Body

From face-lifts to facials and fillers, there's no shortage of ways to reduce the inevitable signs of aging. But there's one cosmetic procedure that most people don't think about as a tool that can make women look years younger.

Rhinoplasty, or cosmetic nose surgery, may make a woman look up to three years younger, according to a new study led by researchers at UCLA that used a type of artificial intelligence known as machine learning.

The researchers used the technology to study before-and-after photos of 100 female patients, ages 16 to 72, all of whom underwent rhinoplasty by Dr. Jason Roostaeian, a UCLA plastic surgeon and senior author of the paper. At 12 or more weeks later, standardized photographs were analyzed with the technology, which estimates a person’s age by cropping the face from a photograph and then extracting a prediction through an algorithm.

"Rhinoplasty is widely recognized as a facial beautification procedure, but it isn't commonly known for its anti-aging effects," said Dr. Robert Dorfman, lead author of the study and a resident physician in the division of plastic and reconstructive surgery at the David Geffen School of Medicine at UCLA. The study was published in the Aesthetic Surgery Journal.

Rhinoplasty involves making structural changes to the bone and cartilage through small incisions inside the nose and when necessary around the nostril, all while a patient is under general anesthesia. The rhinoplasty procedures in this study were customized for each patient to fit the person's face best.

Until now, Dorfman said, there has been little to no objective scientific evidence for the rejuvenating effect of rhinoplasty. "This technology allows us to accurately estimate age in an objective way and has proven to recognize patterns and features of aging beyond what the human eye can perceive," he said.

The results were even more dramatic in women over 40, some of whom were estimated to look seven years younger after rhinoplasty. However, because the sample size of the 40-plus group was small (25 women), the researchers said further studies need to be done to validate the results. (The median age of the study participants was 32.)

The nose is not usually a focus of anti-aging treatment. However, like other features of the body, the human nose, which is made up of soft tissue, cartilage and bone, also ages.

"The nose loses support as it ages and can take on a more prominent or droopy appearance," said Dr. Jason Roostaeian, senior author of the study and associate clinical professor in the division of plastic and reconstructive surgery at the Geffen School.

The nose is also affected when other features of the face age. "When we lose facial fat and volume in our cheeks, which are the canvas that our nose sits on, the nose becomes more prominent."

By refining the nose, he said, the youthful appearance of the entire face can be refined. "This is something we have subjectively thought for many decades but now we have objective evidence through artificial intelligence to support this."

A five-year follow-up study of more than 2,000 U.S. men who received prostate cancer treatment is creating a road map for future patients regarding long-term bowel, bladder and sexual function in order to clarify expectations and enable men to make informed choices about care.

The CEASAR (Comparative Effectiveness Analysis of Surgery and Radiation for Localized Prostate Cancer) study, coordinated by Vanderbilt University Medical Center, is a multi-site research study conducting long-term followup on men who were diagnosed with localized prostate cancer between 2011 and 2012.

The five-year results published in JAMA, with lead author Karen Hoffman, MD, MPH, from MD Anderson, provide evidence on outcomes with radiation, surgery or active surveillance in patients of all ages and ethnicities.

"We are providing information about the side effects of different treatments for prostate cancer that men and their providers can use to make treatment decisions," said senior author Daniel Barocas, MD, MPH, associate professor and vice chair of Urology at VUMC.

"However, we have only illuminated one facet of a complex decision. There is more to a treatment decision than just the side effects, the most obvious being the effectiveness of the treatment, and that is something we hope to be able to demonstrate as we are now funded to look at 10-year cancer outcomes."

Researchers studied 1,386 men who had favorable-risk prostate cancer and another 619 men with unfavorable-risk prostate cancer to evaluate the impact of their treatment decisions on urinary, sexual and bowel function over a five-year period.

The favorable-risk group chose either:

Active surveillance, an observation strategy in which treatment is only used if the cancer gets worse over time.

Nerve-sparing prostatectomy, surgical removal of the prostate with attempt to protect nerves that run alongside the prostate in hopes of minimizing the impact of surgery on erectile function.

External beam radiation therapy (EBRT), a common therapy that uses daily doses of radiation to destroy cancer cells.

Low-dose-rate brachytherapy, a type of radiation therapy involving implantation of radioactive "seeds."

The unfavorable-risk disease group chose either:

Prostatectomy, which is surgery to remove the prostate.

External beam radiation therapy with androgen deprivation therapy (ADT), which is radiation in combination with an anti-hormone therapy used to reduce levels of androgen hormones to enhance the effectiveness of radiation.

Men undergoing surgery experienced an immediate, sharp decline in erectile function compared to other groups. However, on average, men treated with prostatectomy improve with time, while those undergoing radiation decline, so that sexual function differences between treatment groups attenuated by 5 years. While the difference in sexual function between surgery and radiation was still measurable in the unfavorable risk group, most men had such poor scores at five years that the difference between treatments may not be clinically significant.

"For sexual function, all of the treatment options, even surveillance, were associated with significant declines," Barocas said. "Indeed, the magnitude of decline over time within each treatment group was larger than the magnitude of difference between treatment groups at five years."

"Whether you get surgery or radiation there is a chance of reduced erectile function," he said. "While the time course is different for surgery and radiation, our study shows that only about half of men undergoing these treatments who had erections good enough for intercourse before treatment will still have an erection good enough for intercourse five years later. I have started using this sobering statistic in patient counseling about treatment choice."

In terms of urinary function, prostatectomy was associated with worse incontinence compared to other treatments through five years for both the favorable-risk and the unfavorable-risk groups. At five years, 10-16% of men who had surgery reported a moderate or big problem with leakage, compared to only 4-7% of men who had other treatments.

Men undergoing radiation reported worse urinary irritative and obstructive symptoms within the first six to 12 months, particularly those undergoing the low-dose rate brachytherapy. However, these urinary symptoms largely returned to baseline after one year.

In addition, study authors reported no clinically meaningful bowel function differences at the five-year mark, suggesting that contemporary radiation therapy is associated with less urinary and bowel toxicity than older forms of radiation.

"If you look at the side effect profile for external beam radiation, most of those men after a year have rebounded in terms of their urinary and bowel function, which is a novel finding of our study," Barocas said. "The brachytherapy patients have a more difficult time with the urinary and bowel symptoms in that first year."

For men with unfavorable risk disease, EBRT with ADT was associated with low hormonal function scores at six months and bowel function at one year, but these symptoms improved at later time points. The men who got EBRT with ADT also had better sexual function at five years and incontinence at each time point through five years than prostatectomy.

Study authors said, overall, the estimates of long-term bowel, bladder and sexual function after localized prostate cancer treatment may clarify expectations and enable men to make informed choices about care.

"This work provides critical and understandable information to patients and providers to help them make better decisions in localized prostate cancer," said David Penson, MD, MPH, MMHC, chair of the Department of Urology at VUMC.

"The really exciting part is that Dr. Barocas has received funding from the NCI to explore longer-term outcomes in this population and is already working on developing a web-based interface to get this information to his patients," he said.

Barocas said a separate publication in the Journal of Urology will help to translate the domain scores into more understandable results for patients to get a sense of their likelihood of leakage or erectile dysfunction, or bowel function problems.

The researchers have also developed a personalized prediction tool that tries to empower men by putting this information in their hands and allowing them to enter their own data and compute their chance of regaining function after treatment at http://www.ceasar-prostate.org.

Antibiotic-resistant tuberculosis is a common and serious problem globally. In a new article, researchers from Uppsala University describe how tuberculosis bacteria that carries a mutation that in theory should kill them manages to stay alive. The researchers discovered that the same trick that kept the bacteria alive also made them resistant to a very important type of antibiotic.

Tuberculosis (TB) kills at least 1.5 million people annually. A normal treatment requires four different antibiotics taken for several months. If one of the drugs does not work there is a great risk of a treatment failure. Unfortunately, antibiotic-resistant TB is now very common globally. For successful treatment it is important to quickly determine which antibiotics the TB bacteria is susceptible to. This diagnosis used to take several weeks, because TB bacteria grow very slowly. With the revolution in DNA sequencing it is nowadays possible to sequence the bacterial DNA and predict which antibiotics it will be susceptible to, all in a matter of a days.

Recently, scientists at Uppsala University found that many clinical TB bacteria contained 'frameshift mutations' in a gene for making an essential protein (RpoB) that is the target of a very important TB antibiotic, rifampicin. This type of mutation should have killed the bacteria, but they were apparently alive and were recovered from TB patients receiving antibiotic treatment. Intrigued by this finding, scientists in Diarmaid Hughes' group at the Department of Medical Biochemistry and Microbiology set out to isolate a similar mutant in E. coli, a bacterial species that is less dangerous and easier to work on experimentally. Their aim was to discover how a 'frameshift mutation' was compatible with life.

Three scientists, Douglas L. Huseby, Gerrit Brandis and Lisa Praski Alzrigat, isolated a 'frameshift mutation' in RpoB and worked out how the bacteria could stay alive. They found that the mutation created a special sequence of rare 'slippery' codons in the RpoB gene. When the ribosome (the machine that makes protein by reading the genetic code) reached this sequence it slipped on the sequence and made mistakes at a very high frequency. This slippage in reading the genetic code suppressed the effect of the 'lethal frameshift mutation' and allowed the bacteria to survive. However, that was not all. Because of the 'suppression' the RpoB protein was mutated and this mutation caused the bacteria to became highly resistant to the antibiotic rifampicin.

There are important lessons from this work. One is that apparently lethal mutations are not always lethal because the bacteria may be able to 'suppress' the mutation and stay alive, and as in this case cause resistance to an important antibiotic against TB. Another, perhaps more important lesson, is that a diagnosis that is based on reading a DNA sequence is only as good as our ability to correctly interpret the meaning of the sequence. These types of 'lethal' mutations that should not be possible are in fact surprisingly common in clinical bacterial isolates, not only TB but also other infections, suggesting that many of them may also be suppressed. The message is that we need to become much better at interpreting the meaning of DNA sequences so that we can ensure that patients can get the correct diagnosis and the appropriate antibiotic treatment.

Tsukuba, Japan - Chronic kidney disease and heart failure are critical medical problems worldwide, and are closely associated in a phenomenon known as "cardiorenal syndrome." The relationship between kidney dysfunction and heart dysfunction is complex. Many studies have attempted to understand this relationship; few have provided a clear target for treatment of the combined dysfunction, until now.

In a new study published in Proceedings of the National Academy of Sciences, a University of Tsukuba research team investigated the levels of histamine, an important factor in inflammation, in mice with cardiorenal damage, and found that histamine was increased in the blood of these mice, compared with normal mice.

Heart failure is a condition in which the heart cannot pump sufficient blood to meet the body's needs, which is often demonstrated by shortness of breath, excessive fatigue, and leg swelling. Chronic kidney disease involves gradual loss of kidney function, frequently characterized by leg swelling, fatigue, vomiting, loss of appetite, and confusion. Despite many efforts to control these two disorders, treatments for both largely involve modifications of blood vessels to mitigate their effects, rather than curative approaches to reduce the underlying disease processes.

"Histamine is an important factor in various inflammatory processes, and its inhibition generally leads to better disease control," says Akiyoshi Fukamizu, corresponding author on the study. "We found elevated levels of histamine in a mouse model of cardiorenal syndrome, which were surprisingly protective against further damage in these mice."

In the study, mice that could not produce histamine showed worse cardiorenal damage effects, including increased heart size, altered cardiac contractility, and poor urinary filtration. Similar effects were observed when a specific histamine receptor (H3) antagonist was administered to mice with cardiorenal damage, suggesting that this receptor may serve as a useful drug target.

"We found that targeting the H3 histamine receptor with an agonist, immethridine, could markedly alleviate some components of cardiorenal damage in our mouse model," says Dr. Fukamizu. "Additionally, immethridine treatment led to protective changes in gene expression that affected multiple genes linked to inflammation in these mice."

In addition to their finding that histamine can control the severity of cardiorenal syndrome in a mouse model, the researchers showed that activation of a specific histamine receptor could alleviate signs of cardiorenal damage in these mice, providing a new potential treatment for patients with heart failure and patients with chronic kidney disease.

(Boston)--There's a new treatment option available for patients with AL amyloidosis: daratumumab.

Studied in a prospective clinical trial, only one of the two clinical trials of this agent in AL amyloidosis worldwide, researchers have found this anti-cancer drug to be well tolerated and effective in patients with relapsed AL amyloidosis when used with appropriate pre- and post-infusion medications.

AL amyloidosis is a disease related to bone marrow cancer; multiple myeloma. AL amyloidosis is considered life threatening due to amyloid fibril deposition in various organs of the body leading to organ failure.

According to the researchers, daratumumab infusion in myeloma patients can cause infusion related reactions in almost half of the cases so it was important to study this drug with appropriate premedications in AL amyloidosis.

Twenty-two patients with previously treated AL amyloidosis were enrolled in a prospective study. The majority of the patients had received high-dose melphalan and stem cell transplantation (HDM/SCT) and/or treatment with a proteasome inhibitor. The researchers found daratumumab to be safe, tolerable and successful in treating these patients. In addition, due to its favorable toxicity profile, they believe daratumumab is an attractive treatment option for patients with advanced cardiac involvement with AL amyloidosis.

"Only one dose of daratumumab can decrease the amyloidogenic precursor immunoglobulin light chain protein rapidly and can lead to reversal of organ dysfunction in patients with AL amyloidosis," explained corresponding author and principal investigator of this clinical trial Vaishali Sanchorawala, MD, director of the Boston University/Boston Medical Center Amyloidosis Center.

Despite therapeutic advances in the treatment of relapsed AL amyloidosis, it remains a challenging disease to treat. "Effective alternative therapies are needed both for patients ineligible for HDM/SCT and for those with persistent or progressive disease following such treatments," added Sanchorawala, who also serves as professor of medicine at Boston University School of Medicine.

Worldwide, the incidence rates of skin cancer, like other types of cancer, is increasing. People in Europe and the Nordic countries are, compared to other areas of the world, at a higher risk of developing skin cancer due to their predominantly light and sun-sensitive skin type. The number of new cases of cancer in Estonia and Nordic countries has reached the same level as in sunny Australia, New Zealand and Florida. The increasing trend among Estonians to travel to southern counties is also likely to play a role in this.

Of all the types of skin cancer (including e.g. basal cell carcinoma and squamous cell carcinoma), melanoma has the worst prognosis. Melanoma is considered to have the highest metastatic potential, i.e. it spreads most aggressively from its original site in the skin to other parts of the body.

Associate Professor at TalTech Department of Chemistry and Biotechnology, Sirje Rüütel-Boudinot said, "Nowadays, the most advanced, so-called immunomodulatory methods, applied in cancer treatment involve activation or re-activation of immune cells that destroy melanoma cells. In addition, there are methods that block the immune-inhibitory pathways. These are effective but very costly treatments that are unfortunately not available to all patients. These treatments have also serious side effects, which are especially exhausting to elderly patients. Chemotherapy offered so far less expensive alternatives but unfortunately these are difficult for the patient's organism to tolerate and, what is most important, effective only in a small number of patients".

To mitigate the severe overall effects of chemotherapy, researchers in cooperation with doctors have developed a new method known as isolated limb infusion (ILI). "This means that patients with melanoma metastases confined to an extremity can be treated, instead of systemic whole-body chemotherapy, by a less invasive chemotherapy targeted at the concrete affected limb i.e. isolated limb infusion (ILI). ILI was introduced in the 1990's by one of the members of our research group Dr. John F. Thompson in Australia at the Sydney Royal Prince Alfred Hospital," Associate Professor Rüütel-Boudinot said.

Isolated limb infusion as an anti-cancer chemotherapy is an effective treatment option for in-transit metastatic melanoma. Chief of Centre for Surgical Oncology and General Surgery of the North Estonia Medical Centre, Doctor Jüri Teras said, "The term "in-transit melanoma metastase" is used to denote a type of metastasis in which cancer spreads through a lymph vessel and begins to grow more than 2 cm away from the primary tumor but before it reaches the nearest lymph node. So far, ILI has been seldom used in Europe, but it is already available in major cancer treatment centres in Australia and the USA. The North Estonia Medical Centre is the only centre in the Baltic region where patients are treated with this method."

The article "First Eastern European Experience of Isolated Limb Infusion for In-Transit Metastatic Melanoma Confined to the Limb: Is it still an Effective Treatment Option in the Modern Era?" describes the ILI procedure as follows: "Special arterial and venous catheters were inserted in the limb affected with melanoma. A heated chemotherapy drug (a combination of 7.5mg/L melphalan and 75ug/L actinomycin-D) was infused into the limb over 5-10 min. via the catheter. The infusate was then circulated manually for 20-25 min. The entire procedure usually took about an hour. Postoperatively, the patients were monitored for three months to assess limb pain and potential limb muscle toxicity and the overall survival rate in the follow-up period of up to 70 months was analysed."

Doctor Jüri Teras said, "In this study, we analysed the data of 21 patients from Estonia, who underwent treatment with the drug combination of melphalan and actinomycin-D. Drug circulation times were 20-30 min. at 38-39°C. Although all the patients tested, who underwent an ILI treatment, had a poor prognosis (thick primary melanoma, ulceration, high mitotic rate), the overall response rate was 76% and the overall long-term limb salvage rate was 90%."

"This study demonstrates that the results achieved in ILI treatment in Eastern Europe are comparable to those reported by high-volume centres in the USA and Australia and this method is still an important treatment option in immunotherapy," Rüütel-Boudinot said.

New Haven CT: A ketogenic diet -- which provides 99% of calories from fat and only 1% from carbohydrates -- produces health benefits in the short term, but negative effects after about a week, Yale researchers found in a study of mice.

The results offer early indications that the keto diet could, over limited time periods, improve human health by lowering diabetes risk and inflammation. They also represent an important first step toward possible clinical trials in humans.

The keto diet has become increasingly popular as celebrities, including Gwyneth Paltrow, Lebron James, and Kim Kardashian, have touted it as a weight-loss regimen.

In the Yale study, published in the Jan. 20 issue of Nature Metabolism, researchers found that the positive and negative effects of the diet both relate to immune cells called gamma delta T-cells, tissue-protective cells that lower diabetes risk and inflammation.

A keto diet tricks the body into burning fat, said lead author Vishwa Deep Dixit of the Yale School of Medicine. When the body's glucose level is reduced due to the diet's low carbohydrate content, the body acts as if it is in a starvation state -- although it is not -- and begins burning fats instead of carbohydrates. This process in turn yields chemicals called ketone bodies as an alternative source of fuel. When the body burns ketone bodies, tissue-protective gamma delta T-cells expand throughout the body.

This reduces diabetes risk and inflammation, and improves the body's metabolism, said Dixit, the Waldemar Von Zedtwitz Professor of Comparative Medicine and of Immunobiology. After a week on the keto diet, he said, mice show a reduction in blood sugar levels and inflammation.

But when the body is in this "starving-not-starving" mode, fat storage is also happening simultaneously with fat breakdown, the researchers found. When mice continue to eat the high-fat, low-carb diet beyond one week, Dixit said, they consume more fat than they can burn, and develop diabetes and obesity.

"They lose the protective gamma delta T-cells in the fat," he said.

Long-term clinical studies in humans are still necessary to validate the anecdotal claims of keto's health benefits.

"Before such a diet can be prescribed, a large clinical trial in controlled conditions is necessary to understand the mechanism behind metabolic and immunological benefits or any potential harm to individuals who are overweight and pre-diabetic," Dixit said.

There are good reasons to pursue further study: According to the Centers for Disease Control, approximately 84 million American adults -- or more than one out of three -- have prediabetes (increased blood sugar levels), putting them at higher risk of developing type 2 diabetes, heart disease, and stroke. More than 90% of people with this condition don't know they have it.

"Obesity and type 2 diabetes are lifestyle diseases," Dixit said. "Diet allows people a way to be in control."

With the latest findings, researchers now better understand the mechanisms at work in bodies sustained on the keto diet, and why the diet may bring health benefits over limited time periods.

"Our findings highlight the interplay between metabolism and the immune system, and how it coordinates maintenance of healthy tissue function," said Emily Goldberg, the postdoctoral fellow in comparative medicine who discovered that the keto diet expands gamma-delta T cells in mice.

If the ideal length of the diet for health benefits in humans is a subject for later studies, Dixit said, discovering that keto is better in small doses is good news, he said: "Who wants to be on a diet forever?"

Study participants were evaluated with Human Longevity's multi-modal precision health platform, the Health Nucleus™

The assessment yielded highly actionable findings, most of which were not previously known, resulting in early identification of disease and disease risk in conditions that can lead to pre-mature mortality in adults

Study published in the Journal Proceedings of the National Academy of Sciences

San Diego, January 27, 2020 -- Human Longevity, Inc. (HLI), an innovator in providing data-driven health intelligence and precision health to physicians and patients, announced today the publication of a ground-breaking study in the journal Proceedings of the National Academy of Sciences (PNAS). The study titled, "Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging," showed that by integrating whole-genome sequencing with advanced imaging and blood metabolites, clinicians identified adults at risk for key health conditions. Data from 1190 self-referred individuals evaluated with HLI's multi-modal precision health platform, Health Nucleus, show clinically significant findings associated with age-related chronic conditions including cancer, heart disease, diabetes, chronic liver disease, and neurological disorders -- leading causes of pre-mature mortality in adults.

"The goal of precision medicine is to provide a path to assist physicians in achieving disease prevention and implementing accurate treatment strategies," said C. Thomas Caskey, MD, FACP, FACMG, FRSC, chief medical officer for Human Longevity, Inc., lead author of the study, and a member of the National Academy of Sciences. "Our study showed that by employing a holistic and data-driven health assessment for each individual, we are able to achieve early disease detection in adults."

Study highlights include:

Approximately 1 in 6 adult individuals (17.3%) had at least one pathogenic genetic variant, and when integrated with deep phenotyping (imaging, blood test, etc.), 1 in 9 (11.9%) had genotype and phenotype associations, supporting the clinical diagnosis of a genetic disorder.

Additional highly actionable findings in this self-referred cohort, most of which were not previously known, include:

Insulin resistance and/or impaired glucose tolerance (34.2%)

Elevated liver fat (29.2%)

Cardiac structure or function abnormalities such as valvular disorders (16.2%)

Significant calcified coronary artery plaque (calcium score > 100) (11.4%)

Elevated liver iron (9.3%)

Cardiac arrhythmias such as atrial fibrillation (6.1%)

Cardiac conduction disorders (4.8%)

Early stage tumors, most malignant (1.7%)

A lack of phenotype and genotype associations were observed in 5.8% of individuals with pathogenic genetic variants, further suggesting that the identification of pathogenic genetic variant(s) by sequencing alone is not sufficient for a definitive diagnosis, highlighting the importance of a multi-modal assessment.

Genomics and metabolomics associations revealed 5.1% of heterozygous carriers with phenotype manifestations, affecting serum metabolite levels, suggesting that some genetic carriers may not be completely asymptomatic.

"This study shows that the definition of 'healthy' may not be what we think it is and depends upon a comprehensive health evaluation," said J. Craig Venter, PhD, founder, Human Longevity, Inc. and a member of the National Academy of Sciences. "The data underscore Human Longevity's innovative approach to helping clinicians with early detection and personalized treatments, potentially achieving better health outcomes for patients."

"Our traditional approach to the annual health assessment has been very superficial and will need to be replaced by data-driven measures that will be made possible as costs continue to decline for whole- genome sequencing, advanced imaging, especially MRI, and specialized blood analytics," said David Karow, MD, PhD, president and chief innovation officer, Human Longevity, Inc.

PHILADELPHIA (January 27, 2020) - Data show that young adult women in the United States have high rates of sexually transmitted infections (STIs) that increase their risk of HIV. Though epidemiologic and behavioral factors for risk have been studied, we know very little about brain factors that may be linked to STI/ HIV sexual risk.

Research has begun to reveal neural correlates associated with behavior that increase the risk of STIs; much of the early work has focused on adolescents and the role of cortical regulatory circuits. These "executive" circuits govern the pull of rewards and allow an individual to evaluate choices and future consequences associated with a particular behavior (e.g., whether to have sex or not) and enable inhibition of behavior associated with risks (e.g., sex without a condom). Surprisingly, there has been less research in the (subcortical) brain circuits for reward and motivation themselves, and their role in sexual risk.

In a new NIH/NIMH study from the University of Pennsylvania School of Nursing (Penn Nursing) and the Perelman School of Medicine, researchers assessed the link between sexual risk and the brain and behavioral response to sexual cues in emerging adult women. They found that young women who are at increased risk for STIs and/or HIV, through inconsistent condom use by a partner, have a decreased response in rewarding and motivational circuits to sexual cues and feel less positively about sexual-related stimuli, compared to women whose partners used condoms consistently. Though the data are correlational, regular condom use in a relationship may reflect greater caring and consideration for untoward consequences, especially for the woman's risks--contributing to a more positive emotional and brain response to sexual stimuli. Worth noting, these findings contrast to previous studies in men, where a heightened brain response to sexual cues was linked to greater sexual risk behaviors.

"Understanding the relationship of brain response to appetitive cues associated with greater sexual risk--for women and for men--can help to inform treatment interventions that target these brain responses with behavioral therapy, medication, or both," says Anne M. Teitelman, PhD, FNP-BC, FAANP, FAAN, Associate Professor of Nursing, one of the lead authors of the study with Paul S. Regier, PhD, in the Department of Psychiatry, University of Pennsylvania Perelman School of Medicine.

Geneticists and heart specialists around the world had previously reported 17 genes to cause long QT syndrome, a little-known inherited heart condition. However, the Clinical Genome Resource's (ClinGen) expert panel has critically reevaluated the scientific evidence for all 17 reported genes, disputing nine of the genes and revealing only three of the genes to be definitively associated with the most common form of the disease. The work was funded by the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health.

ClinGen is an NHGRI-funded resource that defines the clinical relevance or validity of genes in various genetic disorders for their use in precision medicine and research. Nine other genes have been classified as having limited or disputed evidence for causing the syndrome. Their results were published in Circulation, the peer-reviewed journal of The American Heart Association.

Normal hearts, abnormal rhythms

Twenty years ago, The New York Times published an article about three "apparently healthy" young people who died in seemingly mysterious ways, while sleeping, swimming and after playing soccer. In 2019, about 4,000 children and young adults died in the United States in similar, unusual ways. The apparent cause was long QT syndrome.

Long QT syndrome is caused by mutations in genes that regulate the heart's electrical activity. These mutations can cause the heart to have sudden, irregular heart rhythms, or arrhythmias. Much like the cases in the New York Times article, people with long QT syndrome can have arrythmias that are both unprovoked or a result of stress and exercise. But when the arrythmias do occur, they can be fatal.

Many people with long QT syndrome may be unaware they have the condition, unless they get an unrelated electrocardiogram, know their family history and have undergone genetic testing. The term "QT" refers to the segment of an electrocardiogram which measures the duration of time for the heart to relax after a heartbeat. In long QT syndrome, that duration of time is abnormally prolonged and creates a vulnerability to dangerous arrhythmias.

Ever since the syndrome was described in 1957, researchers have engaged in a genetic race to identify the genes associated with long QT syndrome, which currently includes 17 genes.

By using such a standardized, evidence-based framework, the international ClinGen panel experts on long QT syndrome were able to classify the 17 genes into specific groups.

Three genes, KCNQ1, KCNH2 and SCN5A, had sufficient evidence to be implicated as "definitive" genetic causes for typical long QT syndrome. Four other genes had strong or definitive evidence supporting their role in causing atypical forms of long QT syndrome, presenting in the newborn period with associated heart block, seizures or delays in development. The remaining ten genes did not have sufficient evidence to support a causal role in the syndrome. In fact, nine of these 10 remaining genes were placed in the limited or disputed category. The study authors suggest that these genes not be routinely tested in clinical settings when evaluating patients and families with long QT syndrome, because they lack sufficient scientific evidence for causing for this condition.

ClinGen as an essential resource in precision medicine

Genetic testing providers use research papers to determine which genes to include in their testing panels for diagnostic reporting to physicians. Published papers reporting gene-disease associations vary widely in their study design and strength of evidence to support their conclusions. Until recently, standard guidelines that can differentiate between genes found with strong and valid scientific approaches versus those with insufficient evidence did not exist.

NHGRI developed the ClinGen resource to address this very issue.

ClinGen's expert panels include researchers, clinicians and genetic counselors who apply an evidence-based framework in evaluating the scientific evidence from research papers to place gene-disease relationships into "definitive," "strong," "moderate," "limited," "disputed" or "refuted" categories.

"ClinGen is an impressive community effort. With over 1,000 researchers and clinicians from 30 countries volunteering their time and expertise, ClinGen is providing much needed clarity for the clinical genomics community regarding which gene-disease pairs have sufficient evidence to be used clinically," said Erin Ramos, Ph.D., project scientist for ClinGen and program director in the Division of Genomic Medicine at NHGRI.

Clinical utility

"Our study highlights the need to take a step back and to critically evaluate the level of evidence for all reported gene-disease associations, especially when applying genetic testing for diagnostic purposes in our patients. Testing genes with insufficient evidence to support disease causation only creates a risk of inappropriately interpreting the genetic information and leading to patient harm," says Michael Gollob, M.D., senior author of the paper and researcher at the Toronto General Hospital Research Institute.

Moreover, testing for genes not definitively associated with long QT syndrome can result in inappropriate and costly medical interventions such as implanting of a cardioverter-defibrillator, a heart device that can correct dangerous arrhythmias.

ClinGen researchers published a similar study in 2018, covering another heart condition called Brugada syndrome. In 2019, the American Society of Human Genetics considered the paper as one of the top 10 advances in genomic medicine.

With over 20 expert panels working on different diseases -- breast and ovarian cancer, glaucoma and familial hypercholesterolemia to name a few -- periodic classification of a number of gene-disease pairs is aimed to accelerate development of reliable and useful genetic tests over time.

A new treatment developed by researchers at Aston University and Birmingham Children's Hospital has been found to completely kill a bacterial infection that can be deadly to cystic fibrosis patients and other chronic lung conditions such as bronchiectasis.

The findings, which are published in the journal Scientific Reports, show that scientists from Aston University, Mycobacterial Research Group, combined doses of three antibiotics – amoxicillin and imipenem-relebactam and found it was 100% effective in killing off the infection which is usually extremely difficult to treat in patients with cystic fibrosis. The infection results in severe decline in lung function and sometimes death.

Cystic fibrosis (CF) is a genetic condition affecting more than 10,000 people in the UK (Cystic Fibrosis Trust) and there are more than 70,000 people with the condition worldwide (Cystic Fibrosis Foundation). While bronchiectasis affects 210,000 people in the UK (British Lung Foundation).

Mycobacterium abscessus is a bacterial pathogen from the same family that causes tuberculosis, which causes serious lung infections in people (particularly children) with lung disorders, most notably cystic fibrosis. It is highly drug resistant. Currently patients are given a cocktail of antibiotics that cause serious side effects including severe hearing loss and often doesn't result in cure.

The researchers used samples of the pathogen taken from 16 infected cystic fibrosis patients and tested the new drug combination to discover how much was required to kill the bacteria. They found the amounts of amoxicillin-imipenem-relebactam required were low enough to be given safely to patients.

Until now Mycobacterium abscessus has been virtually impossible to eradicate in people with cystic fibrosis. It can also be deadly if the patient requires a lung transplant because they are not eligible for surgery if the infection is present.

In the UK, of the 10,000 people living with cystic fibrosis, Mycobacterium abscessus infects 13% of all patients with the condition. This new treatment is advantageous not only because it kills off the infection, but it does not have any side-effects on patients, thus ensuring their quality of life and greatly improving survival chances for infected CF patients.

Dr Jonathan Cox, Lecturer in Microbiology, Aston University and leader of the team that discovered this new treatment said: "This new drug combination is a significant step forward for patients with cystic fibrosis that get infected with the deadly Mycobacterium abscessus bacteria. Our new drug combination is significantly less toxic than those currently used, and so far we have managed to kill every patient's bacterial isolate that we have received.

"This shows our drugs, when used in combination, are widely effective and could therefore make a huge difference to people whose treatment options are currently limited.

"Because amoxicillin is already widely available and imipenem-relebactam has just been approved for use by the Food and Drug Administration (FDA) in the US, these drugs are already available to clinicians. We therefore hope to start treating patients as soon as possible. "

The findings of this research will impact children being treated for the infection at Birmingham Children's Hospital - who part funded the research - but it can also be used nationally and further afield.

With more funding, the next stage of the research will be to test the treatment on more people with CF infected by this bacterium, comparing it to the antibiotics that are currently used.

Dr Maya Desai, Consultant in Respiratory Paediatrics, Birmingham Children's Hospital added: "This exciting development will significantly impact on the care of CF patients globally. It has been possible only with close collaboration between Aston University and Birmingham Children's Hospital both from a clinical research and financial point of view."

Dr Paula Sommer, Head of Research at the Cystic Fibrosis Trust said: "It's exciting that these lab-based studies investigating new antibiotic treatments for M. abscessus infection are showing such promise and adding to our expanding knowledge of this devastating bug.

"Mycobacterium abscessus also known as NTM, is the most feared infection a person with cystic fibrosis can develop. Taking drugs to treat NTM can add to an already significant regime of daily treatments and take up to a year to clear infections. We look forward to a time when effective, short courses of treatment are available to treat NTM."

A widespread, fast-growing plant called Chlamydomonas reinhardtii is famous in scientific laboratories due to its position as the world's most exhaustively studied algae.

For decades, the green, single-celled organism, which primarily grows in wet soil, has served as a model species for research topics spanning from algae-based biofuels to plant evolution. While other species of algae have been used as dietary nutraceuticals that provide beneficial oils, vitamins, proteins, carbohydrates, antioxidants and fiber, the benefits of consuming C. reinhardtii were previously unexplored.

Researchers at the University of California San Diego recently completed the first study examining the effects of consuming C. reinhardtii and demonstrated that the algae improves human gastrointestinal issues associated with irritable bowel syndrome (IBS) such as diarrhea, gas and bloating. Results of the project are published in the Journal of Functional Foods.

"People have been looking at this algae for decades, but this is the first study to show what many of us have suspected--it's good for you," said principal investigator and algae expert Stephen Mayfield, a distinguished professor in UC San Diego's Division of Biological Sciences and co-director of the Food and Fuel for the 21st Century Program (FF21). "This is exciting because it demonstrates a clear benefit: If you have IBS-like symptoms, this is good for you."

For years researchers in Mayfield's laboratory have been exploring C. reinhardtii as a cost-competitive and sustainable source of valuable plant-based products, specifically pharmaceuticals and biofuels. Now, working with several collaborators, including UC San Diego's John Chang (School of Medicine), Rob Knight (School of Medicine, Jacobs School of Engineering and Center for Microbiome Innovation) and the San Diego-based startup Triton Algae Innovations, they turned their attention towards investigating the algae as a nutritious food additive for improving human health.

The C. reinhardtii biomass used in the study, which was grown by Triton Algae Innovations, was subject to rigorous safety testing and designated as "Generally Recognized As Safe" by the U.S. Food and Drug Administration, green-lighting the use of the organism in a human study.

Preliminary data in mouse studies demonstrated that consuming C. reinhardtii significantly reduced the rate of weight loss in mice with acute colitis, which is generally linked to inflammation of the digestive tract. Building off these results, the researchers set out to test for a similar effect when the algae was consumed by human volunteers, including those with and without symptoms associated with IBS. Volunteers consumed daily spoonfuls of powdered C. reinhardtii biomass and reported their gastrointestinal health for one month. Of the hundreds of interested participants in the project, data from 51 volunteers met the study's requirements for inclusion in the final data analyses.

Results showed that participants who suffered from a history of frequent gastrointestinal symptoms reported significantly less bowel discomfort and diarrhea, significantly less gas or bloating and more regular bowel movements.

"The benefits of consuming this species of algae were immediately obvious when examining the data from both mice and humans who suffered from gastrointestinal symptoms," said Frank Fields, a research scientist in Mayfield's lab and lead author of the paper. "I hope that this study helps destigmatize the thought of incorporating algae and algae-based products into your diet--it is a fantastic source of nutrition and we have now shown that this species of algae has additional benefits to animal and human health."

Volunteers also were provided with stool sampling kits and sent samples to the American Gut Project, a citizen science effort led by Knight and his lab, to assess any changes in their microbiomes. The results indicated that the gut microbiome composition remained diverse, which is typical of healthier individuals, and that no significant changes to the composition of their gut microbiome occurred during the study as a result of consuming the algae.

The researchers say much more testing with larger groups of participants across longer time periods is needed. At this point, they are unclear about how the algae works to improve gastrointestinal health. The scientists believe the benefits could be traced to a bioactive molecule in algae or perhaps a change in gene expression of gut bacteria caused by algae consumption.

Still, the observed results in human volunteers led them to conclude in the paper that "the addition of C. reinhardtii into the diet will not only add nutritional value but may also function to relieve some gastrointestinal symptoms of certain individuals."

Hypophosphatasia (HPP) is a rare congenital metabolic disorder. The frequency of severe courses of disease is estimated at 1:100 000: A deficiency of the enzyme phosphatase results in insufficient mineralization of the bones and thus in severe skeletal malformations. The course of disease varies greatly - the earlier the onset of the disease, the more severe are symptoms and complaints. Affected infants in whom the disease occurs before the age of 6 months often die of it and at a very early age, whereas the symptoms are sometimes less pronounced when the disease occurs later.

A long-term enzyme replacement therapy with asfotase alfa (trade name Strensiq) is for the first time intended to treat the cause of the disease, i.e. the deficiency of the enzyme, in patients with HPP. Previously, symptomatic treatment was the only option. Being a drug for the treatment of rare diseases (orphan drug), asfotase alfa was initially excluded from scientific assessment of an added benefit. With annual sales exceeding 50 million euros, asfotase alfa had lost this special status and its added benefit was investigated with an early benefit assessment of drugs pursuant to AMNOG) by the German Institute for Quality and Efficiency in Health Care (IQWiG). The dossier assessment yields a hint of a non-quantifiable added benefit for infants in whom the disease occurred before the age of 6 months. Due to lack of data, advantages and disadvantages for other patient groups remain unclear.
In its dossier, the drug manufacturer specified two single-arm studies on the treatment of infants with asfotase, which only consider two outcomes (overall survival and respiratory function). He compared their results with results from a few medical records of patients who had not been treated with asfotase. The observed differences in overall survival between the two comparator groups are so large that they cannot be attributed solely to the existing confounders: More infants are likely to survive under asfotase treatment than without it.

"Infants in which the disease occurs up to the age of 6 months are expected to benefit from treatment with the drug - better courses of treatment than before are possible. In view of the large burden of disease, particularly in children and adolescents, those affected would have deserved a better study situation and more careful data analyses," says Katharina Biester, Division Head in IQWiG's Drug Assessment Department.

Comparison with historical control groups

The manufacturers' dossier presents data from two small single-arm studies (2008-2016) involving asfotase alfa treatment of a total of 80 infants in whom the disease occurred up to the age of 6 months: 11 children were ? 36 months and 69 were ? 5 years old. The manufacturer compared the results with historical data on symptomatic treatment without asfotase alfa based on medical records of 48 infants with perinatal or infantile hypophosphatasia: At the time of data collection (2012-2013), 35 patients with medical records had already died and 13 were still alive. The patients were born between 1970 and 2011 and the diagnostic phase lasted three decades.

However, apart from the primary outcome "overall survival" and several operationalizations for the recording of the respiratory function, the study investigated no other outcomes on the basis of medical records. The patients included in the recording received both drug and non-drug supportive measures.

Inadequate processing of the study data

Processing of the study data in the manufacturer's dossier is non-transparent and thus makes it difficult to derive a concrete added benefit. Thus, the proportion of patients with perinatal onset of disease remains unclear. Moreover, inconsistent, in some cases even contradictory information on the same data can be found at different points in the dossier. The fact that the manufacturer conducted no systematic search on the appropriate comparator therapy (best supportive care, BSC) without justification is scientifically questionable, because this approach might result in an incomplete study pool.

However, the effect on overall survival is at least so clear that it cannot be solely attributed to potential bias. For this reason, IQWiG researchers not only searched for additional relevant data on the appropriate comparator therapy for the population of infants with perinatal or infantile HPP, but also estimated the proportion of patients with perinatal onset of disease on the basis of information presented in the study documents.

Added benefit only for one group of patients

Overall, the differences between the comparator groups cannot be attributed solely to other confounders: More infants in whom the disease occurs before the age of 6 months survive under treatment with asfotase. However, due to the weak evidence the results are potentially biased, thus providing not more than a hint of a non-quantifiable added benefit of asfotase alfa versus the appropriate comparator therapy BSC in infants with perinatal or infantile hypophosphatasia.

As the manufacturer either submitted no data at all (for infants with disease onset from 6 months of age) or no suitable data (for children from 5 years of age, adolescents, adults with perinatal, infantile or juvenile disease onset) for the other patient groups in the approved therapeutic indication, an added benefit is not proven for these patients.

Better study data for better care

The conclusion of the benefit assessment follows the assessment of the Federal Joint Committee (G-BA) after approval in 2015: However, its demand for further evidence in order to ensure reliable, appropriate and economical care for those affected was not met.

Therefore, no added benefit can be derived for the majority of those affected (age group five years and older). The legally assumed added benefit for orphan drugs comes along with insufficient data also in this case. Like all other new active substances, orphan drugs should therefore be subject to an early benefit assessment already at the time of market access.

The small randomized controlled trial (RCT) on the age group of 13 years and older presented by the manufacturer cannot be used for this dossier assessment due to lacking compliance with the approval. However, it shows once again that RCTs can also be conducted for the assessment of rare diseases. With an adequate dosage and more study participants, it would probably have been possible to achieve a more reliable result on the added benefit and thus for health care - because in Germany alone, there are potentially about 1000 patients with HPP among those with statutory health insurance.

G-BA decides on the extent of added benefit

The dossier assessment is part of the early benefit assessment according to AMNOG supervised by the G-BA. After publication of the dossier assessment, the G-BA conducts a commenting procedure and makes a final decision on the extent of the added benefit.

A new study published in Seizure gives insight into the short-term outcome of patients treated for status epilepticus in Kuopio University Hospital in Finland. The researchers found a 9% risk of death and a 32% risk of functional loss at one month after status epilepticus. The patient's risk of death could be predicted relatively reliably already in the emergency room by using status epilepticus-related prognostic tools.

The study, conducted by the University of Eastern Finland and the Epilepsy Centre in Kuopio University Hospital, enrolled 137 status epilepticus patients during 2015. Fourteen patients were enrolled twice because of another episode of status epilepticus during the study period. The outcome was assessed at one month after hospital discharge by means of a phone interview and a patient record review.

The prognostic scores STESS (Status Epilepticus Severity Score) and EMSE (Epidemiology-based Mortality score in Status Epilepticus) proved themselves useful in mortality prediction. They were both able to predict survival with over 95% certainty in many episodes of status epilepticus with low risk features. The scores are simple enough to be calculated in the emergency room. They require information about the etiology and clinical presentation of status epilepticus, and the age and comorbidities of the patient.

Status epilepticus is a prolonged epileptic seizure that lasts for more than 30 minutes. Status epilepticus is a life-threatening emergency which requires rapid treatment. Any epileptic seizure lasting longer than 5 minutes is treated as an early status epilepticus. Status epilepticus can occur even without a prior diagnosis of epilepsy.

Toxoplasma gondii is best known as the parasite that may lurk in a cat's litter box. Nearly a third of the world's population is believed to live with a chronic Toxoplasma infection. It's of greatest concern, however, to people with suppressed immune systems and to pregnant women, who can pass the infection to their fetuses.

Toxoplasma's "success," scientists believe, owes in part to its ability to evade the immune response of its host, whichever warm-blooded vertebrate it has infected. Now a new study suggests the parasite employs a sophisticated manipulation to suppress that immune response.

The work, led by researchers from Penn's School of Veterinary Medicine and the University of Arizona and published in the Journal of Experimental Medicine, shows that T. gondii parasites inject their host's macrophages, a type of immune cell, with a protein that changes the activity of the macrophage itself, creating what is known as an M2 macrophage. Those changes, the team showed, rein in the response of T cells that are normally responsible for killing parasites.

"This is the first time that it's been shown that injection alone is sufficient to drive the creation of M2 macrophages," says Christopher A. Hunter, an immunologist at Penn Vet and senior author of the paper. "Pharmaceutical companies have been targeting the pathways that create M2 macrophages for a long time because they're very important in wound healing, fibrosis, lung repair, and so on. But here's a parasite that manages to target it perhaps more efficiently than pharma has been able to."

As the ability of the parasite to affect the infected and injected host cell populations has an impact on the course of infection, Hunter hopes further studies will help define the underlying mechanism.

For T. gondii, infection is a careful balancing act. It wants to spread far and wide within a host--and eventually be passed on to other hosts--but protective immunity is needed to prevent the death of the host. Scientists have long known that macrophages are critical players in maintaining this balance.

Macrophages are the cells normally responsible for cleaning up infections by consuming foreign invaders. Around a decade ago, scientists found that they come in different "flavors."

"Some macrophages are profoundly pro-inflammatory and kill pathogens; these are known as M1 macrophages." Hunter says. "M2 macrophages are profoundly anti-inflammatory but are less able to kill parasites. So M1 macrophages induce inflammation, and M2s help clear it up."

Earlier work by other labs had shown that T. gondii can act on a family of proteins that in turn has an influence over whether a macrophage becomes an M1 or M2. The parasite turns off the host STAT1 protein, which drives M1 production, and turns on host STAT3 and STAT6, which had both been shown to support the creation of M2 macrophages. But the consequences of this M2 production have been unclear, so Hunter and colleagues, led by lab members Longfei Chen and David A. Christian, sought to deepen their understanding of the parasite's influence.

Previous work had suggested that the parasite activates STAT3 and STAT6 through an enzyme, ROP16 and that the parasite injects in host cells in a "package" of 2-300 proteins, of which the function of most is unknown. A collaborator and coauthor, Anita A. Koshy of the University of Arizona, enabled the research team to focus on the consequences of ROP16 injection by creating a genetically engineered strain of T. gondii. When this strain of parasite injects proteins into a cell, that cell glows green.

"We had previously recognized that some cells only receive this injection; they're not actively infected with parasites," Koshy says. "So, we thought if we can look only at the cells that received the injection we could ask what the consequences of that injection are."

Unexpectedly, the researchers found that this population of immune cells that were injected but not infected were quite prominent. Both in cell culture and in mice infected with the engineered strain of T. gondii, the scientists were able to isolate this population and examine which genes were turned on in the injected only cells.

"In an infected cell you see nearly 2,000 genes are changed," says Hunter. "But if they're only injected, you still see about 600 genes changing in expression."

These changes alone were enough to sway macrophages over to the M2 type and to suppress the activity of T cells that normally act to kill parasites.

Finally, to investigate the effect of ROP16 on the parasite itself and its ability to infect mice, Josh Kochanowsky of the University of Arizona engineered a ROP16-deficient strain of T. gondii.

"If you put these parasites in immune-deficient mice, they grow normally" says Christian, "but if you put them in immune competent mice you get a reduced amount of M2s and a reduced parasite burden. So, we're seeing that taking away ROP16 leads to a more effective immune response."

Next for the team is to further study this pathway to get more conclusive information about how the M2 macrophages that are caused by the injection of ROP16--or other proteins--are able to suppress the host T cell response.

And because M2 macrophages are key players in anti-inflammatory processes that cancers also exploit to avoid detection by the immune system, Hunter says it's possible that studying these parasites could reveal new information about the general biology of these M2 macrophages.

"Maybe this will tell us a bit more about how macrophages associated with tumors and infection can suppress a T cell response," he says.