Body

BOSTON -Increasingly, Alzheimer's disease (AD) research has focused on the preclinical stage, when people have biological evidence of AD but no or minimal symptoms, and when interventions might have the potential to prevent future decline of older adults. Researchers from Massachusetts General Hospital (MGH) have shed important new light on this area, reporting in a study published in JAMA Network Open that depression symptoms in cognitively healthy older individuals together with brain amyloid, a biological marker of AD, could trigger changes in memory and thinking over time.

"Our research found that even modest levels of brain amyloid deposition can impact the relationship between depression symptoms and cognitive abilities," says Jennifer Gatchel, MD, PhD, of the MGH Division of Geriatric Psychiatry, and lead author of the study. "This raises the possibility that depression symptoms could be targets in clinical trials aimed at delaying the progression of Alzheimer's disease. Further research is needed in this area"

Past research has shown an association between depression and cognitive deficits in older individuals. The MGH study, however, is among the first to reveal that this association is influenced by the presence of cortical amyloid in unimpaired older adults, even when depression symptoms are mild to moderate. Data were collected by researchers over a seven-year period from 276 community-dwelling older adults, all participants in the landmark Harvard Aging Brain Study (HABS). What they discovered was a significant link between worsening depression symptoms and declining cognition over two to seven years that was influenced by AD pathology, as measured by PET imaging of brain amyloid.

"Our findings offer evidence that in healthy older adults, depression symptoms together with brain amyloid may be associated with early changes in memory and in thinking," explains Gatchel. "Depression symptoms themselves may be among the early changes in the preclinical stages of dementia syndromes. Just as importantly, these stages represent a clinical window of opportunity for closely monitoring at-risk individuals, and for potentially introducing interventions to prevent or slow cognitive decline."

MGH researchers also learned from their extensive work that not all older adults with depression symptoms and cortical amyloid will experience failing cognition. Other risk factors investigated by the authors that could modify the relationship between depression and cognition include brain metabolism and volume of the hippocampus, the part of the brain associated with learning and forming of new memories. The authors also note that other mechanisms, including tau-mediated neurodegeneration, hypertension, hypercortisolemia and inflammation, may be involved and need to be investigated.

"These findings underscore the fact that depression symptoms are multi-factorial and may actually work synergistically with amyloid and related processes to affect cognition over time in older adults," notes Gatchel. "This is an area we will continue to actively study."

CHICAGO -- Moderate exercise is not only good for memory as people age, it also appears to help prevent the development of physical signs of Alzheimer's, known as biomarkers, in those who are at risk for the disease, according to research presented at the annual convention of the American Psychological Association.

"Our research shows that, in a late-middle-age population at risk for Alzheimer's disease, physically active individuals experience fewer age-related alterations in biomarkers associated with the disease, as well as memory and cognitive functioning," said Ozioma Okonkwo, PhD, an assistant professor of medicine at the University of Wisconsin School of Medicine and Public Health who presented findings from multiple studies.

Okonkwo and his colleagues examined 317 participants enrolled in the Wisconsin Registry for Alzheimer's Prevention, an ongoing observational study of more than 1,500 people with a history of parents with probable Alzheimer's dementia. Registrants were cognitively healthy and between the ages of 40 and 65 years at the time of enrollment. Participation in the registry included an initial assessment of biological, health and lifestyle factors associated with the disease and follow-up assessments every two to four years.

All participants completed a questionnaire about their physical activity and underwent neuropsychological testing and brain scans to measure several biomarkers associated with Alzheimer's disease. The researchers compared data from individuals younger than 60 years with older adults and found a decrease in cognitive abilities as well as an increase in biomarkers associated with the disease in the older individuals. However, the effects were significantly weaker in older adults who reported engaging in the equivalent of at least 30 minutes of moderate exercise five days a week.

"The most interesting part of our research is that we now show evidence that lifestyle habits - in this case regular, moderate exercise - can modify the effect of what is commonly considered a non-modifiable risk factor for Alzheimer's, in this case aging," said Okonkwo.

In another study, also presented by Okonkwo, researchers studied 95 people, also from the registry, who were given scores called polygenic risk scores, based on whether they possessed certain genes associated with Alzheimer's. Similar to the previous research, the researchers also looked at how biomarkers changed with genetic risk and what role, if any, aerobic fitness might play. Not surprisingly, people with higher risk scores also showed increased biomarkers for the disease. Again, the researchers found that the effect was weaker in people with greater aerobic fitness, a score incorporating age, sex, body mass index, resting heart rate and self-reported physical activity.

A third study examined MRIs from 107 individuals from the registry who were asked to run on a treadmill to determine their oxygen uptake efficiency slope, a measure of aerobic fitness. In line with previous studies, the researchers again found an indicator of the Alzheimer's, known as white matter hyperintensities, significantly increased in the brain with age, but not so much in participants with high levels of aerobic fitness.

"Overall, these studies suggest that the negative effect of aging and genetic risk on Alzheimer's' disease biomarkers and cognition can be lessened in physically active, older adults at risk for the disease compared with their less active peers," said Okonkwo. "If these findings are supported by more prospective, controlled studies, it would provide compelling evidence for physical activity as an effective approach to prevention, particularly in at-risk populations."

DALLAS - Aug. 9, 2019 - A new study from the UT Southwestern Simmons Comprehensive Cancer Center demonstrates that antiviral drugs for hepatitis C reduce liver-related deaths by nearly 50% in patients with a history of liver cancer.

The finding builds on a December 2018 study by the same researchers who found that antiviral drugs do not increase the risk of liver cancer recurrence, as was previously feared.

Dr. Amit Singal's study was published in the journal Gastroenterology on July 30. Dr. Singal is an Associate Professor of Internal Medicine, Medical Director of the UT Southwestern Liver Tumor Program, and Clinical Chief of Hepatology. He collaborated on these studies with Dr. Caitlin Murphy, Assistant Professor of Population and Data Sciences and Internal Medicine. They are both members of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern.

Their studies overturn prior misconceptions that made doctors reluctant to prescribe direct-acting antivirals to treat hepatitis C in patients with a history of liver cancer. Many doctors previously believed that hepatitis C, for all its harmfulness, activates the immune system when it infects the liver, and the immune system kept liver cancer recurrence at bay.

But this notion appears to be false. Drs. Singal and Murphy studied nearly 800 patients from 31 medical centers across the country and found that the drugs are not only safe, they decrease death from cirrhosis and liver cancer by 46%.

"Not only are these drugs safe in this patient population, but we have now demonstrated that they are helpful," Dr. Singal said. "Our study changes the paradigm from you could treat a patient's hepatitis C to you should treat it."

Dr. Carlos L. Arteaga, Director of the Simmons Cancer Center, said the study's scope and impact are something that can only be produced by a National Cancer Institute-designated Comprehensive Cancer Center.

"Dr. Singal had more patients involved in the study than any other participating site. As an epidemiologist, Dr. Murphy brought rigor to the data that removes prior doubt on this issue," he said.

Dr. Murphy said previous studies compounded the misunderstandings of direct-acting antiviral therapy because they, among other things, failed to account for the timing of therapy relative to liver cancer diagnosis, did not include a comparison group, or did not properly consider clinical differences among patients.

The new study is a significant contribution because it clears the path to beneficial drug treatment.

"Hepatitis C therapy is so important because it provides a cure," Dr. Singal said. "You take oral medications for two or three months, with minimal to no side effects, and you're done. You're cured of hepatitis C. There's less than a 1% chance of relapse if you're cured of hepatitis C."

Defeating hepatitis C is an important step because infection can otherwise lead to cirrhosis - scarring of the liver - which can be deadly. Cirrhosis can increase the risk for liver cancer, which also may be fatal. Curing hepatitis C with antivirals breaks the first link in a deadly chain of events and can lead to improvement in liver function among those who have previously developed cirrhosis.

Hepatitis C rapidly made its way into the American blood stream in the 1970s and 1980s when intravenous drug use spiked and blood products were not screened for the hepatitis C virus. Hepatitis C infected 2 to 3% of the baby boomer population, the largest generation in U.S. history. Millions were affected.

The disease can lie dormant for 25 to 30 years and resurface as a life-threatening specter years after someone has stopped using drugs and turned to a healthy lifestyle. Hepatologists saw an alarming spike in cirrhosis as baby boomers aged. By 2017, The New York Times called hepatitis C "an enormous public health problem." In 2018, the Centers for Disease Control and Prevention announced there were nearly 2.4 million people living with hepatitis C in the U.S.

"Dr. Singal's and Dr. Murphy's study reports a welcome, fact-based way to oppose the adverse effects of hepatitis C infection in various demographic groups," Dr. Arteaga said. "Their findings will have a global, lifesaving impact on how hepatitis C is treated. It is particularly important to Texas because the liver cancer incidence rate in Texas is the highest in the nation."

Dr. Arteaga said the study is also important because liver cancer is highest among the Hispanic population in Texas, and research-based advances in reducing cancer in underserved groups are a Simmons Cancer Center priority.

FINDINGS

A Veterans Health Administration program that added mental health specialists, care managers or both in primary care clinics significantly improved access to mental health and primary care services to veterans with behavioral health needs. In a clinic of 100 patients, each additional patient seen by such a mental health specialist or care manager was on average associated with 11% more mental health visits and 40% more primary care visits. The practice also resulted in 9% higher average annual costs for each patient.

BACKGROUND

The Department of Veterans Affairs launched the Primary Care-Mental Health Integration initiative nationally in 2007 to deliver mental health services directly to veterans at all its primary care clinics that treat more than 5,000 patients each year.

METHOD

The researchers examined data from October 2013 to September 2016 for nearly 5.4 million patients treated at 153 hospital-based and 243 community-based VA clinics.

The study has some limitations. Among them, the researchers did not control for factors such as mental health care staffing that might have affected health care use or cost. Also, there may be inaccuracies in the way that some mental health conditions were noted due to changes in the codes used to log them in the medical records.

IMPACT

The Veterans Affairs' Primary Care-Mental Health Integration initiative required significant financial investment and strong multidisciplinary partnerships in order to expand prompt access to specialty mental health care among its primary care patients. The experience of the Veterans Health Administration -- which has one of the largest programs to integrate mental health and primary care services -- may inform other health systems aiming to improve fragmented care delivery.

DALLAS - Aug. 9, 2019 - Changing the standard dose and timing of two therapies greatly cut tumor relapse and reduced side effects in mouse models of kinase mutated breast cancer and lung cancer, UT Southwestern Simmons Cancer Center researchers have found.

The study published today in Science Immunology suggests that giving the two therapies as short course, first-line treatment might work better than the current practice of providing one treatment early and the other treatment only if tumors relapse.

"This study reveals the importance of the proper combination and timing of tyrosine kinase inhibitors and immunotherapy such as the programmed death-ligand 1 (PD-L1) inhibitor, also known as immune checkpoint blockade. If borne out by future research, these findings might open new treatment avenues for many cancer patients," said corresponding author Dr. Yang-Xin Fu, Professor of Pathology, Immunology, and Radiation Oncology and a member of the Harold C. Simmons Comprehensive Cancer Center.

"Many cancers have high and abnormal tyrosine kinase activities. Tyrosine kinase inhibitors, or TKIs - which target specific cancers - are a common first-line treatment for rapidly shrinking tumors such as those associated with kinase-driven breast cancer and lung cancer. But tumor relapse or resistance often occurs. The standard of care is to use TKIs first and then use immunotherapy such as PD-L1 inhibitors after relapse occurs," Dr. Fu explained. "Our study showed that immunotherapy should be used together with the TKIs as the first-line - not second-line or third-line - treatment. We also demonstrated that the dose and timing of the TKI is important."

The team, which included first authors and postdoctoral researchers Drs. Zhida Liu and Chuanhui Han, also found that hypofractionated TKI (HypoTKI) - giving a high dose over a short time - was more effective in mouse models of breast cancer and lung cancer than standard hyperfractionated TKI (HyperTKI) - lower doses over a longer time. Compared with standard therapy, the high-dose/short time TKI approach appeared to significantly reduce tumor burden and limit relapse with fewer side effects.

Earlier studies that found increased side effects when TKI and PD-L1 were given together had used HyperTKI rather than the HypoTKI provided in this investigation, said Dr. Fu, a physician-scientist who holds the Mary Nell and Ralph B. Rogers Professorship in Immunology.

The researchers found that TKIs work in part by activating both innate and adaptive immunity - that is, both of the body's immune systems. The innate immune system is activated as soon as a threat is identified. Adaptive immunity is the body's response to threats it has learned to recognize, Dr. Fu explained.

PD-L1 inhibitors are thought to enhance adaptive immunity to overcome the ability of some tumor cells to develop resistance to TKIs, he added.

Compared with standard HyperTKI therapy, the HypoTKI approach triggered greater innate immune sensing and a more potent release of type I interferon and other cytokines through an innate immunity signaling pathway to enhance tumor-specific T cell infiltration and reactivation. The researchers also found that HypoTKI was more potent than HyperTKI in limiting tumor relapse in a host immune response-dependent manner. More importantly, they observed that PD-L1 blockade could further enhance the anti-tumor effectiveness of HypoTKI treatment in advanced large tumors and limit the relapse. The timing of the dose of the drugs was important, he said.

The study is among the first to find that this class of TKIs can trigger the innate immune response, Dr. Fu said. "We think there might be a threshold effect with HypoTKI in which the treatment more effectively alerts the innate immune system. It appears that higher-dose/shorter duration TKI treatment may spark a more potent anti-tumor response by better triggering the innate immunity system."

In one series of experiments, the researchers found that tumors were completely resistant to anti-PD-L1 therapy alone, so-called monotherapy. When HypoTKI was given by itself, it markedly reduced tumor burden initially, but all tumors relapsed eventually.

When the two treatments were given concurrently and early, it resulted in the best tumor regression and most mice showed no relapse over more than two months of follow-up. Tumor relapse in mice usually occurs within two to three weeks.

"The maximum synergistic effect of combination therapy depends on the timing of the anti-PD-L1 treatment. When it was started within three days of TKI administration, there was total tumor regression and only two of eight tumors relapsed," Dr. Fu said.

Almost no synergistic effect was seen if PD-L1 inhibitors were provided a week after TKI therapy.

"Our study demonstrates that HypoTKI and PD-L1 blockade can work in combination to effectively control advanced large tumors, increase overall survival, and reduce tumor relapse. These data suggest that proper timing - giving the two agents together at the start of treatment - provides maximum synergistic anti-tumor effects in these tumors and should be studied further," Dr. Fu said.

A new study from The Westmead Institute for Medical Research (WIMR) has demonstrated how dual DNA barcoding could help improve the diagnosis of invasive fungal diseases, giving patients access to potentially life-saving treatment much sooner.

The early detection of fungal pathogens - the specific species of fungi responsible for disease - is crucial in ensuring that patients have fast access to treatment, preventing complications. However, current diagnostic methods are time-consuming, complex and are not always accurate, resulting in delays in treatment and inappropriate therapy, increasing the risk of morbidity and mortality.

Dual DNA barcoding is an emerging technique used to identify fungal pathogens. It uses two unique regions of DNA that are specific to each pathogenic fungal species - the primary barcoding region, internal transcribed spacer region (ITS) and the secondary barcoding region, translational elongation factor 1α (TEF1α).

Fungal DNA is extracted from a patient sample, where it is then 'amplified' or multiplied to increase the amount of DNA available for sequencing. The DNA information is data-mined, and compared to a reference database to identify the fungal pathogen.

Although the secondary barcoding region was introduced in 2017, its impact and effectiveness has, until now, not been assessed.

Lead researcher, Professor Wieland Meyer said, "Our study is the first to compare the accuracy of the two barcoding regions, and to evaluate the effectiveness of ITS and TEF1α combined.

"We were able to correctly identify all disease-causing fungal species, from the most common human fungal pathogen Candida albicans, to species which rarely cause infections. We found that the primary barcoding region alone could not detect all species - however, the secondary region, as well as the two combined, filled in this gap.

"Overall, we found that the combination of both barcodes enabled a more accurate identification of fungal species, particularly in cases where a single barcoding system is unable to do so."

Invasive fungal diseases (IFD), such as Cryptococcus neoformans infections or Aspergillosis are an increasing threat to global health, with more than 1.6 million deaths attributed to IFDs each year. New infections continue to emerge, such as the new multidrug resistant species of Candida, C. auris, which has the capacity to spread rapidly and persist in health care environments.

Professor Meyer said, "Identifying the type of fungi that is causing infection will help us administer appropriate treatment faster, reducing harm and, potentially, mortality rates associated with IFDs.

"It may also improve other complications associated with IFDs, such as drug resistance, and the financial impact IFDs can have on both patients and the healthcare system.

"While we now know that the dual DNA barcoding system is more effective at identifying fungal species, we need to increase the amount of sequences available in reference sequence databases to maximise the number of species we can identify.

"We are now asking researchers from around the world to submit reference sequences that can be used to identify fungal pathogens.

"By improving our database, and, in turn, increasing our capacity to use dual DNA barcoding, we will be able to reduce the diagnostic turnaround time from days or weeks to less than 24 hours, which could have a major impact on patient outcomes, and could potentially save lives."

Ultrasound is a non-invasive and relatively inexpensive means of diagnosing a number of medical conditions. This review presents an analysis of the diagnostic value of ultrasound to draw comparison between different types of arthritic conditions. The 7 major arthritic conditions included in this study are osteoarthritis, rheumatoid arthritis, gouty arthritis, pseudogout (calcium pyrophosphate deposition disease), psoriatic arthritis, infectious arthritis and spondyloarthritis.

In this review, researchers at SouthWest Medical University, China have conducted a computerized literature search in Pubmed and identified a list of 206 publications related to arthritis. Out of this list, a total of 52 studies out of those met the search criteria for involving diagnostic ultrasonography.

The researchers found that ultrasound was effective in delineating characteristic features in each of the above mentioned 7 major types of arthritis. When performed by a trained sonographer and combined with a good history and physical examination, ultrasound proved to be a convenient, feasible, economic and accurate imaging modality in the evaluation and monitoring of disease process and progression in each type of arthritis. Some of the features overlapped while some were idiosyncratic to each.

Although MRI has been considered as the main modality for musculoskeletal (MS) pathology evaluation, high resolution ultrasound with colour doppler imaging is suggested as the imaging method of choice for the assessment of superficial MS lesions.

Researchers identified a gene in fruit flies that helps prevent the hyperexcitability of specific neurons that trigger seizures. In humans, mutations in the gene may be linked to seizures associated with Long QT Syndrome. A research team led by Yehuda Ben-Shahar of Washington University in St. Louis report these findings in a paper published 8th August in PLOS Genetics.

The nervous system can be highly sensitive to environmental changes such as swings in temperature or oxygen levels. These environmental stresses are known to cause seizures, but scientists have little understanding of the genetic and molecular causes behind them. Using fruit flies, researchers investigated certain proteins, called ion channels, involved in passing electrical signals between neurons and other cells. They studied a fly gene necessary to block stress-induced seizures, called sei, which functions throughout the nervous system and in the heart. They found that sei primarily protects against heat-induced seizures through its action in specific cell types in the nervous system, but that blocking the gene in the heart had no effect.

Humans have a comparable gene called hERG and previous work has linked mutations in hERG to a condition called Long QT Syndrome, where a sudden erratic heart beat can lead to fainting spells, seizures and potentially even death. The discovery raises the possibility that seizures associated with Long QT Syndrome are related to problems with hERG, not in the heart, but in the brain.

"Individuals with mutations in the potassium channel hERG suffer from seizures, which are often assumed to be a secondary consequence of heart disease," said author Yehuda Ben-Shahar. "Here we have identified a role for the fly version of the hERG gene in specific brain cell types in preventing the development of seizures in response to acute environmental stresses. We plan to continue using the fruit fly as a model system for investigating the genetic and physiological networks that protect the brain from stress-induced hyperexcitability associated with seizures and related pathologies."

The new study provides compelling evidence that hERG ion channels play an essential role in protecting the nervous system from environmental stresses, such as heat. It may also give insight into the mechanisms behind diseases associated with hERG mutations in human patients.

BOSTON (August 8, 2019) - Amid the worsening Ebola outbreak in the Congo, now threatening to spill into Rwanda, a new study suggests that an existing, FDA-approved drug called nitazoxanide could potentially help contain this deadly, highly contagious infection. In meticulous experiments in human cells, led by Boston Children's Hospital, the drug significantly amplified immune responses to Ebola and inhibited Ebola replication.

The study, published in the Cell Press journal iScience, also showed how the drug works: It enhances the immune system's ability to detect Ebola, normally impeded by the virus.

Nitazoxanide, or NTZ, is currently used to treat gastrointestinal infections caused by parasites such as Giardia and Cryptosporidium. It has been shown to be safe and even comes in a formulation for children. Study leader Anne Goldfeld, MD, of the Program in Cellular and Molecular Medicine at Boston Children's, hopes that, with further testing and validation, it could be part of the solution for Ebola.

"Currently, there is no easily deployable therapy for Ebola virus," she says. "There are some very promising vaccines, but there is no oral, inexpensive medication available."

Outsmarting Ebola

The Ebola virus caused more than 10,000 deaths in the 2014-2016 West African epidemic and more than 1,800 lives (as of August 6th) in the current outbreak in the Democratic Republic of the Congo. The virus is very good at evading human immune defenses. Though very small, it has two genes devoted to blocking immune responses.

Goldfeld and collaborators Chad Mire, PhD and Thomas Geisbert, PhD at the University of Texas Medical Branch, Galveston, showed in Biosafety Level 4 laboratory experiments that NTZ inhibits the Ebola virus (isolated from an earlier outbreak). Additional experiments performed in collaboration with Sun Hur, PhD of Boston Children's showed that NTZ works by broadly amplifying the interferon pathway and cellular viral sensors, including two known as RIG-I and PKR. By deleting RIG-I and PKR in human cells through CRISPR editing, Goldfeld and University of Texas colleagues showed that NTZ works through these molecules to inhibit Ebola virus.

"Ebola masks RIG-I and PKR, so that cells don't perceive that Ebola is inside," explains Goldfeld. "This lets Ebola get a foothold in the cell and race ahead of the immune response. What we've been able to do is enhance the host viral detection response with NTZ. It's a new path in treating Ebola."

Goldfeld hopes to move into animal studies soon, especially given that NTZ has already been used in millions of people with minimal side effects. If effective, it could thus be easily repurposed for Ebola treatment or prevention.

An effort to improve the scheduled cesarean section delivery experience found that changes to preoperative and postoperative processes can lead to reductions in opioid use without increased pain and with faster recovery, according to research from Kaiser Permanente published in the journal Obstetrics & Gynecology.

The study compared 4,689 women who underwent scheduled C-section deliveries at Kaiser Permanente hospitals in northern California in the year before the Enhanced Recovery After Surgery program, known as ERAS, began with 4,624 women who delivered after it began.

ERAS includes innovations such as allowing a carbohydrate drink before surgery (rather than the traditional fast), pain management that reduces opioids in favor of local anesthetics and acetaminophen, getting patients up and walking soon after surgery, and educating patients about what to expect.

Taking fewer painkillers, along with moving around sooner after the surgery, can allow women to recover more quickly and care for their newborns, the researchers said.

"We found our new moms are more alert and engaged in the recovery process and in breastfeeding," said study co-author Kimberly Lee, MD, an obstetrician-gynecologist at Kaiser Permanente Santa Clara Medical Center. "Babies and mothers both can decrease exposure to opioids while hospitalized."

Researchers with Kaiser Permanente's Division of Research examined outcomes for the patient groups before and after ERAS and found decreases in opioid exposure and improvements in eating and walking. They found no significant change in length of hospital stay or surgical site infections, though those metrics were not expected to decrease as they were already low.

The significant finding was that women could decrease opioids without experiencing greater pain, said lead author Monique Hedderson, PhD, a research scientist with the Division of Research.

"This study provides evidence we can successfully implement Enhanced Recovery After Surgery with patients undergoing cesarean deliveries, and that hasn't been shown before," Hedderson said. "It seems to result in a decrease in opioid exposure without an increase in pain."

As with any surgery, women undergoing a C-section who take opioids for pain may have trouble stopping their use. Recent research found that 2.2% of women who are given opioids after a cesarean delivery continued using the painkillers weeks or months later.

In this study, mean inpatient opioid exposure was nearly cut in half (from 10.7 average daily morphine equivalents to 5.4). The proportion of time patients reported acceptable pain scores increased from 82% to 86%. The time to first post-surgical ambulation went down by 2.7 hours, while the first post-surgical solid food intake decreased by 11 hours.

The typical pain control regimen for a scheduled C-section patient under ERAS is spinal anesthesia for the procedure, followed by scheduled non-steroidal pain medication and acetaminophen every 6 hours, with use of oxycodone (an opioid) as needed for breakthrough pain.

The other elements of ERAS also contributed to a better experience, Dr. Lee said, including allowing liquid nutrition in the hours before the surgery and encouraging food afterwards. Patients were given information about what to expect during recovery in the hospital on a specially designed calendar in their cesarean section ERAS kit.

Elective C-sections are done for medical reasons, such as a baby in breech position or if the mother has had a C-section in the past and does not want to deliver vaginally. The study did not consider emergency C-sections because those patients would not be able to participate in the full ERAS experience, though Kaiser Permanente hospitals in northern California are now using many of the ERAS elements with those patients as well.

Kaiser Permanente's 21 northern California hospitals have adopted ERAS practices for many surgeries and some outpatient procedures. All C-sections are now carried out under ERAS protocols following positive results from the pilot programs described in this research.

WASHINGTON (Aug. 8, 2019) --There are several barriers that prevent the consistent use of fungal diagnostic preparations to correctly identify cutaneous fungal infections, according to a survey from a team at the George Washington University (GW). The study is published in the Journal of Drugs in Dermatology.

Cutaneous fungal infections account for between 3.5 and 6.5 million dermatologist office visits per year. Despite their frequency, the diverse presentations of fungal infections often lead to misdiagnosis, resulting in additional costs, time, and delays in proper care. Direct microscopy using potassium hydroxide (KOH) or other stains provides an inexpensive method to diagnose fungal infections. However, this requires clinics to have the Clinical Laboratory Improvement Amendment (CLIA) certification.

"Because of the extraordinary ability for these fungal infections to mimic other skin diseases, identification based on clinical inspection alone can often lead to misdiagnosis and mismanagement," said Adam Friedman, MD, professor and interim chair of the Department of Dermatology at the GW School of Medicine and Health Sciences and senior author on the study. "Little is known regarding the frequency with which dermatologists use these simple, yet diagnosis changing bedside fungal preparations, nor do we know if and what barriers exist preventing accurate diagnosis of infections."

Friedman's team previously published research highlighting the difficulty even dermatologists have when distinguishing between skin fungal infections and other inflammatory skin diseases, highlighting the importance of using laboratory-based tools to aid in patient care.

This survey, led by Emily Murphy, a research fellow in the Department of Dermatology at the GW School of Medicine and Health Sciences, was distributed via email to participants of the Orlando Dermatology Aesthetic and Clinical Conference, and the data was compiled in a web-based platform. Of the respondents, around 21% indicated they rarely/never perform fungal preparations and about 20% reported they sometimes do, often because they think clinical diagnosis is adequate or because fungal preparations take too long. Additionally, about 21% of respondents reported not having CLIA certifications, mostly because the process requires too much work or because they do not know how to apply. Of the providers who have CLIA certification, more than 25% reported that it was difficult to obtain.

"Our results indicate the need for increased education about the many clinical faces of cutaneous fungal infections and proper use of bedside diagnostics," Friedman said. "It also highlights the need for policy-based interventions in order to ease the process of CLIA certification, to ensure that dermatology clinics are equipped to accurately diagnose infections."

ANN ARBOR, Mich. - Sixty percent of privately insured children undergoing tonsil removal received opioids -with average prescriptions lasting about six to 10 days - a new study finds.

And while the more powerful painkillers are often prescribed because they have been believed to reduce the risk of complications such as poorly controlled pain, researchers did not find evidence indicating that opioids protected children against those risks.

The Michigan Medicine study appears in the journal JAMA Otolaryngology-Head & Neck Surgery.

"Our findings suggest that it may be possible to reduce opioid exposure among children who undergo this common surgery without increasing the risk of complications," says lead author Kao-Ping Chua, M.D., Ph.D., a researcher and pediatrician at University of Michigan C.S. Mott Children's Hospital and the U-M Institute for Healthcare Policy and Innovation.

Researchers analyzed national data between 2016 and 2017 from a private insurance database. Among 15,793 children (ages 1 to 18) who underwent a tonsillectomy, six in 10 had one or more filled opioid prescription.

Tonsillectomy is one of the most common surgical procedures performed in children. American Academy of Otolaryngology guidelines strongly recommend non-opioids, such as nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen, for these procedures.

Chua says there are several possible explanations for why so many children still received opioid prescriptions despite these guidelines. Among the biggest potential reasons is that the potent painkillers have been believed to provide superior pain relief and reduce risk of return visits for uncontrolled pain leading to dehydration.

In the University of Michigan study, having a filled opioid prescription wasn't associated with a difference in risk of return visits for pain or dehydration. But it was linked to an increased risk of constipation and in at least one case, an opioid overdose, the study found.

Chua believes surgeons may also prescribe opioids after tonsillectomy because they fear that NSAID use increases bleeding risk. But clinical trials have not demonstrated a significant increase in bleeding risk with NSAID use. In the new Michigan study, having a filled opioid prescription was not associated with increased risk of bleeding, suggesting that prescribing opioids may not protect against this complication.

Among children with perioperative fills, the median prescription duration was eight days, an amount that could represent 48 doses of opioids. This is far greater than what the average patient needs, researchers say. A previous study at Mott found that children undergoing tonsillectomy in 2013 were prescribed an average of 52 opioid doses but had an average of 44 leftover opioid doses.

Over-prescribing opioids to children isn't just a health risk to children, Chua says, but also to family and friends who may have access to the leftover opioids that may not be properly disposed.

"To minimize the risks of opioids to children and their families, clinicians should rely on non-opioids when possible. When opioids are used, clinicians should aim to prescribe only the amount that patients need," Chua says.

"However, our study suggests that many children receive opioid prescriptions after tonsillectomy and that the amount of opioids in these prescriptions may be excessive. We need to conduct research to identify interventions that safely and effectively reduce opioid exposure for these children."

A new study from the University of Eastern Finland shows that the health-related quality of life of most people who have or have a higher risk of knee osteoarthritis remained unchanged over an eight-year trajectory. Worsening of quality of life was associated with several risk factors, such as obesity and smoking, and it also reflected the patient's need for treatment. Published in PLOS ONE, the findings can help to identify patients who will benefit from early treatment.

Osteoarthritis (OA) is the most common type of arthritis and one of the most disabling diseases. While the root cause of osteoarthritis remains unknown, ageing, obesity and joint injuries have been found to be major risk factors. It is estimated that knee osteoarthritis affects more than 10% of individuals aged over 60 years. The societal burden is made up of different costs, for example, joint replacement surgeries, sickness benefits and disability pensions. At an individual level, joint pain, activity limitations and worsening of quality of life are major consequences of knee osteoarthritis. Health-related quality of life refers to subjective experience of one's health.

Several international studies have identified distinctive subgroups in the evolution of knee pain and also in the functional limitations experienced by persons with knee OA. The newly published study focused on changes in the health-related quality of life in individuals with mild or moderate knee OA as well as in individuals at an increased risk of knee OA. The researchers used group-based trajectory modelling to identify patient subgroups with similar change patterns in their quality of life. The study participants were classified into groups on the basis of changes occurring in their quality of life during an eight-year follow-up. The researchers also used statistical modelling to explore the associations of patient-specific risk factors, joint replacement surgeries and pain medication use with the health-related quality of life trajectory.

Four health-related quality of life trajectory groups were identified. 62.9% of the study participants belonged in the "no change" group that experienced no worsening in their quality of life. The quality of life worsened "slowly" in 17.1% of the study participants and "rapidly" in 9.5%, while 10.4% experienced their quality of life as "improving".

Female gender, higher body mass index, smoking, knee pain and lower income at baseline were associated with rapidly worsening quality of life. During the follow-up, 8.2% of the study participants in the rapidly worsening group, and 4.8% in the slowly worsening group underwent joint replacement surgery. In the "no change" group, the percentage was as low as 1.4%.

Furthermore, the use of pain medications was lowest in the "no change" group, where 22-32% of the participants reported pain medication use. In other groups, 29-45% of the participants reported pain medication use.

The findings show that the health-related quality of life trajectory in people with knee osteoarthritis varies from one patient group to the next, and that the patient's subjective experience of quality of life reflects their need for treatment. These observations can help to identify patients with knee OA who are at risk of worsening quality of life and who could benefit from early treatment. The findings can also provide insight for surveys addressing health care resources. According to the researchers, increasing attention should be paid on patients' subjective experience of their health-related quality of life. In the case of chronic diseases, measuring the patient's quality of life provides valuable information on the efficacy of different treatments, among other things.

Data used in the study were obtained from the Osteoarthritis Initiative (OAI) database. The OAI is a longitudinal cohort study on knee OA, hosted by the US National Institutes of Health: https://data-archive.nimh.nih.gov/oai/.

A team of biologists has discovered how cells become different from each other during embryogenesis, a finding that offers new insights into genetic activity and has implications for better understanding the onset of disease and birth defects.

"Scientists have known for many years that changing which genes are turned on in a particular cell can lead to birth defects and cancer," explains Stephen Small, a professor in New York University's Department of Biology and the senior author of the paper, which appears in the journal Molecular Cell. "However, the intricacies of this activation had not been clear. Our results reveal how the process is orchestrated during an embryo's development."

Specifically, previous research had identified promoters--or "on/off" switches"--for thousands of genes. However, these studies had not delineated how these promoters are activated, leaving unclear fundamental aspects of how cells become different from each other during embryogenesis.

The Molecular Cell study focused on a gene called hunchback (hb), which makes cells in the head region of the fly embryo that are different from cells in the abdomen.

The NYU biologists uncovered hb's DNA sequence code in a region called the "hb promoter," or genetic "on/off switch."

"If the hb promoter switch is turned off, the hb gene is silent and is not expressed," explains Small. "However, if it is switched on, the gene produces an RNA copy of itself, which is required for specifying head development."

Specifically, in the embryo, the hb promoter switch is turned on by a protein called Bicoid, which binds to a different DNA sequence called an "enhancer," located very far from the hb promoter. Once bound to the enhancer, Bicoid proteins physically touch the hb promoter and subsequently flip the promoter switch on.

Small and his colleagues took advantage of a characteristic of the hb gene to help illuminate this process: the gene has two promoters, an active one that responds to Bicoid and an inactive one that does not.

"By precisely swapping sequences between the inactive and active promoters, we discovered that the active promoter contains two short sequences that are required for the response to Bicoid," notes Small. "When we mutated these sequences, the active promoter was efficiently turned off, and when we inserted them into the inactive promoter, it was efficiently turned on."

"The bodies of complex animals contain many types of cells, and each cell type is unique because it turns on a specific set of genes," he adds. "This paper describes how one of the first cell-specific genes is turned on in a particular region of the early embryo."

Patients with a history of coronary heart disease (CHD) or acute coronary syndrome (ACS) benefit more from treatment with a statin in combination with ezetimibe than from treatment with a statin alone. However, there is no hint that the combination therapy of a statin plus ezetimibe is also superior to the combination of a statin plus the lipid-lowering drug alirocumab. No studies on other lipid-lowering combination options were available.

These are the findings of the German Institute for Quality and Efficiency in Health Care (IQWiG) in a current benefit assessment commissioned by the Federal Joint Committee (G-BA) in November 2018.

The most common cause of death worldwide

Cardiovascular diseases are diseases that originate from the vascular system and/or the heart. These include hypertension, CHD, ACS, heart attack and stroke. Cardiovascular diseases were the most common cause of death worldwide in 2016, accounting for 31 percent of all deaths. Of these causes of death, 85 percent resulted from a heart attack or stroke.

One of the largest modifiable risk factors for cardiovascular diseases is a high LDL cholesterol level (LDL = low-density lipoprotein). The reduction in LDL cholesterol (LDL-C) is therefore an important goal in the prevention of cardiovascular diseases. In patients with a history of CHD or ACS, the administration of cholesterol-lowering drugs is recommended. Statins are currently the most commonly prescribed group of drugs in this regard.

For some time now, a combination of statin and ezetimibe has also been used to further reduce LDL cholesterol. The German Federal Institute for Drugs and Medical Devices (BfArM) approved this extension of the therapeutic indication for ezetimibe in patients with a history of CHD and ACS in 2016.

One relevant large study for each question

On behalf of the G-BA, the IQWiG researchers investigated the benefit of treatment with ezetimibe in combination with a statin to reduce the risk of cardiovascular events in patients with a history of CHD or ACS with regard to patient-relevant outcomes

- versus treatment with a statin alone (research question 1) and

- versus treatment with a combination of a statin and another drug influencing lipid metabolism (research question 2).

The assessment of research question 1 was ultimately based only on the IMPROVE-IT study. The other studies identified did not contain any relevant additional information. The IMPROVE-IT study included 18,144 patients who had experienced an ACS within 10 days prior to randomization. The study was designed to examine the effect of ezetimibe on clinical outcomes (the primary outcome was a combined outcome of fatal and non-fatal cardiovascular events) rather than on surrogate outcomes (such as a reduction in LDL-C). The median follow-up period was six years.

For research question 2, the IQWiG researchers identified COMBO II as the only relevant study. This randomized controlled trial included 720 patients with a high to very high cardiovascular risk whose LDL-C levels were insufficiently controlled with an existing statin therapy. The primary outcome of the study was the change in LDL-C levels after 24 weeks compared with baseline. The "other drug influencing lipid metabolism" was alirocumab.

Fewer heart attacks and fewer strokes than with statin monotherapy

In patients with a history of CHD or ACS, the IQWiG researchers see an indication of a greater benefit of ezetimibe in combination with a statin versus a statin alone (research question 1). For these patients, the additional administration of ezetimibe reduces the risk of suffering a major adverse cardiovascular event. In the benefit assessment, serious adverse cardiovascular events were evaluated as a combined outcome of the patient-relevant components of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke.

For other patient-relevant outcomes such as all-cause mortality, hospitalization for unstable angina pectoris, hospitalization for heart failure or other serious adverse events, however, the IMPROVE-IT study showed no statistically significant difference between treatment groups.

No superiority over alirocumab plus statin

In patients with a history of CHD or ACS, the IQWiG project team found no hint that the combination therapy of a statin plus ezetimibe was also superior to the combination of a statin plus alirocumab (research question 2).

For the combined outcome "major adverse cardiovascular event", the COMBO II study did not provide data for the relevant subpopulation. Therefore, the IQWiG team assessed the individual components separately: for "non-fatal myocardial infarction", "fatal and non-fatal stroke" and "hospitalization due to unstable angina pectoris", there were no statistically relevant differences between the treatment groups. However, due to the relatively small number of patients, the data are just as inadequate as for the outcome "all-cause mortality".

Process of report production

In December 2018, the G-BA commissioned IQWiG to prepare the report in an accelerated procedure as a so-called rapid report. Interim products were therefore not published or made available for a hearing. This rapid report was sent to the contracting agency, the G-BA, on 28 June 2019.

More English-language information will be available soon (an extract of the rapid report as well as easily understandable information on informedhealth.org). If you would like to be informed when these documents are available, please send an e-mail to info@iqwig.de.