to address routine issues, such as folic acid supplementation and screening for genetic disorders, and to be counseled on the risks of advanced-age pregnancy, such as infertility, miscarriage, gestational diabetes and pre-term delivery. Transgender men also likely will need to update health screenings that could have lapsed during transition, such as pap smears and, when indicated for those who have not had chest surgery, mammograms.

After delivery, Brandt said doctors should address long-acting and reversible methods of contraception if the individual is at risk for unplanned pregnancy. "Transgender men who intend to restart testosterone after delivery may decide to defer contraception since they perceive that their male hormone therapy induces a state of infertility, which is not always the case," he said.

Westbury, NY - Aug. 15, 2019 - BioIVT, a leading provider of research models and services for drug and diagnostic development, today announced that researchers in its Transporter Sciences Group have co-authored a peer-reviewed DMD paper, which investigates the inhibitory effects of a class of HIV drugs known as integrase inhibitors on folate transporter pathways.1 Previously published studies had appeared to show a correlation between exposure to dolutegravir, and other HIV integrase inhibitor drugs, at conception and an increased risk of neural-tube defects (NTDs). NTDs are birth defects of the brain and spinal cord that cause conditions such as spina bifida in infants.2 NTDs can be caused by several factors, including inhibition of folate transporters in the gut, brain, and placenta.

This new research, which results from a collaboration between BioIVT and GlaxoSmithKline (GSK) and is based on studies conducted in BioIVT's laboratory in Santa Clara, CA, set out to investigate whether HIV integrase inhibitor drugs also inhibit folate transporters, leading to drug-induced folate deficiency and an increased likelihood of NTDs.

"We were pleased to collaborate with our colleagues at GSK on this important research, using BioIVT's technology platform and our combined scientific knowledge and thinking. Through timely and effective communication, we were able to develop new assays quickly and generate high quality data," said Dr. Xuexiang Zhang, BioIVT's lead investigator on the study. "We hope that our investigation into the pharmacology of dolutegravir will help physicians to develop optimal recommendations for their patients."

Their study assessed the impact of dolutegravir and four other integrase inhibitor drugs, together with positive controls (methotrexate and pemetrexed) and a negative control (valproic acid), in vitro on the three major folate transport pathways: reduced folate carrier (RFC), proton-coupled folate transporter (PCFT), and folate receptor α (FRα) endocytosis.

Their research set out to determine what effects, if any, dolutegravir and the other HIV integrase inhibitors had on folate transporter activity. Particular attention was paid to FRα since concerns about dolutegravir's interaction with that pathway had been expressed recently in the scientific literature.

BioIVT used its proprietary OPTI-EXPRESSION™ technology to express human folate transporters in mammalian cells (MDCK-II cells). Then the potential of dolutegravir to inhibit folate transporters was measured using well-described, validated methods.

The study demonstrated that dolutegravir is not a clinical inhibitor of folate transport pathways and is not predicted to elicit clinical decreases in maternal and fetal folate levels.

Reaching a related conclusion, the World Health Organization (WHO) recommended on July 22, 2019 that dolutegravir be used as the preferred first-line and second-line treatment for all populations with HIV, including pregnant women and those of childbearing potential.2 It based its decision in part on two large clinical trials comparing the efficacy and safety of dolutegravir and efavirenz in Africa.2

BioIVT's approach can also be used to predict the risk of folate transporter inhibition by drugs in other classes. It is employed during the drug discovery process to select and develop drugs with optimal pharmacological properties, i.e. high efficacy and minimized risk to patients.

New research published this week in JAMA Oncology has found a lack of racial and ethnic diversity in clinical trials for cancer drugs.

The study--conducted by researchers from UBC, the University of Texas MD Anderson Cancer Center, the Fred Hutchinson Cancer Center in Seattle and Baylor University in Texas--raises concerns about the effectiveness of cancer drugs in some patients, especially since genetic differences may affect how well a patient responds to a drug.

The researchers found that fewer than eight per cent of cancer drug trials reported participation from the four major races in the United States -- white, Asian, black and Hispanic -- between 2008 and 2018. Black and Hispanic patients were particularly underrepresented at 22 per cent and 44 per cent, respectively, considering their populations' incidence of cancer.

"Our findings show that the science might not be applicable to the population that's going to receive the medications," said the study's lead author, Dr. Jonathan Loree, assistant professor in the department of medicine, division of medical oncology. "If patients are going to be receiving the drug, we need to know that it's going to work for them with the same effectiveness that's seen in the trial."

Loree cited an example of a medication used to treat lung cancer that showed mediocre trial results in the global population, but exhibited incredible success with young women who had never smoked in a study in Asia due to a genetic mutation that's common in this population.

The researchers found that both reporting about race in trials and enrolment rates had changed minimally over the decade.

For this study, Loree and colleagues reviewed all reported trials supporting U.S. Food and Drug Administration (FDA) oncology drug approvals granted between July 2008 and June 2018. They scrutinized 230 trials with a total of 112,293 participants. They calculated the U.S. population-based cancer estimates by race using National Cancer Institute and U.S. Census data.

Although the researchers used U.S. data, Loree said the findings are relevant in Canada, as well. Pharmaceutical companies typically apply for drug approvals through the FDA first, because it serves the largest market, and then submit to the European Medicines Agency and Health Canada. The trials considered in the approvals are usually the same.

"One thing particularly relevant to the Canadian context is that we weren't able to analyze the participation of Native Americans in trials because there were only 13 patients reported out of a total of 112,000 participants," Loree said. "That's shocking and definitely shows an area where improvement is needed."

The researchers are now looking at whether clinical trials represent the same gender ratio as the general population to ensure the drugs are effective in all people.

WASHINGTON -- Researchers have developed a new self-calibrating endoscope that produces 3D images of objects smaller than a single cell. Without a lens or any optical, electrical or mechanical components, the tip of the endoscope measures just 200 microns across, about the width of a few human hairs twisted together.

As a minimally invasive tool for imaging features inside living tissues, the extremely thin endoscope could enable a variety of research and medical applications. The research will be presented at the Frontiers in Optics + Laser Science (FIO + LS) conference, held September 15-19 in Washington, D.C., U.S.A.

According to Juergen W. Czarske, Director and C4-Professor at TU Dresden, Germany and lead author on the paper: "The lensless fiber endoscope is approximately the size of a needle, allowing it to have minimally invasive access and high-contrast imaging as well as stimulation with a robust calibration against bending or twisting of the fiber." The endoscope is likely to be especially useful for optogenetics - research approaches that use light to stimulate cellular activity. It also could prove useful for monitoring cells and tissues during medical procedures as well as for technical inspections.

A self-calibrating system

Conventional endoscopes use cameras and lights to capture images inside the body. In recent years researchers have developed alternative ways to capture images through optical fibers, eliminating the need for bulky cameras and other bulky components, allowing for significantly thinner endoscopes. Despite their promise, however, these technologies suffer from limitations such as an inability to tolerate temperature fluctuations or bending and twisting of the fiber.

A major hurdle to making these technologies practical is that they require complicated calibration processes, in many cases while the fiber is collecting images. To address this, the researchers added a thin glass plate, just 150 microns thick, to the tip of a coherent fiber bundle, a type of optical fiber that is commonly used in endoscopy applications. The coherent fiber bundle used in the experiment was about 350 microns wide and consisted of 10,000 cores.

When the central fiber core is illuminated, it emits a beam that is reflected back into the fiber bundle and serves as a virtual guide star for measuring how the light is being transmitted, known as the optical transfer function. The optical transfer function provides crucial data the system uses to calibrate itself on the fly.

Keeping the view in focus

A key component of the new setup is a spatial light modulator, which is used to manipulate the direction of the light and enable remote focusing. The spatial light modulator compensates the optical transfer function and images onto the fiber bundle. The back-reflected light from the fiber bundle is captured on the camera and superposed with a reference wave to measure the light's phase.

The position of the virtual guide star determines the instrument's focus, with a minimal focus diameter of approximately one micron. The researchers used an adaptive lens and a 2D galvometer mirror to shift the focus and enable scanning at different depths.

Demonstrating 3D imaging

The team tested their device by using it to image a 3D specimen under a 140-micron thick cover slip. Scanning the image plane in 13 steps over 400 microns with an image rate of 4 cycles per second, the device successfully imaged particles at the top and bottom of the 3D specimen. However, its focus deteriorated as the galvometer mirror's angle increased. The researchers suggest future work could address this limitation. In addition, using a galvometer scanner with a higher frame rate could allow faster image acquisition.

"The novel approach enables both real-time calibration and imaging with minimal invasiveness, important for in-situ 3D imaging, lab-on-a-chip-based mechanical cell manipulation, deep tissue in vivo optogenetics, and key-hole technical inspections," said Czarske.

A study from Vanderbilt-Ingram Cancer Center and the Department of Veterans Affairs led by Anna Vilgelm, MD, PhD, and Ann Richmond, PhD, has identified a possible second-line treatment for melanoma patients.

The potential treatment would render CDK4/6 inhibitors, a class of drugs prescribed for some breast cancers, also effective against melanoma by combining the inhibitors with MDM2 compounds, which are currently in drug development. Utilizing melanoma patient-derived xenografts in mouse models, Vilgelm and colleagues first uncovered the molecular mechanisms of CDK4/6 resistance and then tested whether the combination therapy would reverse that process. They reported tumor regression in multiple mouse models and in human tumor slice culture assays.

The research was published Aug. 14 in Science Translational Medicine.

"Over 40% of melanoma tumors exhibit loss or mutation of CDKN2A, a gene that regulates CDK4/6 and MDM2 to control cell cycle," said Richmond, Ingram Professor of Cancer Research.

Although activation of CDK4/6 is a key mechanism of melanoma development, the inhibitors have not had the same efficacy with melanoma as they have with breast cancer. Vilgelm and colleagues sought to understand why. They identified the scarcity of a specific protein, p21, in melanoma cell lines as a likely cause.

The MDM2 antagonists stabilize the tumor suppressor, p53, and induced expression of p21, which functions as a regulator of cell cycle progression and counteracts resistance to CDK4/6 inhibitors.

"MDM2 inhibitors require functional p53 to work," Vilgelm said. "In many types of cancer, p53 will be mutated or deleted, and this loss of tumor suppressor allows tumors to progress. In melanoma, however, mutations of p53 are relatively rare. Therefore, the combination therapy of MDM2 and CDK4/6 inhibitors is likely to benefit a large group of melanoma patients."

Thus, the combination therapy of MDM2 and CDK4/6 inhibitors are likely to benefit only patients with p53 and RB wild-type melanoma, she said.

Although effective therapies for melanoma, particularly immunotherapies, have become available in recent years, nearly half of melanoma patients are not responsive to immunotherapies. Patients also often develop resistance to targeted therapies and require a second-line treatment once resistance develops.

"I think this is a good potential second-line treatment for melanoma patients with p53 and RB wild type tumors who don't respond to or who develop resistance to immunotherapies or other targeted therapies," Vilgelm said. "I think this combination really makes sense in terms of the genetics of melanoma."

"Our finding that combining a CDK4/6 inhibitor with an MDM2 inhibitor can overcome this genetic driver of melanoma, i.e., mutation or loss of CDKN21, is very promising and should be tested further in clinical trials," Richmond said.

A team at the University of Cambridge has shown how, in osteoarthritis patients, the viscous lubricant that ordinarily allows our joints to move smoothly triggers a pain response from nerve cells similar that caused by chilli peppers.

Osteoarthritis is the most common form of arthritis. It causes joint pain and stiffness, and in some people swelling and tenderness of the joints. The condition affects an individual's quality of life and costs millions to the global economy, both directly in terms of healthcare costs and indirectly due to impact on the individual's working life.

Osteoarthritis tends to occur later in life and has been largely considered as a degenerative disorder in which pain is produced by damage and wear and tear to bone and cartilage. However, in recent years it has become clear that osteoarthritis is not restricted to cartilage damage, but is a failure of the entire joint, with inflammation - the body's response to stress and injury - being a major contributor to the pain experienced by patients. A recent collaboration between the two pharmaceutical companies Pfizer and Eli Lilly has found that their anti-inflammatory drug, tanezumab, produced pain relief for osteoarthritic patients in a phase 3 clinical trial.

When inflammation occurs during osteoarthritis, the body produces an increased number of cells within and around the joint. These cells release inflammatory substances into the synovial fluid, the lubricant that allows joints to move smoothly. During osteoarthritis, synovial fluid becomes less viscous and these inflammatory substances come into direct contact with sensory nerve cells in the joint, producing the sensation of pain.

In a study published in the journal Rheumatology on 13 August 2019, researchers at the University of Cambridge and Addenbrooke's Hospital, part of Cambridge University Hospitals, examined whether synovial fluid produced during osteoarthritis is capable of directly exciting sensory nerves supplying knee joints - those nerves responsible for transmitting pain signals.

"Osteoarthritis can be a very painful condition, but we only know a little about what causes this pain," says Sam Chakrabarti, a Gates Cambridge Scholar. "We wanted to investigate what was happening in the joint and to see whether it was the lubricant that ordinarily keeps these joints moving that was contributing to the pain. Studies such as these are important in helping us develop better treatments."

The researchers obtained synovial fluid from consenting osteoarthritis patients at Addenbrooke's Hospital and from post-mortem donors with no known joint disease. They then incubated knee sensory nerves isolated from mice in either healthy or osteoarthritis synovial fluid and recorded the activity of these nerves.

The team found that when incubated with osteoarthritic synovial fluid, the knee nerves were more excitable. The nerves also showed an increase in the function of TRPV1, a molecule that detects the hotness of chilli peppers (TRPV1 is also activated by heat, which is why chillis tastes hot). Although the presence of inflammatory chemicals in osteoarthritis synovial fluid has been known since 1959, this is the first evidence that synovial fluid can directly excite sensory nerves and hence is an important contributor to an individual's experience of pain.

"This is the first time we have been able to use synovial fluid from human osteoarthritis patients to excite sensory nerve cells, making it more clinically-relevant than mouse studies alone, and so will hopefully help translating treatments from bench to bedside," says Dr Ewan St John Smith from the Department of Pharmacology at the University of Cambridge.

"In the future, this set up can be used to identify the specific components of synovial fluid that cause pain and then to test if and how a drug will be useful in arthritic pain. Since synovial fluid is regularly collected from arthritic patients as part of their treatment regime, our technique can be easily set up in laboratories throughout the world to understand and help to identify a cure for arthritic pain."

Dr Deepak Jadon, Director of the Rheumatology Research Unit at Cambridge University Hospitals, adds: "This study highlights how much we can learn with the help of our patients, as well as the importance of collaboration between clinicians and basic scientists."

CHAPEL HILL, NC - Staphylococcus aureus bacteria are a major cause of serious infections that often persist despite antibiotic treatment, but scientists at the UNC School of Medicine have now discovered a way to make these bacteria much more susceptible to some common antibiotics.

The scientists, in a study published in Cell Chemical Biology, found that adding molecules called rhamnolipids can make aminoglycoside antibiotics, such as tobramycin, hundreds of times more potent against S. aureus - including the strains that are otherwise very hard to kill. The rhamnolipids effectively loosen up the outer membranes of S. aureus cells so that aminoglycoside molecules can get into them more easily.

"There's a great need for new ways to kill bacteria that tolerate or resist standard antibiotics, and to that end we found that altering membrane permeability to induce aminoglycoside uptake is an extremely effective strategy against S. aureus," said study senior author Brian Conlon, PhD, an assistant professor in the department of microbiology and immunology at the UNC School of Medicine.

The U.S. Centers for Disease Control has estimated that in 2017 there were more than 119,000 cases of serious bloodstream Staph infections in the United States, of which more than 20,000 were fatal.

Standard treatments for many strains of the S. aureus do not kill the bacteria, either because the bacteria have genetically acquired specific antibiotic resistance or because they grow in the body in a way that makes them inherently less vulnerable. For example, S. aureus can adapt its metabolism to survive in low-oxygen zones in abscesses or in the mucus-filled lungs of people with cystic fibrosis. In these environments, the bacterial outer wall or membrane becomes relatively impermeable to aminoglycosides, such as tobramycin.

Conlon and colleagues, including first author Lauren Radlinski, a PhD candidate in the Conlon laboratory, found in a 2017 study that rhamnolipids greatly enhance tobramycin's potency against standard test strains of S. aureus. Rhamnolipids are small molecules produced by another bacterial species, Pseudomonas aeruginosa, and are thought to be one of P. aeruginosa's natural weapons against other bacteria in the wild. At high doses they make holes in rival bacteria's cell membranes. The UNC researchers found that rhamnolipids greatly boost the uptake of tobramycin molecules, even at low doses where they have no independent anti-bacterial effect.

In the new study, Conlon, Radlinski and colleagues tested rhamnolipid-tobramycin combinations against S. aureus populations that are particularly hard to kill in ordinary clinical practice. The researchers found that rhamnolipids boost tobramycin's potency against:

S. aureus growing in low-oxygen niches;

MRSA (methicillin-resistant S. aureus), which are a family of dangerous S. aureus variants with genetically acquired treatment resistance;

tobramycin-resistant S. aureus strains isolated from cystic fibrosis patients;

and "persister" forms of S. aureus that normally have reduced susceptibility to antibiotics because they grow so slowly.

Radlinski said, "Tobramycin doses that normally would have little or no effect on these S. aureus populations quickly killed them when combined with rhamnolipids."

Conlon, Radlinski, and colleagues determined that rhamnolipids even at low doses alter the S. aureus membrane in a way that makes it much more permeable to aminoglycosides. Each antibiotic in this family that they tested - including tobramycin, gentamicin, amikacin, neomycin, and kanamycin - had its potency enhanced. The experiments showed, moreover, that this potency-boosting strategy is effective not just against S. aureus but several other bacterial species, including Clostridioides difficile (C-diff), which is a major cause of serious, often-fatal diarrheal illness among the elderly and patients in hospitals.

Rhamnolipids come in many variants, and the scientists now hope to determine if there is an optimal variant that works powerfully against other bacteria while having little or no toxic effect on human cells. The team also plans to study other microbe-vs.-microbe weapons to find new ways to enhance the potency of existing antibiotics.

"There's a huge number of bacterial interspecies interactions that could be influencing how well our antibiotics work," Radlinski said. "We aim to find them with the ultimate goal of improving the efficacy of current therapeutics and slowing the rise of antibiotic resistance."

An extensive study has confirmed that the risk of developing coeliac disease is connected to the amount of gluten children consume. The new study is observational and therefore does not prove causation; however, it is the most comprehensive of its kind to date. The results are presented in the prestigious journal JAMA.

In total, 6 600 children at increased risk of developing coeliac disease were followed from birth until the age of five, in Sweden, Finland, Germany and the USA.

"Our study shows a clear association between the amount of gluten the children consumed and the risk of developing coeliac disease or pre-coeliac disease. This confirms our earlier findings from studies on Swedish children", says Daniel Agardh, associate professor at Lund University and consultant at Skåne University Hospital in Malmö, and leader of the study.

The previous findings were from a smaller pilot study in 2016 by the same research group. Only Swedish children took part in that study, and the follow-up time was shorter.

The current results also show that the risk of developing pre-coeliac disease or coeliac disease was highest in 2-3 year olds at increased risk of developing coeliac disease. The increase in risk was noticeable even with small amounts of gluten - a daily intake of 2 grams - or the equivalent of one slice of white bread.

"A daily gluten intake over 2 grams at the age of 2 was associated with a 75 per cent increase in risk of developing coeliac disease. This is in comparison with children who ate less than 2 grams of gluten. However, determining a recommendation or limit is a challenge as gluten intake varies and increases during the first years of life", says Carin Andrén Aronsson, lead author of the article and dietician at Lund University.

The association was evident in all participating countries except for Germany, where there was insufficient data to draw any definitive conclusions.

When it comes to dietary advice, Daniel Agardh considers it is the Swedish National Food Agency or equivalent organisations in other countries that should draw conclusions on if and how recommendations on gluten should be changed. He also emphasises that the majority of the group at increased risk of coeliac disease do not develop the disease.

"Therefore, serious consideration should be taken before issuing advice on a particular diet or food restrictions", says Daniel Agardh.

The research team previously carried out several comprehensive studies on the causes of coeliac disease. Among other things, they have demonstrated that the significance of the timing of when a child begins to eat gluten likely to play a very small role, if any. Neither have they been able to demonstrate any clear protective effect from breastfeeding.

The current research is based on total intake of gluten. The next step is to study which food groups that contain gluten are of greater significance compared to others for the development of coeliac disease. In other research projects, Daniel Agardh and his colleagues are investigating the significance of infectious diseases as well as whether an entirely gluten-free diet could reduce the risk of coeliac disease in children who have been assessed as being at the highest risk of developing the disease.

ANN ARBOR, Michigan -- A clinical trial testing a new drug in pancreatic cancer had promising initial results, report researchers from the University of Michigan Rogel Cancer Center.

A phase 1 clinical trial looked at AZD1775, an inhibitor designed to block an enzyme called Wee1, which plays a role in DNA damage repair. The trial builds on almost 20 years of research at U-M focused on improving the treatment of pancreatic cancer that is too advanced for surgery.

Radiation and the chemotherapy drug gemcitabine, which are standard treatment for pancreatic cancer, both work by causing damage to DNA. But pancreatic cancer has a way of repairing that damage, which limits how effective these therapies can be. Rogel Cancer Center laboratory researchers, led by Meredith Morgan, Ph.D., found AZD1775 prevents pancreatic cancer from protecting itself against the effects of radiation and gemcitabine, while leaving normal cells relatively unaffected.

"If we can disable the DNA damage response in pancreatic cancer cells, it might eliminate treatment resistance and sensitize the cancer to the effects of both radiation and chemotherapy," says lead study author Kyle Cuneo, M.D., associate professor of radiation oncology at Michigan Medicine.

The trial enrolled 34 patients with locally advanced pancreatic cancer. Patients received AZD1775 in addition to radiation and gemcitabine. The goal of the study was to determine the maximum tolerated dose of AZD1775 in this combination. In the process, the researchers also found that this combination resulted in better than expected overall survival.

Pancreatic cancer is particularly known for spreading to distant parts of the body, part of the reason overall five-year survival is just 9%.

"If we're ever going to cure pancreatic cancer, we're going to need effective systemic treatment as well as local therapy. Our data suggests that AZD1775 can do both," says senior study author Ted Lawrence, M.D., Ph.D., Isadore Lampe Professor and chair of radiation oncology at Michigan Medicine.

The median overall survival in the study was 22 months, with no progression for a median of nine months. A previous study using gemcitabine alone in a similar group of patients found overall survival of 12-14 months.

"Adding AZD1775 to radiation and gemcitabine was relatively well tolerated with encouraging survival results. Further studies with this promising combination are needed," Cuneo says.

DALLAS, Aug. 14, 2019 -- Stroke survivors who completed group-based aerobic exercise programs similar in design and duration to cardiac rehabilitation programs significantly improved their aerobic endurance and walking ability, according to new research in Journal of the American Heart Association, the Open Access Journal of the American Heart Association/American Stroke Association.

Stroke remains the leading cause of disability in the U.S. and physical therapy is often prescribed to improve physical impairments after stroke. Most current rehabilitation care following stroke has little to no focus on aerobic fitness, and when continued rehabilitation activity is suggested patients often fail to keep active without any support or guidance, according to an analysis of 19 published studies to assess the impact of aerobic exercise programs on endurance and walking ability after stroke.

"The physical therapy we currently provide to patients after a stroke focuses more on improving the ability to move and move well rather than on increasing how far and long you can move," said Elizabeth Regan, DPT, study lead author, and Ph.D. candidate in Exercise Science at the University of South Carolina. "It doesn't matter how well you can walk if your endurance level keeps you at home."

Nearly 500 adults average ages between 54-71 completed aerobic exercise programs similar in structure to cardiac rehabilitation. Participants attended two to three sessions per week for about three months. Of nearly two dozen different exercise groups, walking was the most common type of activity, followed by stationary cycling and then mixed mode aerobic exercise. Physical abilities were tested before and after the intervention.

Looking at results by activity type, researchers found:

Mixed aerobic activity provides the best result (4 treatment groups) followed by walking (12 treatment groups).

Cycling or recumbent stepping (machine that allows stepping while in seated position) while still significant was the least effective (7 treatment groups).

Overall, participants significantly improved their endurance level and walking speed.

On average, participants walked almost half the size of a football field farther during a six-minute walking test. Participants with mild movement impairments benefited the most.

"These benefits were realized regardless of how long it had been since their stroke," Regan said. "Our analysis included stroke survivors across a wide range, from less than six months to greater than a year since their stroke, and the benefits were seen whether they started an aerobic exercise program one month or one year after having a stroke."

"Cardiac rehab programs may be a viable option for patients after a stroke who have health risks and endurance losses similar to traditional cardiac rehab participants," said Stacy Fritz, Ph.D., PT, the study's co-author and associate professor of exercise science in the Physical Therapy Program at the University of South Carolina. "Almost every hospital has a cardiac rehab program, so it's an existing platform that could be used for stroke survivors. Funneling patients with stroke into these existing programs may be an easy, cost-effective solution with long-term benefits."

While this study suggests group-based aerobic exercise programs improve health and endurance in stroke survivors, no control group analysis was performed for results comparison. Limited follow-up data were available to determine whether the health benefits persisted.