Body

When girls reach puberty at an unusually early age, they face a significantly higher risk of developing breast cancer later in life. Now, experts at Cincinnati Children's and the University of Cincinnati offer a new, unified explanation for why that increased risk occurs.

Detailed findings were published online Sept. 1, 2020, in the Journal of Adolescent Health. The study was led by Frank Biro, MD, one of the nation's leading experts on puberty and the environment and a team of colleagues.

Essentially, girls who enter puberty early in life--as measured by early breast development and age of first menstrual period--have a longer window of susceptibility to breast cancer. This window stays propped open for too long because their bodies have higher concentrations of growth hormone and they experience a slower progression ("tempo") during puberty. This in turn results in a longer exposure to environmental factors that could influence the developing breast tissue.

"We have been concerned for many years about girls entering puberty at steadily younger ages. A number of studies have established a link between early puberty and breast cancer risk," Biro says. "Our study is one of the very few to gather many years of data to comprehensively track the changes young women experience."

Previous studies have linked earlier age of menarche (the first menstrual period), greater pubertal growth velocity, and earlier age of the pubertal growth spurt as being related to breast cancer risk. These three pubertal factors are also related to each other.

Previous studies also have found that breast development has been occurring at younger ages, with some girls showing signs as early as age 7. Typically, menstrual periods begin two to three years afterwards. For most girls, their periods begin around ages 12 or 13, Biro says.

The age of breast development has been dropping much faster than the age of menarche. The new study is part of a long-running project to find out why.

"We found important, dynamic relationships between the concentration of human growth factor and of other hormones at critical stages in growth that were not evident in short-term studies and cross-sectional studies. This gives us a more accurate understanding of why early puberty poses a breast cancer risk--and suggests ways for families to help their daughters reduce that risk."

When a growth window stays open too long

Of several biochemical changes happening as young girls grow, the new study reports that hormonal factors found in adult women that have been associated with elevated breast cancer risk also are associated with early puberty. These include higher concentrations of the growth factor IGF-1, and the ratio between the hormones estrone and androstenedione (E:A). IGF-1 is a potent growth stimulant that is associated with breast density and with breast cancer in adult women. A greater ratio of estrone to androstenedione leads to greater overall exposure to estrogen, another risk factor for breast cancer.

What does this mean for young women who start puberty early?

These findings suggest that girls experiencing early puberty can take steps throughout their lives to reduce their breast cancer risk. These include:

Healthy exercise and eating habits to avoid obesity, a known risk factor for breast cancer.

Specifically increasing consumption of fruits, vegetables, soy and other foods that contain plant-based weak estrogens called phytoestrogens. Previous work from the Breast Cancer and the Environment group has found that increased levels of phytoestrogens in the body can replace other stronger estrogens and thus can moderately delay the onset of puberty.

Another approach includes living a "greener" lifestyle that minimizes exposure to surprisingly common "endocrine disrupting" chemicals, such as phthalates found in many consumer products. Click here for more information about phthalates.

In some of the most extreme cases, which doctors define as "precocious" puberty, the new data may help clinicians decide which girls are most at-risk and should consider treatments to delay the onset of puberty.

Longer term, targeting IGF-1 may become an alternative or additional approach for slowing down early puberty.

A long, complex project

The work began in 2004 as part of the "Growing Up Female" study conducted by the Breast Cancer and the Environment Research Program in collaboration with two other medical centers in New York City and Northern California. The Cincinnati team worked with parents and schools to follow a group of more than 370 girls who entered the study at ages 6 and 7.

The current study reflects data from more than 180 girls, all from the Cincinnati region, who had stayed with the project all 14 years and provided multiple blood samples.

In the first six years of the study, girls were seen every six months either at their schools or at Cincinnati Children's. In the following years, families brought their daughters back to Cincinnati Children's once a year until 2018, when the girls had reached ages 20 and 21. Participants received small payments for their time and were invited to various events over the years to share study results and have fun.

"My mom told me there was a study going on that would help the doctors learn more about how young women's bodies grow. I thought that would be interesting because I didn't know much about any of that," says Heaven Taylor, a Cincinnati-area resident who participated in the study.

The research team tracked numerous measures, including height, weight and "height velocity." They tracked when breast development began and when menstrual cycles started. They analyzed blood to measure hormone levels and gathered a wide range of demographic, geographic, environmental and behavioral information from questionnaires and interviews.

Among the findings:

Earlier puberty onset was associated with greater peak height velocity (PHV).

The duration of the pubertal growth spurt was greatest in the earliest-maturing girls

Higher concentrations of growth hormone were correlated with earlier age of breast development, longer duration of puberty, and earlier age of peak height velocity.

Girls starting puberty early also showed greater conversion of hormone precursors to estrogen.

Taylor recalls having her first period at school, long before she expected it.

"I remember that like it was yesterday," Taylor says. "When it happened, I thought I was dying. I freaked out and called my mom from the bathroom. She wasn't that surprised, though. She said something like, 'Well, you're a woman now.' And I said, 'I don't want that!' Then she said, 'Well, there's no going back now.' "

Taylor recalls having her first period around age 10, which is unusually early. "Typically, menarche starts at about age 12 for Black girls," Biro says.

What's Next?

This study represents one of the last major reports from the Growing Up Female project. There are no current plans, nor funding, to track the participants for the rest of their lives.

More study will be needed to determine if managing IGF-1 has value in preventing early puberty, Biro says. Likewise, other research projects may be needed to address certain limitations of this research.

For example, the Cincinnati study was unable to recruit large numbers of Latina and Asian girls, so some of the findings may not apply to them. The study did not attempt to search for genetic variations that may or may not contribute to early puberty risk. It also does not address ongoing questions, studied primarily in adults, about cancer risks posed by breast density.

To Biro, the important lesson for families is that learning more about the hormone combinations that drive early puberty will help clinicians to discover approaches that help more women reduce their risk of breast cancer.

"Risk is not fate," Biro says. "There are steps people can take to minimize their risks."

Sophia Antipolis, France - 31 Aug 2020: Blood pressure medication can prevent heart attacks and strokes - even in people with normal blood pressure. That's the finding of late breaking research presented in a Hot Line session today at ESC Congress 2020.1

"Greater drops in blood pressure with medication lead to greater reductions in the risk of heart attacks and strokes," said principal investigator Professor Kazem Rahimi of the University of Oxford, UK. "This holds true regardless of the starting blood pressure level, in people who previously had a heart attack or stroke, and in people who have never had heart disease."

"The fact that the relative effects are similar for everyone does not mean that everyone should be treated," he added. "This decision will depend on an individual's likelihood of suffering cardiovascular disease in the future - there are a number of risk calculators health professionals can use. Other factors to consider are the potential for side effects and the cost of treatment."

There has been controversy about whether pharmacological blood pressure lowering is equally beneficial in people with versus without a prior heart attack or stroke, and when blood pressure is below the threshold for hypertension (typically 140/90 mmHg). Evidence from previous studies has been inconclusive, leading to contradictory treatment recommendations around the world.

This was the largest - and most detailed - study ever conducted to examine these questions. The researchers combined data on individuals who had participated in a randomised clinical trial and conducted a meta-analysis. The study included 348,854 participants from 48 trials.

Participants were divided into two groups: those with a prior diagnosis of cardiovascular disease and those without. Each group was divided into seven subgroups based on systolic blood pressure at study entry (less than 120, 120-129, 130-139, 140-149, 150-159, 160-169, 170 and above mmHg).

Over an average four years of follow-up, each 5 mmHg reduction in systolic blood pressure lowered the relative risk of major cardiovascular events by about 10%. The risks for stroke, ischaemic heart disease, heart failure and death from cardiovascular disease were reduced by 13%, 7% and 14% and 5%, respectively.

Neither the presence of cardiovascular disease nor the level of blood pressure at study entry modified the effect of treatment.

Professor Rahimi said: "The decision to prescribe blood pressure medication should not be based simply on a prior diagnosis of cardiovascular disease or an individual's current blood pressure. Rather, blood pressure medication should be viewed as an effective tool for reducing cardiovascular risk when an individual's probability of having a heart attack or stroke is elevated."

Researchers at Flinders University are expanding work on a promising blood test model to help predict or diagnose head and neck cancer, a difficult cancer to pick up early and treat.

With cancer accounting for almost 10 million a year, the Global Burden of Disease report (2017) attributed more than 380,000 deaths to head and neck cancer.

The Australian research at Flinders University has discovered a blood serum microRNA biomarker signature for oropharyngeal squamous cell carcinoma, recently reported in a new study in the Journal of Translational Medicine (BMC Springer Nature).

The signature might have potential for the detection of other squamous mucosal Head and Neck cancers, the researchers say, adding the latest development, flowing from previous NHMRC Australian Government funding for developing blood biomarkers for oesophageal cancer, is encouraging.

"MicroRNAs are potential biomarkers for early head and neck squamous cell cancer diagnosis, prognosis, recurrence, and presence of metastatic disease. However, there is no widespread agreement on a panel of miRNAs with clinically meaningful utility for head and neck squamous cell cancers," says Flinders University researcher Dr Damian Hussey.

"If our test can be translated to clinic, then it could facilitate surveillance, earlier diagnosis and treatment - including for identifying people with early stage, or at increased risk of developing, Head and Neck cancer," says fellow researcher Associate Professor Eng Ooi.

The latest study used a novel approach to produce a biomarker signature with good cross validated predictive capacity. Researchers say the results warrant further investigations.

Research from the Centre for Health Evaluation and Outcome Sciences (CHÉOS) sheds new light on the factors behind drug shortages in Canada, a common problem across the country.

In 2018 alone, Canadian patients faced shortages for hundreds of medications, including EpiPens, opioid drugs, and treatments for Parkinson's disease, schizophrenia, and depression.

In many cases, these shortages can have severe and life-threatening consequences. While there are several studies from the United States about this topic, there have been very few investigations about drug shortages in Canada, mostly due to lack of reliable data.

To understand drug shortages in the Canadian context, the CHÉOS research team--led by Wei Zhang and Aslam Anis--analyzed prescription drug data from the Canadian Drug Shortage Database. The team also included Larry Lynd, director of the Collaboration for Outcomes Research and Evaluation, and senior statisticians Daphne Guh and Dr. Huiying Sun.

"Since early 2017, Canadian drug manufacturers are required to report drug shortages and state the reason they are unable to meet demand for the drug," said Zhang, the study's first author and program head for health economics at CHÉOS. "We looked at the first year and a half of data from this database to describe the factors associated with drug shortages."

The researchers found that, of the over 9,000 different drugs marketed in Canada, one quarter were reported in shortage during the study period. The average length of a shortage was five months.

The researchers also grouped the drugs with the same ingredients, dosage, type, and strength into a "market." The drugs under the same market were considered as interchangeable. This allowed them to look at shortages at the market level, rather than at the level of individual manufacturer. There was a total of 3,470 distinct markets; of these, 13 per cent were reported as having a shortage.

Related to the reasons behind these shortages, the team found several factors that could be at play.

"Our main finding was that markets with a single generic manufacturer were the most vulnerable to shortage," said Zhang. "We did not see the same result with single branded manufacturers."

This result suggests that shortage could be related to the low profit margins for generic drugs compared to branded drugs. "One of the reasons behind this finding could be related to the lower reimbursement price for generic drugs based on the pan-Canadian tiered pricing framework and provincial price-cap policies" said Anis, study co-lead and director of CHÉOS.

The team also found that markets with a larger proportion of their drugs covered under provincial formularies were more likely to be in shortage. Other factors related to shortages included complex manufacturing processes and certain types of therapies.

"This study gives Canadian policy makers who are trying to balance cost with drug supply security a number of red flags to look out for in order to avoid drug shortages," said Zhang.

People living with Chagas disease without symptoms or signs of cardiac injury are at high risk of developing cardiomyopathy, a progressive heart disease, and the risk more than doubled among patients with acute infections, according to a new study from the University of Colorado School of Medicine at the Anschutz Medical Campus.

The study was published today in JAMA Network Open.

Chagas disease is caused by a parasite, Trypanosoma cruzi, and is prevalent throughout Latin America. The disease is also a growing health concern in the U.S., affecting an estimated 300,000 people according to the Centers for Disease Control and Prevention.

"It's important to study infections like Chagas disease and its tie to fatal or disabling cardiac disease because it can help inform public health programs that can save people's lives," said lead author Andrés Henao-Martínez, MD, assistant professor of infectious diseases at the CU School of Medicine. "We're hoping our research can be used by clinicians and public health agencies to implement Chagas screening programs, as well as enhance the treatment of asymptomatic individuals."

The researchers conducted a systematic review and meta-analysis of cardiomyopathy development in patients with Chagas disease. The goal was to address, for the first time in a scientific framework, the compiled data on factors contributing to progression from the acute phase or the indeterminate form of Chagas disease to the chronic cardiac form, as well as the annual rate of cardiomyopathy development.

The study found that asymptomatic people living with Chagas disease --without evidence of cardiac injury-- or individuals with acute infection are at significantly increased risk to develop cardiomyopathy at annual rates of 2 percent and 5 percent, respectively.

"Now knowing this, public health programs and clinicians must develop more robust screening programs for Chagas disease that includes assessment for antitrypanosomal treatment at the time of diagnosis," Henao-Martínez adds. Antitrypanosomal drugs are the only proven efficacy against Chagas disease.

STONY BROOK, NY, August 31, 2020 - Findings from a positron emission tomography (PET) brain imaging study of the amygdala reveals that low levels of the enzyme aromatase, which catalyzes estrogen biosynthesis, are associated with a higher body mass index (BMI) and lower self-control, as measured by a standard personality test. Published in PNAS, the study is led by Anat Biegon, PhD, Professor of Radiology and Director of the Center on Gender, Hormones and Health at the Renaissance School of Medicine at Stony Brook University. The results suggest that brain aromatase imaging offers a novel method for characterizing the role of estrogen produced in the brain in obesity and other conditions involving impairments in self-regulation.

Obesity is a public health problem affecting a growing proportion of children and adults. Because estrogen influences body weight and behavioral responses to appetitive stimuli, the researchers used an aromatase-specific radiotracer with PET to measure aromatase in the brains of 43 men and women (average age: 40 years) of healthy to obese weight ranges.

"This is the first study to show a direct correlation between aromatase availability in the amygdala and BMI," said Dr. Biegon. "It is also the first to show an inverse correlation between amygdala aromatase and self-control in the same individuals."

She explained that this particular finding raises the potential for amygdala aromatase to be a sex neutral contributor to BMI and therefore a possible marker to measure for both men and women with obesity and self-regulation problems.

Dr. Biegon said a possible extension of this work is to examine other brain regions where estrogen was shown to regulate appetite and energy utilization. Such studies could determine the value of aromatase measures within the brain to discriminate between binge eating and healthy populations, as well as help predict weight maintenance versus regain following bariatric surgery in adults.

Sophia Antipolis, France - 30 Aug 2020: Sacubitril/valsartan reduces NT-proBNP, a biomarker predictive of long-term clinical outcomes in heart failure, but does not improve functional capacity compared to individualised background therapy in patients with heart failure with preserved ejection fraction. That's the main finding of the PARALLAX trial presented in a Hot Line session today at ESC Congress 2020.1

Heart failure with preserved ejection fraction (HFpEF) affects approximately half of patients with heart failure. Prevalence is expected to rise with the ageing population and increased rates of risk factors such as hypertension, diabetes, obesity and atrial fibrillation. Patients are often highly symptomatic, with shortness of breath, reduced ability to exercise, impaired quality of life, and frequent rehospitalisations.

There is currently no approved therapy to reduce morbidity and mortality in patients with HFpEF. Treatment recommendations mainly focus on symptom relief with diuretics and treating comorbidities, typically with inhibitors of the renin-angiotensin system (RAS) including angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs).

The PARAGON-HF outcome trial suggested that sacubitril/valsartan may reduce heart failure hospitalisations in HFpEF patients compared to valsartan (an ARB).2 However, in daily practice, not all HFpEF patients receive an ARB. Many take an ACE inhibitor, and some no RAS inhibitor at all.

PARALLAX therefore tested the effects of sacubitril/valsartan versus optimal individualised background therapy, which could be the ACE inhibitor enalapril, the ARB valsartan, or placebo. The co-primary endpoints were chosen to assess heart failure severity and functional capacity: 1) change from baseline to 12 weeks in plasma N-terminal pro B-type natriuretic peptide (NT-proBNP); and 2) change in six-minute walk distance from baseline to 24 weeks.

A total of 2,572 HFpEF patients were randomly allocated to sacubitril/valsartan or their current RAS medication (enalapril, valsartan or placebo if they were not taking a RAS inhibitor). Patients in the trial had a mean age of 73 years and 51% were women. The mean left ventricular ejection fraction at baseline was 56%.

The trial met the first primary endpoint: after 12 weeks, patients treated with sacubitril/valsartan showed a highly significant 16.4% greater reduction in NT-proBNP than patients treated with optimal individualised medical therapy (p

The trial did not meet the second primary endpoint: at week 24, six-minute walk distance had improved in both groups compared to baseline (mean change was 9.7 m in the sacubitril/valsartan group and 12.2 m in the individualised medical therapy group), with no significant difference between groups (mean difference -2.5 m; 95% confidence interval -8.5 to 3.5 m; p=0.79).

Secondary endpoints included change from baseline to 24 weeks in quality of life (measured by the Kansas City Cardiomyopathy Questionnaire; KCCQ) and New York Heart Association (NYHA) functional class. Quality of life improved in both groups and was better with sacubitril/valsartan than the comparator at week 4 but there was no difference between groups at week 24. Changes in NYHA class were similar in both groups at week 24.

Overall, except for heart failure events, serious adverse events were reported in similar proportions of patients in both groups. Heart failure events (such as worsening heart failure requiring hospitalisation or not necessitating hospital admission) were the most common serious adverse events and occurred in more patients in the individualised medical therapy group than in the sacubitril/valsartan group. Based on this, a post hoc analysis showed that sacubitril/valsartan reduced the risk for heart failure hospitalisation by 50% (p=0.005). Patients in the sacubitril/valsartan group also had a significantly lower decline in renal function (estimated glomerular filtration rate; eGFR) at 24 weeks.

Principal investigator Professor Burkert Pieske from Charité University Medicine Berlin and the German Heart Centre, Berlin said: "The trial showed a consistent decline of the surrogate outcome marker NT-proBNP with sacubitril/valsartan, as compared to individual medical therapy."

Sophia Antipolis, France - 31 Aug 2020: Patients with acute pulmonary embolism can be selected for home management using the sPESI score or the Hestia criteria, according to results of the HOME-PE trial presented in a Hot Line session today at ESC Congress 2020.1

Principal investigator Professor Pierre-Marie Roy of the University Hospital of Angers, France said: "The pragmatic Hestia method was at least as safe as the sPESI score for triaging haemodynamically stable pulmonary embolism patients for outpatient care."

Acute pulmonary embolism is the most severe presentation of venous thromboembolism (VTE). Incidence is approximately 60 to 70 per 100,000 people, but increases with age, in cancer patients, during prolonged bedrest or after surgery. It occurs when a blood clot, usually in veins of the legs, travels to the right side of the heart and blocks the pulmonary arteries. The most frequent symptoms are acute dyspnoea and chest pain. In severe cases, patients may develop acute right heart failure with shock and, sometimes, sudden death.

Apart from haemodynamically unstable patients requiring specific management, treatment is mainly based on anticoagulation to avoid recurrence of pulmonary embolism and allow natural fibrinolysis. However, anticoagulation increases the risk of bleeding. Historically, hospitalisation was justified due to the risks of recurrence and bleeding. In the last decade, several studies have demonstrated the possibility of home treatment for selected haemodynamically stable patients. But controversy persists about the optimal referral strategies and eligibility criteria for outpatient care.

European guidelines recommend the Pulmonary Embolism Severity Index (PESI) score or the simplified PESI score (sPESI) to assess the risk of all-cause mortality.2 Patients with an sPESI score of 0 can be treated at home, providing that proper follow-up and anticoagulant therapy can be provided. American guidelines do not require a predefined score,3 and advise using pragmatic criteria such as those in the Hestia Study.4

The HOME-PE trial examined whether a strategy based on the Hestia criteria was at least as safe as a strategy based on the sPESI score to select patients for home treatment. In addition, it evaluated whether the Hestia method was more efficient compared to the sPESI score - in other words, whether it led to more patients being selected for home treatment.

This was a randomised, open-label non-inferiority trial comparing the two triaging strategies. It was conducted in 26 hospitals in France, Belgium, the Netherlands and Switzerland, which had set up, prior to study initiation, a thrombosis team for outpatient care of patients with acute pulmonary embolism.

In 2017 to 2019, 1,974 patients with normal blood pressure presenting to the emergency department with acute pulmonary embolism were included. Patients randomised to the sPESI group were eligible for outpatient care if the score was 0; otherwise they were hospitalised. Patients randomised to the Hestia group were eligible for outpatient care if all 11 criteria were negative; otherwise they were hospitalised. In both groups, the physician in charge could overrule the decision on treatment location for medical or social reasons.

The primary outcome was a composite of recurrent VTE, major bleeding, and all-cause death within 30 days. The Hestia strategy was non-inferior to the sPESI strategy: the primary outcome occurred in 3.8% of the Hestia group and 3.6% of the sPESI group (p=0.005).

A greater proportion of patients were eligible for home care using sPESI (48.4%) compared to Hestia (39.4%). However, the doctor in charge of the patient overruled sPESI more often than Hestia. Consequently, a similar proportion of patients were discharged within 24 hours for home treatment: 38.4% in the Hestia group and 36.6% in the sPESI group (p=0.42). All patients managed at home had a low rate of complications.

Professor Roy said: "These results support outpatient management of acute pulmonary embolism patients using either the Hestia method or the sPESI score with the option for physicians to override the decision. In hospitals organised for outpatient management, both triaging strategies enable more than a third of pulmonary embolism patients to be managed at home with a low rate of complications."

Sophia Antipolis, France - 31 Aug 2020: Colchicine reduces the risk of major cardiovascular events in patients with chronic coronary disease, according to results of the LoDoCo2 trial presented in a Hot Line session today at ESC Congress 2020.1

"Over a decade, more than one in three heart patients will have another heart attack or stroke, or die from heart disease, despite taking preventive medication," said study author Dr. Mark Nidorf of GenesisCare, Australia. "Our study shows that this could be reduced to one in four with the addition of low-dose colchicine."

Colchicine, originally derived from the bulb of the crocus plant, has been used since ancient times to treat inflammation. Now synthetically made, it is a generic medication taken to treat gout. The drug also inhibits several inflammatory pathways known to be important in atherosclerosis. The LoDoCo (Low Dose Colchicine) pilot trial suggested that colchicine 0.5 mg once daily was safe and effective for preventing cardiovascular events in patients with coronary artery disease.

The LoDoCo2 trial randomised 5,552 patients who had chronic coronary disease, and were tolerant to colchicine during a 30-day open-label run-in phase, to colchicine 0.5 mg daily or matching placebo on a background of lipid lowering and antithrombotic therapy.2,3 The primary endpoint was a composite of cardiovascular death, myocardial infarction, ischaemic stroke, or ischaemia-driven coronary revascularisation.

During a median follow-up of almost 30 months, the primary endpoint occurred in 187 (6.8%) patients in the colchicine group and 264 (9.6%) patients in the placebo group (hazard ratio [HR] 0.69; 95% confidence interval [CI] 0.57-0.83; p

More than 90% of patients were tolerant to open-label colchicine. Of those who were intolerant, most reported transient gastrointestinal symptoms. In patients randomised into the trial, low-dose colchicine was well tolerated over the longer term: the rate of permanent discontinuation was low (

During a maximum follow-up of five years, low-dose colchicine was not associated with any serious adverse effects. Neutropenia and myotoxicity were rare and no more frequent with the drug than with placebo. No unfavourable effects were found to occur with combined statin therapy even at high doses of statins. The risk of infection leading to hospitalisation or death, or new or fatal cancer, was also no different to placebo.

Dr. Nidorf said: "The trial confirmed that low-dose colchicine was tolerated over the long-term and significantly reduced the risk of the primary endpoint by almost one-third. The benefits were seen soon after initiating therapy, continued to accrue over time, and were observed patients already receiving other effective prevention therapies."

He noted that the magnitude of colchicine's effect on cardiovascular outcomes was consistent with that found in the CANTOS and COLCOT trials.4,5 Dr. Nidorf said: "The results of the LoDoCo2 trial establish colchicine as a potential new option for long-term prevention of cardiovascular events in patients with chronic coronary disease. "

A practice-changing study, NRG Oncology clinical trial NRG-RTOG 9802, has demonstrated, for the first time, a survival benefit of adjuvant chemotherapy following radiotherapy over radiotherapy alone in certain subgroups of patients with high-risk, low-grade glioma (WHO classification: LGG, grade II), a type of brain tumor that originates from glial cells.

The study results, published in a recent issue of the Journal of Clinical Oncology, sought to determine the prognostic and predictive impact of WHO-defined molecular subgroups and corresponding molecular alterations, known as IDH1/2 mutations, in people with the disease. LGG patients display highly variable survival outcomes depending on which molecular subgroup they are in. These subgroups are: IDH-wild type, IDH-mutant/1p19q non-codeleted, and IDH-mutant/1p19q codeleted. Genetic mutations were determined by testing patients' tissue samples through immunohistochemistry and/or deep sequencing.

A total of 116 of 251(46%) enrolled "high-risk" patients with LGG from the two treatment arms had adequate tissues available for genomic analyses using multiple platforms. After neuropathology review, representative areas (70% tumor) were selected for DNA isolation. Of the eligible patients successfully profiled for the WHO-defined molecular groups, 26 of them (24%) were IDH-wild type, 43 (41%) were IDH-mutant/non-codeleted, and 37 (35%) were IDH-mutant/codeleted. Treatment with postradiation chemotherapy (PCV; procarbazine, lomustine (CCNU), and vincristine) was associated with longer progression-free survival (HR, 0.32; P =.003; HR, 0.13; P

"Our study is the first to our knowledge to demonstrate the predictive value of the WHO-defined molecular subgroups in a practice-changing phase III clinical trial of high-risk grade II glioma in correlation to overall survival with long-term follow-up data," said the study's lead author Arnab Chakravarti, MD, professor and chair of the Department of Radiation Oncology at The Ohio State University Comprehensive Cancer Center, the Klotz Family Chair of Cancer Research, and Director of the Brain Tumor Program. "Our evidence suggests that IDH mutation status could serve as the primary predictor of response to PCV in addition to radiotherapy in high-risk LGGs and is a more accurate predictor of response than historical histopathological classifications."

Importantly, the analysis supports the notion that patients with IDH-mutant high risk LGG, regardless of codeletion status, receive benefit from the addition of PCV. "This study can now help clinicians interpret the results within the context of the altered molecular landscape and serve as a basis for survival times for the design of future high-risk LGG clinical trials," added Dr. Chakravarti.

Sophia Antipolis, France - 30 Aug 2020: Dapagliflozin reduces the risk of kidney failure, death from cardiovascular causes or heart failure hospitalisation and all-cause mortality in chronic kidney disease patients with or without type 2 diabetes. That's the main result of the DAPA-CKD trial presented in a Hot Line session today at ESC Congress 2020.1

The DAPA-CKD trial tested the hypothesis that treatment with dapagliflozin is superior to placebo in reducing the risk of renal and cardiovascular events in patients with chronic kidney disease (with or without type 2 diabetes) already receiving a stable dose of either an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) as background therapy.2

The primary composite endpoint was worsening kidney function (defined as >_50% sustained decline in estimated glomerular filtration rate [eGFR] or onset of end-stage kidney disease), or death due to kidney disease or cardiovascular disease.

The secondary endpoints were, in hierarchical order: 1) a composite endpoint of worsening kidney function (defined as >_50% sustained decline in eGFR or onset of end-stage kidney disease), or death from kidney failure; 2) a composite endpoint of hospitalisation for heart failure or cardiovascular death; and 3) all-cause mortality.

The trial enrolled 4,304 patients, aged 18 years and over, from 386 centres in 21 countries. All patients had an eGFR >_25 and _200 mg/g and

Patients were randomly allocated to dapagliflozin 10 mg or placebo once daily in addition to standard of care (i.e. an ACE inhibitor or ARB). The average age of participants was 61.8 years and 66.9% were male. A total of 2,906 (67.5%) patients had type 2 diabetes.

During a median follow-up of 2.4 years, there were 197 primary endpoint events with dapagliflozin and 312 with placebo. The hazard ratio (HR) for the primary endpoint was 0.61 (95% confidence interval [CI) 0.51-0.72; p=0.000000028). The benefit of dapagliflozin on the primary endpoint was consistent in patients with and without type 2 diabetes.

Dapagliflozin reduced all three secondary endpoints compared to placebo. The HRs were: 1) worsening renal function or death from kidney failure 0.56 (95% CI 0.45-0.68; p

The safety and tolerability of dapagliflozin was in keeping with its established profile. In the placebo group, the proportion of patients who discontinued the study drug due to an adverse event or experienced a serious adverse event were 5.7% and 33.9%, respectively. The proportion of patients with these events was similar in the dapagliflozin group (5.5% and 29.5% respectively). Diabetic ketoacidosis was not reported in any patient randomised to dapagliflozin and occurred in two patients in the placebo group. Neither diabetic ketoacidosis nor severe hypoglycaemia were observed in patients without type 2 diabetes.

Study author Professor Hiddo J.L. Heerspink of University Medical Centre Groningen, the Netherlands, said: "DAPA-CKD showed that dapagliflozin reduced the risk of worsening kidney function or death from cardiovascular or kidney disease in patients with chronic kidney disease with and without type 2 diabetes. The results highlight the medicine's potential to benefit patients with chronic kidney disease who are in need of improved treatment options."

A team including researchers from the Institute for Astrophysics of the University of Cologne has for the first time directly observed the columns of matter that build up newborn stars. This was observed in the young star TW Hydrae system located approximately 163 light years from Earth. This result was obtained with the Very Large Telescope Interferometer (VLTI) and its GRAVITY instrument of the European Southern Observatory (ESO) in Chile. The article 'A measure of the size of the magnetospheric accretion region in TW Hydrae' has been published in a recent issue of Nature.

The formation of stars in the Galaxy involves processes in which primordial matter such as gas and dust present in the giant molecular clouds is rapidly aggregated via gravity to form a protostar. This 'accretion' of gas occurs through the disk that forms around the newborn star and represents the major mechanism of supply of material to the growing central baby star. These so-called protoplanetary disks are one of the key ingredients to explain the formation of very diverse exoplanets that are to date frequently discovered orbiting our closest neighbours.

Based on theoretical and observational evidence, many scenarios were hypothesized to describe the mechanism of interaction between the star and the parent circumstellar disk, like for instance the funnelling and accretion of host gas onto the central star along the local magnetic field. But this could never be directly observed and proven so far with any telescope. The main reason is that the level of details of the image - astronomers talk about angular resolution - necessary to observe what happens very close to the star was simply out of reach. For comparison, detecting these events would be like discerning a small one-cubic meter box on the surface of the Moon. With a normal telescope, this is not possible. However, with an interferometer like the VLTI in Chile and its instrument GRAVITY, which delivers unprecedented angular resolution in the infrared, such a precise observation has now become possible. An interferometer collects and combines the light from different telescopes a few hundred meters apart, which provides the same level of accuracy as a hypothetical giant telescope with a comparable diameter.

With the contribution of members of Cologne's Institute for Astrophysics, astrophysicists from several European institutions exploited the GRAVITY instrument at the VLTI to probe the closest regions around the young solar analog TW Hydrae, which is thought to be the most representative example of what our Sun may have looked like at the time of its formation, more than 5 billion years ago. By measuring very precisely the typical angular size of the very inner gaseous regions - using a particular infrared atomic transition of the hot hydrogen gas - the scientists were able to directly prove that the hot gas emission was indeed resulting from magnetospheric accretion taking place very close to the stellar surface. 'This is an important milestone in our attempt to confirm the mechanisms at work in the field of star formation', said Professor Lucas Labadie, co-author of the paper. 'We now want to extend such exploration to other young stars of different nature to understand how the evolution of the circumstellar disk, the birthplace of planets, goes.'
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he team is part of the GRAVITY collaboration, named after the instrument that was co-developed by the University of Cologne and which combines interferometrically the four large 8-m telescopes of ESO in Chile. The team members include Lucas Labadie, Rebekka Grellmann, Andreas Eckart, Matthew Horrobin, Christian Straubmeier and Michael Wiest. 'This result illustrates what is the unique potential of interferometry at the VLTI', added Dr Christian Straubmeier, team member and co-investigator of the GRAVITY instrument in Cologne. 'This is why we decided to look ahead and develop the upgrade GRAVITY+ in the hope of being able to observe and image even fainter objects than what GRAVITY currently does.'

Cambridge, Mass. - In March 2020, federal officials declared the COVID-19 outbreak a national emergency. Around the same time, most states implemented stay-at-home advisories - to different degrees and at different times. Publicly available cell phone location data - anonymized at the county-level - showed marked reductions in cell phone activity at the workplace and at retail locations, as well as increased activity in residential areas. However, it was not known whether these data correlate with the spread of COVID-19 in a given region.

In a new study published in JAMA Internal Medicine, researchers from Mount Auburn Hospital and the University of Pennsylvania analyzed anonymous, county-level cell phone location data, made publicly available via Google, and incidence of COVID-19 for more than 2,500 U.S. counties between January and May 2020. The researchers found that changes in cell phone activity in workplaces, transit stations, retail locations, and at places of residence were associated with COVID-19 incidence. The findings are among the first to demonstrate that cell phone location data can help public health officials better monitor adherence to stay-at-home advisories, as well as help identify areas at greatest risk for more rapid spread of COVID-19.

"This study demonstrates that anonymized cell phone location can help researchers and public health officials better predict the future trends in the COVID-19 pandemic," said corresponding author Shiv T. Sehra, MD, Director of the Internal Medicine Residency Program at Mount Auburn Hospital. "To our knowledge, our study is among the first to evaluate the association of cell phone activity with the rate of growth in new cases of COVID-19, while considering regional confounding factors."

Sehra and colleagues, including senior author Joshua F. Baker, MD, MSCE, of the University of Pennsylvania, incorporated publicly available cell phone location data and daily reported cases of COVID-19 per capita in majority of U.S. counties (made available by Johns Hopkins University), and adjusted the data for multiple county- and state- level characteristics including population density, obesity rates, state spending on health care, and many more. Next, the researchers looked at the change in cell phone use in six categories of places over time: workplace, retail locations, transit stations, grocery stores, parks and residences.

The location data showed marked reductions in cell phone activity in public places with an increase in activity in residences even before stay-at-home advisories were rolled out. The data also showed an increase in workplace and retail location activity as time passed after stay-at-home advisories were implemented, suggesting waning adherence to the orders over time, information that may potentially be useful at a public health level.

The study showed that urban counties with higher populations and a higher density of cases saw a larger relative decline in activity outside place of residence and a greater increase in residential activity. Higher activity at the workplace, in transit stations and retail locations was associated with a higher increase in COVID-19 cases 5, 10, and 15 days later. For example, at 15 days, counties with the highest percentage of reduction in retail location cell phone activity -- reflecting greater adherence to stay-at-home advisories -- demonstrated 45.5 percent lower rate of growth of new cases, compared to counties with a lesser decline in retail location activity.

"Some of the factors affecting cell phone activity are quite intuitive," said Sehra, who is also an Assistant Professor of Medicine at Harvard Medical School. "But our analysis helps demonstrate the use of anonymous county-level cell phone location data as a way to better understand future trends of the pandemic. Also, we would like to stress that these results should not be used to predict the individual risk of disease at any of these locations."

An Australian-Dutch trial led by Perth GenesisCare cardiologists, Professor Peter Thompson and Dr Mark Nidorf, in collaboration with the Dutch Network for Cardiovascular Research (WCN) in the Netherlands, confirmed that low dose colchicine was safe, well tolerated over the long-term, and significantly reduced the risk of cardiovascular death, heart attack, and ischemic stroke in patients with chronic coronary disease.

The Australian-Dutch trial was the world's largest trial of colchicine. It examined the effect of low dose colchicine (0.5mg daily) in patients with chronic coronary disease who were already taking established treatments.

Professor Thompson, Deputy Director of Perth's Harry Perkins Institute of Medical Research and a GenesisCare Cardiologist, said the trial involving almost 2000 WA patients and 3,500 from the Netherlands, found low dose colchicine reduced the risk of heart attack and the need for stents or bypass surgery due to progressive angina.

"We found the benefits of colchicine therapy were seen soon after starting on the drug and continued to build over time. Over the course of the trial, colchicine was found to reduce the risk of cardiovascular death, heart attack and stroke by almost one third," Professor Thompson said.

Dr Nidorf from GenesisCare was the first to demonstrate, seven years ago in a small trial of 500 patients, that low dose colchicine might be beneficial in patients with coronary disease. The 2013 pilot trial generated several other trials around the world for conditions including heart attack and stroke. Trials in Sydney and Canada occurred for high-risk patients with coronary disease.

"It's now understood that when cholesterol gets into the arterial wall it can spontaneously form into crystals, which like gout crystals, can incite a low-grade inflammatory response that causes chronic scarring of the artery.

"When this inflammatory process is more acute it can lead to the breakdown of plaques which can lead to heart attack and stroke.

"What we've been unable to do until now is reduce the inflammatory process that goes on inside the arterial wall.

"This is a ground-breaking, practice changing result, because colchicine is inexpensive and widely available.

"We found it to be a profoundly powerful drug at low-dose, with no danger signals associated with long-term use and excellent long-term tolerance.

"This medication does not come with the added cost of bleeding or lowering blood pressure so it is a nice fit with current treatments and will likely form a cornerstone treatment in patients with coronary disease, alongside aspirin and statins," Dr Nidorf said.

Former Fremantle Football Club CEO and Hockey Australia President Mr David Hatt AM enrolled in the two-year trial, hoping to avoid family history repeating.

"I was a patient of Dr Nidorf's and very happy to be involved. I have heart disease which is controlled by tablets to reduce blood pressure and the build-up of plaque.

"I was motivated to be a part of the program because at a similar age my father had a serious heart attack and I was anxious to avoid that and I wanted to be involved in something that could help so many others," Mr Hatt said.

"GenesisCare is delighted to partner with Perth's Harry Perkins Institute of Medical Research and the Dutch Network for Cardiovascular Research to deliver the results of this international clinical trial, which will offer new hope to patients with coronary artery disease all over the world," Dr Nidorf said.

A new study from North Carolina State University and Virginia Commonwealth University highlights several factors that play key roles in determining the extent to which fathers who don't have custody are involved in their children's lives - specifically in cases where the children are in "kinship care."

"A lot of work has been done on mothers and children who are in kinship care, meaning that the primary caregiver for the children is a member of the extended family, including friends who are 'like family,'" says Qiana Cryer-Coupet, who is senior author of the study and an assistant professor in NC State's School of Social Work. "But fathers are also often significant figures in kinship-care arrangements, and there is far less research on how we can work with fathers and kinship caregivers to support the well-being of children.

"This study is exploratory, but it is fundamental to the broader goal of fostering engagement with fathers," Cryer-Coupet says.

For this qualitative study, researchers conducted in-depth interviews with 25 fathers whose children were in kinship care. And they found three factors that played an important role in determining the extent to which fathers felt they could be involved in the lives of their children.

A significant factor was self-efficacy, or the extent to which the fathers felt that they had the tools they needed to parent successfully. Much of the concern here revolved around having sufficient financial resources to support their child. For example, one father highlighted the difficulty of feeding and housing a family on minimum-wage earnings.

A second factor was the relationship that each father had with his child's primary caregiver. For example, fathers were better able to be part of their children's lives when caregivers shared information with the fathers about opportunities to be actively engaged - such as upcoming doctor's appointments, school meetings or children's sports.

"This finding is valuable, because it tells us that we need to train social workers in how to navigate co-parenting circumstances in which the parents were never partners," Cryer-Coupet says. "For example, the father may be co-parenting with the child's maternal grandmother. The dynamics can be very different."

The third factor was the father's relationship with the child. This included the degree of comfort and familiarity between father and child, but it also extended to how the father was able to relate to the child in the context of institutional systems.

"Many fathers are not always clear on what their parental rights are," Cryer-Coupet says. "And social workers may need to help fathers navigate social services, education, healthcare and the legal system. These systems are often complex and complicated, which may pose an obstacle to the father being as engaged as they want to be with their children's lives.

"One other finding that we found interesting was the extent to which fathers were using various technologies to create additional opportunities to interact with their children - whether that was through the chatrooms on video games or through video-call apps.

"This work represents a significant step forward in our understanding of fathers with children in kinship care, but it also underscores how understudied this group is," Cryer-Coupet says. "Further research is warranted, and we are hoping to secure funding that would allow us to conduct a larger, longer-term study. There's every reason to believe that work in this area could have significant benefits for both children and fathers."