Body

HOUSTON ? Ivosidenib, an experimental drug that inhibits a protein often mutated in several cancers has been shown to be safe, resulting in durable remissions, in a study of acute myeloid leukemia (AML) with relapsed or refractory disease.

The multi-center Phase I trial, led by researchers at The University of Texas MD Anderson Cancer Center, was designed to determine ivosidenib's safety and efficacy in treatment of patients with a form of AML in which the enzyme isocitrate dehydrogenase 1 (IDH1) is mutated. IDH1 mutations occur in 6 to 10 percent of AML patients. Findings are published today in the June 2 online issue of the New England Journal of Medicine and presented at the American Society of Clinical Oncology Annual Meeting in Chicago.

This first study of ivosidenib in humans, which enrolled patients between March 2014 and May 2017, administered a daily dose of the targeted IDH1 inhibitor to 258 patients.

"Ivosidenib, when administered orally as a single agent, was associated with acceptable side effects and induced durable and deep remissions," said Courtney DiNardo, M.D., assistant professor of Leukemia at MD Anderson. "In the trial's primary analysis cohort of 125 patients with IDH1-mutated relapsed or refractory AML treated at the recommended 500 mg daily dose, ivosidenib led to an overall response rate of 41.6 percent and a complete remission rate of 21.6 percent."

The study also reported that 30.4 percent of those 125 patients were in complete remission but with blood counts not fully restored. The overall survival rate was 50.1 percent at 18 months, as compared to historical overall survival of less than five months for patients with relapsed AML and two prior therapies.

"Among patients achieving complete remission or complete remission with partial hematologic recovery, 21 percent had no residual detectable IDH1 mutations," said DiNardo. "While the significance and prognostic impact of ongoing detection of IDH1 mutations remains unknown, further evaluation of changes in IDH1 mutations over time with ivosidenib therapy will be important avenues of research."

New research presented at this year's Euroanaesthesia congress in Copenhagen, Denmark shows that the quality of chest compressions during cardiopulmonary resuscitation (CPR) can be improved by using either a smartphone app or by using the song "La Macarena" as a mental memory aid.

The study is by Professor Enrique Carrero Cardenal and colleagues at the University of Barcelona, Hospital Clinic Barcelona, and Universitat Autònoma Barcelona, Spain.

Improving the quality of compressions performed during CPR can significantly increase the chance of survival and lead to better health outcomes. The goal of the study was to compare the effectiveness of a smartphone metronome application, and a musical mental metronome in the form of the song "La Macarena" at improving the quality of chest compressions. Both the app and the song provide a regular rhythm to help time compressions.

The team selected a group of 164 medical students from the University of Barcelona to perform continuous chest compressions on a manikin for 2 minutes. Subjects either received no guidance (control), were provided with the smartphone app (App group), or were asked to perform compressions to the mental beat of the song "La Macarena" (Macarena group).

The smartphone app made a noise for each compression at 103 beats per minute (bpm), but in the Macarena group the students needed to prove first that they knew the song La Macarena in order to do the compressions correctly. The authors also collected demographic data and information about the quality of chest compressions, as well as conducting a satisfaction survey.

The study found that the average percentage of compressions occurring in the target range of 100-120 bpm was significantly higher in the App and Macarena groups (91% and 74% respectively) compared to the control group (24%). No group achieved the required compression depth of 5 cm, but those using the App had the best overall quality compression scores despite having the longest onset delay before performing the first compression. The students who participated in the experiment also rated the app as being the most useful help method.

The authors conclude that: "Both the app and using mental memory aid 'La Macarena' improved the quality of chest compressions by increasing the proportion of adequate rate but not the depth of compressions. The metronome app was more effective but with a significant onset delay."

DURHAM, N.C. -- Contrary to current perceptions, certain African-American men with advanced prostate cancer have as good a chance of survival as white men and might actually have a small advantage, according to a new analysis of more than 8,000 patients who participated in clinical trials.

In a study presented June 1 at the American Society of Clinical Oncology, lead author Susan Halabi, Ph.D., professor of biostatistics and member of the Duke Cancer Institute, said the racial disparities long associated with prostate cancer are complex and persistent. But for men with advanced disease who are treated with a common chemotherapy drug along with steroids, the risk of death is actually lower for African-Americans.

"When we looked at the raw, median survival for white and African-American men in our study, it was equal, at about 21 months," Halabi said. "But when you compare the men based on similar characteristics that influence survival, the African-American men actually had a 19 percent lower risk for death than white men."

Halabi and colleagues conducted their analysis on pooled data from nine large studies that used the chemotherapy drug docetaxel, which is a standard therapy and is typically taken along with the steroid prednisone.

Of the more than 8,000 men included in the analysis, 500 were African-American -- a large cohort despite low enrollments of African-American men for each of the individual studies. They then took into consideration patient characteristics already known to affect survival in the analysis, including age, performance status such as ability to manage daily activities, prostate-specific antigen (PSA) levels, site of metastases and other factors.

African-American men in the analysis were younger and sicker than the white men, as measured by the key survival factors. Despite that, the overall median survival for African-American men was nearly equal to the white men at 21 months.

That alone was unexpected, Halabi said, since the African-American men carried a heavier burden of disease. But when they compared men of different races to each other based on the key disease variables, the survival advantage for African-Americans was even more surprising.

"These findings are specific to men who enrolled in these trials and who have been treated with docetaxel-based therapies. The results of this analysis suggest there might be biological variations in either the disease or response to treatments that should be further explored," Halabi said.

June 1, 2018--Immunosuppressed patients with sepsis appear more likely to die if they are treated in a hospital caring for a relatively small number of these patients, according to new research published online in the Annals of the American Thoracic Society.

Sepsis, a leading cause of death in U.S. hospitals, occurs when the body produces an out-of-cont

In "Hospital Volume of Immunosuppressed Sepsis Patients and Sepsis Mortality," Jared A. Greenberg, MD, MSc, and coauthors analyzed the medical records of 350,183 patients with sepsis at 60 U.S. hospitals. One of five of those patients was classified as being immunocompromised based on being HIV-positive or having an intrinsic immune disorder, having a blood cancer or being prescribed an immunosuppressive drug for certain medical conditions while hospitalized.

"While there is a lot of focus on improving sepsis outcomes through early interventions, some patients have poor outcomes from sepsis because their chronic medical conditions may worsen after the initial infectious insult," said Dr. Greenberg, an assistant professor and critical care physician at Rush University Medical Center in Chicago, Illinois. "We hypothesized that septic patients who are immunocompromised may have improved outcomes if they are managed at hospitals that have the most experience managing immunocompromising conditions."

The study found:

15 percent of immunosuppressed patients with sepsis died during hospitalization compared to 12 percent of non-immunosuppressed patients with sepsis at all hospitals.

At hospitals seeing fewer than 225 immunosuppressed patients with sepsis each year, these patients were 38 percent more likely to die while hospitalized, compared to 21 percent more likely to die at hospitals that saw 225 or more of these patients yearly.

Above 225, caring for greater numbers of immunosuppressed patients with sepsis (one hospital treated 1,056 such patients) did not appear to reduce mortality.

Immunosuppressed patients with sepsis were more likely than non- immunosuppressed patients to return to their homes after discharge, rather than another health facility, 60 percent vs. 50 percent, respectively.

The authors said this last finding was a surprise. They believe that non-immunosuppressed patients may have been more likely to be experiencing declining states of health prior to sepsis than immunosuppressed patients, as they were more likely to be older and to be admitted directly from other health care facilities.

Researchers adjusted their findings for a range of factors, including severity of sepsis when hospitalized, other medical problems and whether a patient's infection was hospital acquired.

Study results do not explain why immunosuppressed patients fared better at hospitals treating large numbers of such patients. They speculate that "immunosuppressed patients with sepsis had improved survival at hospitals where clinicians had greater familiarity caring for immunosuppressed patients."

Without this familiarity, the authors write, physicians might miss atypical signs of sepsis in an immunocompromised patient and therefore miss the opportunity to treat the disease early before it gets out of control. It is also possible that the physicians may not comply with the Surviving Sepsis Campaign's international guidelines for clinical care, which many studies have shown reduce sepsis mortality, according to the authors.

Dr. Greenberg said the study is important for administrators and clinicians focused on improving quality of sepsis care because "patients with a medical condition that is relatively uncommon at a hospital may have worse outcomes from sepsis than patients with the same conditions who are managed at hospitals where the condition is more common."

He added that more research was necessary to determine the "mechanism of this finding" before suggesting that an immunosuppressed patient should seek out a specific hospital based on the number of immunosuppressed patients treated by that hospital.

DURHAM, N.C. -- African-American men with advanced prostate cancer might be more responsive than white men to an anti-androgen drug and steroids, according to a study led by Duke Cancer Institute researchers.

While median survival was similar for both black and white participants in the study, the findings suggests that racial determinants may factor into the degree of response in patients. This difference could help drive strategies to improve outcomes in those who respond better to the drugs.

"African-Americans have a 2.5 times greater chance of dying from prostate cancer compared to whites," said Daniel George, M.D., director of Duke's Prostate & Urologic Cancer program, who presented the findings at the 2018 annual meeting of the American Society of Clinical Oncology in Chicago.

"Our study provides prospective evidence that there might be inherited genes that could affect treatment response and track with African ancestry in prostate cancer patients," George said. "We need to look closely at the underlining genetic differences that associate with treatment response and build on that to improve survival for these patients."

George and colleagues enrolled 50 black men and 50 white men in a prospective, multi-center study. All participants had metastatic, recurrent prostate cancer and were treated with the anti-hormone therapy abiraterone and the steroid prednisone.

Responses to therapy, measured by a decline in prostate-specific antigen, or PSA, differed by race. For the African-American men, PSA levels declined at higher rates than they did for white patients and remained stable for a median 16.6 months, compared to 11.5 months for the white participants.

The changes in disease progression were less striking; both groups had a median time to radiographic progression of 16.8 months. Still, the authors said the study suggests a potential strategy for new therapies and hormonal treatment regimens that could narrow the prostate cancer survival disparity between blacks and whites.

"This is the first prospective multicenter study by race of an anti-androgen hormonal therapy in advanced prostate cancer," George said. "Further prospective studies in African-American patients are possible and needed to understand the impact of racial determinants on outcome of new hormonal regimens in earlier disease settings."

Teenage girls who diet are more likely to engage in other health-compromising behaviours, including smoking, binge drinking, and skipping breakfast, a University of Waterloo study recently found.

The study found that, compared to girls who were not dieting at the time of initial data collection, those who were dieting were more likely to engage in one or more clusters of other risky behaviours three years later.

"It might seem natural for there to be a connection between dieting and behaviours such as smoking and skipping meals, but the explanation is not so clear for something like binge drinking," said Amanda Raffoul, who led the study and is now a PhD candidate in Public Health and Health Systems. "Our findings suggest that dieting and other risky health behaviours may be related to common underlying factors, such as poor body image.

"The link between dieting and other health-compromising behaviours is worrisome since 70 percent of girls reported dieting at some point over the three years", Raffoul added. "Post-puberty changes often lead to weight gain among girls and there is incredible pressure from social media and elsewhere to obtain and maintain the ideal body."

The study found dieters were 1.6 times more likely to smoke and skip breakfast, and 1.5 times more likely to smoke and engage in binge drinking.

"Intentional weight loss is not something we should necessarily encourage, especially among this population, since it's possible that well-meaning initiatives that promote dieting may be doing more harm than good," Raffoul added. "Instead, we should focus on health broadly rather than weight as an indicator of health."

The researchers examined data from more than 3,300 high school girls in Ontario who participated in a longitudinal school-based study called COMPASS.

"This study points to the importance of looking at factors related to health, including behaviours and the array of influences on them, in combination," said Sharon Kirkpatrick, a professor in the School of Public Health and Health Systems and co-author on the study, "Only by understanding the complex ways in which these factors interact can we identify effective interventions, as well as predict and monitor potential unintended effects of such interventions."

In a new study, researchers at Uppsala University and other institutions have identified genetic material from the recently identified Alkhurma hemorrhagic fever virus in the tick species Hyalomma rufipes. The discovery was made after thousands of ticks were collected from migratory birds captured in the Mediterranean basin. The results indicate that birds could contribute to spreading the virus to new geographical areas.

The Alkhurma virus (a.k.a Alkhumra) was first found in Saudi Arabia in the mid-1990s, in patients with typical hemorrhagic fever symptoms. The condition resembles diseases like Ebola but seems to be spread by contact with cattle and camels or from tick bites and not directly between humans. The knowledge about this relatively novel virus is still limited, and it is not known exactly which animals can act as hosts for the virus and which insects or tick species transmit the disease. Previous research has pointed to camels and other domestic livestock as potential carriers of the virus, and to one or several tick species possibly spreading the disease between mammals, including humans. The virus is a close relative to another tick-borne virus (Kyasanur Forest Disease virus) found in India. So far, the Alkhurma virus has only been seen on the Arabian Peninsula and in Egypt.

In a multi-national collaboration, researchers at Uppsala University have detected Alkhurma virus RNA in several ticks that were removed from birds migrating from Africa to Europe. The purpose of the study is to find out which tick-borne diseases that could potentially spread to new regions with migratory birds. Thousands of ticks were removed from migrating birds at seven different bird observatories in the Mediterranean basin.

"Our findings of the Alkhurma virus in ticks collected in Turkey and Greece are the first in the tick species Hyalomma rufipes, which is common in large parts of Africa and on the Arabian Peninsula. These findings mean that we have identified one more tick species that have carried RNA from this virus and shows that there is a risk of spread of the virus to new geographical areas," says Tove Hoffman, leader of the study and PhD student at the Department of Medical Sciences and the Zoonosis Science Center at Uppsala University.

A clearer understanding of the ecology of Alkhurma virus and continuing surveillance is important, both for populations in areas where it is already found as well as in regions in the Mediterranean basin, to where the virus could spread, since Alkhurma hemorrhagic fever is a potentially fatal disease and there is no effective treatment at present.

"We see that infectious diseases can spread to new geographical areas and that is why it is necessary to understand the role of different animal species in the dynamics of these diseases," says Tove Hoffman.

The multibillion-dollar MIECHV program was formed as part of the 2010 Patient Protection and Affordable Care Act. It provides funding to organizations that offer home visiting services to improve maternal-child health. These organizations are required to demonstrate improvements over time, and the MIECHV program monitors this progress through specific benchmarks.

"Our country has one of the highest infant mortality rates compared with peer countries, so it's vital that this program mobilize the right resources in the most effective ways possible," said Julie Kapp, PhD, associate professor of health management and informatics at the MU School of Medicine and an author of the study. "While the MIECHV program as a whole and the federal initiatives around maternal-child health are trying to take the right steps to help families, our research suggests there may be ways to improve upon their implementation."

The MIECHV program has established six benchmarks for organizations to demonstrate improvement, which can ultimately impact funding decisions. The research team evaluated the evidence for one benchmark, "Maternal and Newborn Health," which is broken down into six measurable sub-categories, or constructs.

Preterm birth

Breastfeeding

Depression screening

Well-child visits

Postpartum care

Tobacco cessation referrals

Using a federally established database called the Home Visiting Evidence of Effectiveness, or HomVEE, the team reviewed literature to determine whether or not these constructs are supported by evidence-based research.

"We were surprised to find that only three of the six constructs -- preterm birth, breastfeeding and well-child visits -- are supported by established research," said Sofia Campos with the global consulting and digital services provider ICF, a co-author of the review. "Of the 59 articles we reviewed, only 14 measured outcomes aligned with any of the six constructs. None of the articles directly measured depression screening, postpartum care or tobacco cessation referrals. That means that we have no evidence from this key library that home visiting actually improves these maternal and child health outcomes."

While only three of these six federally mandated constructs is supported by a federal library of evidence-based home visiting research, the team identified 16 other non-mandated constructs that have evidence of home visiting improving maternal-child health. These constructs include maternal depression symptoms and psychological outcomes, use of community resources, emergency visits and more.

"Based on our review, we recommend that the process for establishing these constructs include evaluation of the evidence-based research," Kapp said. "By setting goals that have been proven to improve the health of mother and child, MIECHV can make more positive, sustained changes for hundreds of thousands of families nationally. Additionally, more confident funding decisions can be made when informed by performance measures that are evidence-based."

New guidelines developed by the American Cancer Society (ACS) recommend that screening for colorectal cancer for average-risk adults begin at age 45, five years earlier than the previous recommendation. The guideline update, published as an Early View paper in CA: A Cancer Journal for Clinicians available online here, was co-authored by Elizabeth T. H. Fontham, DrPH, Emeritus Professor and Founding Dean of LSU Health New Orleans School of Public Health and Co-Chair of the American Cancer Society’s Screening Guideline Development Group.

The recommendations are based in part on research that found an increased incidence of colorectal cancer in younger adults. Among adults younger than 55 years, there was a 51% increase in the incidence of colorectal cancer (CRC) from 1994 to 2014 and an 11% increase in deaths 2005 to 2015. The authors reported that colorectal cancer incidence has declined steadily over the past two decades in people 55 and older, partly due to screening that results in the removal of polyps. A recent analysis found that adults born around 1990 have twice the risk of colon cancer and four times the risk of rectal cancer compared with adults born around 1950, who have the lowest risk. Studies suggest that the increased risk for younger people will remain as they age.

Colorectal cancer is the 4th most commonly diagnosed cancer. It is the second leading cause of cancer deaths. When detected and treated early, the five-year survival rate is near 70%.

“The options for colorectal cancer screening are fecal immunochemical test annually; high-sensitivity, guaiac-based fecal occult blood test annually; multitarget stool DNA test every 3 years; colonoscopy every 10 years; computed tomography colonography every 5 years; and flexible sigmoidoscopy every 5 years,” said Dr. Fontham. “It is important to note that all positive results on non-colonoscopy screening tests should be followed up with timely colonoscopy.”

The Guideline Committee also developed new materials to facilitate conversations between clinicians and patients to help patients decide which test is best for them.

“Given the evidence that adults vary in their test preferences, we believe that screening rates could be improved by endorsing the full range of tests without preference. People should have a conversation with their physicians to decide which type of screening is best for them,” Fontham added.

The guidelines recommended in the paper focus on people at average risk. Those at high risk for colorectal cancer, including those with a family history, a personal history of inflammatory bowel disease or polyps diagnosed before age 60, should discuss their risk and appropriate screening with their physicians.

The authors conclude, “The ACS recommends that all US adults at average risk of CRC undergo regular screening with any of the 6 options outlined in this guideline, beginning at age 45 years. Adults in good health should continue screening until age 75 years, beyond which the decision to continue screening should be individualized based on patient preferences, health status, life expectancy, and screening history. Ascribing to the adage that the best CRC screening test is the one that gets done, and done well, the ACS recommends that patients initiating screening or previously nonadherent with screening be offered a choice of tests based on the availability of high-quality options. It is our hope that widespread adoption of this guideline will have a major impact on the incidence, suffering, and mortality caused by CRC.”

Increased physical activity, not weight loss, gives individuals with coronary heart disease a longer lease on life, according to a new study conducted at the Norwegian University of Science and Technology (NTNU).

NTNU researchers have found that heart disease patients can gain weight without jeopardizing their health, but sitting in their recliner incurs significant health risks.

Weight loss seems to be associated with increased mortality for the participants in the study who were normal weight at baseline. The survey, which is an observational study based on data from HUNT (the Nord-Trøndelag Health Study), was recently published in the Journal of the American College of Cardiology (JACC).

Researcher Trine Moholdt in NTNU's Department of Circulation and Medical Imaging collaborated on the study with cardiologist Carl J. Lavie at the John Ochsner Heart and Vascular Institute in New Orleans, and Javaid Nauman at NTNU.

They studied 3307 individuals (1038 women) with coronary heart disease from HUNT. Data from HUNT constitute Norway's largest collection of health information about a population. A total of 120,000 people have consented to making their anonymized health information available for research, and nearly 80,000 individuals have released blood tests.

HUNT patients were examined in 1985, 1996 and 2007, and followed up to the end of 2014. The data from HUNT were compared with data from the Norwegian Cause of Death Registry.

During the 30-year period, 1493 of the participants died and 55 per cent of the deaths were due to cardiovascular disease.

"This study is important because we've been able to look at change over time, and not many studies have done that, so I am forever grateful to HUNT and the HUNT participants," said Moholdt.

Exercise and live longer

The study revealed that people who are physically active live longer than those who are not. Sustained physical activity over time was associated with substantially lower mortality risk.

Participants in the study were divided into three categories: inactive; slightly physically active, but below recommended activity level; and physically active at or above recommended activity level.

The recommended activity level is at least 150 minutes per week of moderate physical activity or 60 minutes per week of vigorous physical activity.

A little is better than nothing

The risk of premature death was higher for the group of patients who were completely inactive than for either of the other groups. The prognosis for people who exercise a little bit, even if it is below the recommended level, is better than not exercising at all.

"Even being somewhat active is better than being inactive, but patients have to maintain the activity level. Physical activity is perishable - if you snooze you lose its benefits," Moholdt says.

Exercise hard

HUNT participants were asked how hard the exercise activity was for them. Moholdt points out that this is a good way to determine the intensity of the exercise. A half-hour walk can be experienced very differently depending on how fit the person is.

The question then becomes how to translate these findings into practical guidelines.

"The clinical guidelines for heart disease patients currently include having normal weight and being physically active. I would put more emphasis on the exercise aspect. When it comes to physical activity, you have to do what gets you in better shape. That means training with high intensity. Do something that makes you breathe hard, so that it's hard to talk, but not so hard that you can't do it for four to five minutes," says Moholdt. She adds that heart disease patients are often in poor shape, so it often doesn't take much to get into high intensity mode.

When asked whether any of the study results were unexpected, Moholdt said that they weren't surprising in terms of physical activity. "But the fact that gaining weight posed no increased risk when patients were already overweight, I think is a bit surprising," she said.

Correlation between weight loss and increased mortality

The results indicate that weight gain does not seem to increase risk for already overweight patients, which would mean that it isn't dangerous for a fat heart patient to gain a few pounds. What is dangerous is if the person does not engage in any form of exercise.

The findings in the study showed higher mortality among normal weight heart patients who lost weight. Moholdt points out that the survey is an observation study that does not look at underlying causes. It may be that patients who lost weight were sicker.

The obesity paradox

The development of cardiovascular disease has a causal relationship with obesity. Despite this strong correlation, the results from major meta-analyses indicate that people with cardiovascular disease who have a body mass index (BMI) above the normal weight range have better prognoses. This is often called the obesity paradox.

"What we've known for a while is that for heart patients it seems to be an advantage to be fat - the so-called obesity paradox. But although it seems like it pays to be overweight and that weight loss affects these patients adversely, all of these data are based on observation studies. To prove causality, randomized controlled trials are needed," says Moholdt.

The relationship between BMI and life expectancy is complicated and depends on several factors. Erroneous sources are plentiful. Results from another analysis showed that normal weight, healthy non-smokers have the lowest risk of premature death.

Slimming down isn't necessarily wrong

This study's results do not mean that it is never a good idea for an overweight heart patient to slim down. Moholdt and her colleagues note in their JACC article that "in our view, desired or intentional weight reduction may be useful for overweight or obese individuals, although little data supports this view in studies of coronary heart disease patients."

One hypothesis is that weight loss is associated with improved survival among overweight and obese coronary heart disease patients. This correlation was not evident in the study.

"It may be that weight is less important for heart patients, but we know that physical activity is very important," Moholdt says.

Get rid of the bathroom scale

She believes that many people start exercising to lose weight, and then quit when they don't get the desired results in the form of weight loss.

Moholdt encourages people to get rid of their bathroom scale. She says that numerous studies have shown that body composition changes through exercise and that muscles weigh more than fat.

"Exercise has a beneficial effect on all organs in the body - on the brain, heart, liver, vascular system and of course on our musculature," she says.

NCI-MATCH (Molecular Analysis for Therapy Choice), the largest precision medicine trial of its kind, achieves a milestone with the release of results from three treatment arms of the trial at the American Society of Clinical Oncology (ASCO) 2018 annual meeting. Spokespersons are available for interviews.

The new results offer findings of interest for future cancer research. They could help identify targeted treatments for patients with certain gene abnormalities regardless of their cancer type. The results are the first of a large trove of data to come from nearly 40 treatment arms in new populations of patients not yet studied in any other clinical trials.

NCI-MATCH is a signal-finding trial for adults who have solid tumors, lymphomas, or myeloma that have progressed on standard treatment or rare cancers for which there is no standard treatment. The trial was co-developed by the National Cancer Institute (NCI), part of the National Institutes of Health, and the ECOG-ACRIN Cancer Research Group, part of the NCI-sponsored National Clinical Trials Network (NCTN). ECOG-ACRIN is leading the trial.

Identify and prioritize treatment options based on a patient's profile of genetic alterations is a major challenge in personalized cancer medicine. Data-driven approaches such as PanDrugs can help to this end. This new computational resource has been developed by researchers from the Bioinformatics Unit at the Spanish National Cancer Research Centre (CNIO) and is described in a paper published in Genome Medicine.

A large majority of cancers carry a long list of genetic alterations whose biological and clinical relevance, and susceptibility to be pharmacologically-targeted isn't always clear. Several tools have been developed to identify clinically actionable genomic alterations and to suggest targeted therapies but they have some limitations and there's still a gap between raw genomic data and clinical usefulness.

To overcome this, researchers lead by Fátima Al-Shahrour, head of the Bioinformatics Unit at the CNIO, have implement this novel method called PanDrugs. "The main novelty introduced in this methodology compared with current tools is the broadening of the search space to provide therapeutic options", explains Al-Shahrour.

In other words, PanDrugs suggests treatments for direct targets (e.g. genes that contribute to disease phenotype and can be directly targeted by a drug) and biomarkers (e.g. genes that have a genetic status associated with drug response but the protein product is not the drug target itself). But also, PanDrugs integrates a systems biology knowledge-based layer that automatically inspects biological circuits expanding cancer candidate therapies from beyond limited cancer-related gene lists to the whole druggable pathway.

"This novel strategy (called 'pathway member') extends the treatment opportunities of cancer patients by enriching the therapeutic arsenal against tumours and opens new avenues for personalized medicine", states Al-Shahrour. Thanks to pathway member strategy, the paper describes how PanDrugs is able to identify treatments used in clinical practice that might benefit prostate, breast and colorectal cancer patients without druggable cancer driver altered genes.

Researchers emphasize that PanDrugs database represents, by itself, a remarkable contribution. "This database is the largest public repository of drug-target associations available from well-known targeted therapies to preclinical drugs. Current version of PanDrugsdb integrates data from 24 primary sources and supports >56000 drug-target associations".

PanDrugs can be fully integrated with custom pipelines through its programmatic API and its docker image facilitates PanDrugs in-house installation, enhancing reproducibility and improving performance. PanDrugs and PanDrugsdb are open-source and fully available at http://www.pandrugs.org.

Women who are obese and who have been metabolically healthy for decades are still at higher risk of developing cardiovascular disease compared to metabolically healthy women of normal weight, according to an observational study that followed over 90000 American women for up to 30 years, published in The Lancet Diabetes & Endocrinology journal.

The findings indicate that obesity is a risk factor for cardiovascular disease, regardless of whether or not women develop any of the common metabolic diseases such as high blood pressure or type 2 diabetes.

The study also found that the majority of metabolically healthy women are likely to become metabolically unhealthy over time, even if they were normal weight.

"Our large cohort study confirms that metabolically healthy obesity is not a harmless condition, and even women who remain free of metabolic diseases for decades face an increased risk of cardiovascular events," explains Professor Matthias Schulze from the German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany, who led the research. [1]

"What's more, we observed that most healthy women are likely to develop type 2 diabetes, high blood pressure, or high cholesterol over time, irrespective of their BMI, putting them at much higher risk for cardiovascular disease." [1]

Obesity (BMI of more than 30kg/m²) affects almost all of the cardiovascular disease risk factors, particularly those related to metabolic syndrome including high blood pressure, poor blood sugar control or diabetes, and abnormal blood fats, which double the risk of cardiovascular disease such as heart attacks and stroke. However, some people with obesity seem to be free of these metabolic abnormalities - estimates suggest as many as a third of obese people might be metabolically healthy.

Whether this so called 'metabolically health obesity' is associated with a higher risk of cardiovascular disease has been hotly debated for many years. It remains unclear how changes or maintenance of metabolic status affect the development of cardiovascular disease in both normal weight and overweight/obese individuals.

To investigate this further, Schulze and colleagues examined the association between obesity and cardiovascular disease incidence in 90257 women (initially free from cardiovascular disease) from the Nurses' Health Study - a study tracking the health of female nurses (aged 30-55 years) in the USA since 1976.

Participants were divided into groups by BMI category, metabolic health (defined as the absence of three metabolic risk factors - type 2 diabetes, high blood pressure, and high blood cholesterol), and change in metabolic health status, and followed for 30 years between 1980 and 2010. Participants were sent questionnaires every two years to update their BMI and metabolic health status, as well as to assess their lifestyle, health behaviour, and medical history.

The researchers adjusted for a range of factors that may have influenced the results including age, diet, smoking status, physical activity, alcohol consumption, ethnicity or race, highest education level, menopausal status, aspirin use, and family history of heart attack or diabetes.

During an average follow-up of 24 years, 6306 new cases of cardiovascular disease, including 3304 heart attacks and 3080 strokes were recorded.

Cardiovascular disease risk was especially high in all metabolically unhealthy women, regardless of their BMI. Metabolically unhealthy normal weight women were around 2.5 times more likely to develop cardiovascular disease compared to normal weight women with no metabolic abnormalities, whilst those with 'metabolically healthy obesity' were also at higher risk of cardiovascular disease (39% higher risk) [2].

Importantly, the majority of women who were initially metabolically healthy obese (84%), and around two-thirds (68%) of normal weight metabolically healthy women, converted to unhealthy phenotypes over 20 years.

Furthermore, even women who maintained metabolically healthy obesity over 20 years still had a 57% higher risk of developing cardiovascular disease compared with normal weight metabolically healthy women [3].

"Long-term maintenance of metabolic health is a challenge for overweight/obese, but also for normal-weight women," says Professor Schulze. "Our findings highlight the importance of preventing the development of metabolic diseases, and suggest that even individuals in good metabolic health may benefit from early behavioural management to improve their diet and increase physical activity in order to guard against progression to poor metabolic health." [1]

The authors acknowledge that their findings show observational associations rather than cause and effect. They note some limitations, including that the study included mainly women of European descent, so the findings cannot be generalised to other ethnic groups and men; and that their definition of metabolic health (the absence of three metabolic diseases), may identify a different subgroup than in other studies. However, key strengths include the large cohort, repeated measurements, and long follow up time.

Writing in a linked Comment, Professor Carl Lavie from the University of Queensland School of Medicine, New Orleans, USA and colleagues discuss whether fitness is more important than fatness, pointing out that, "Those with metabolically healthy obesity and decent levels of cardiorespiratory fitness have a quite good overall prognosis from cardiovascular disease and overall survival."

He adds: "Drastic efforts are needed to prevent obesity in the first place and, especially, to prevent conversion to more severe degrees of obesity and the metabolic syndrome. Public health policies aiming to increase cardiorespiratory fitness through physical activity and exercise will further contribute to improve people's health. It is prudent to remind ourselves that an ounce of prevention is better than a pound of cure."

The pitch of new mothers' voices temporarily drops after they have had their first baby, according to a new longitudinal study by Dr Kasia Pisanski, Kavya Bhardwaj, and Prof David Reby at the University of Sussex.

The researchers analysed women's voices over a 10-year period - five years before and five years after childbirth - and found that new mothers' voices get lower, and become more monotonous after pregnancy. This 'vocal masculinising' is not caused by aging, as the voice reverts to its previous frequency one year later.

Dr Kasia Pisanski led the research at the University of Sussex's School of Psychology. She said:

"We found that women's voices become lower-pitched and more monotonous after giving birth. One possible explanation is that this is caused by hormone changes after childbirth. Previous research has shown that women's voices can change with fertility, with pitch increasing around the time of ovulation each month, and decreasing following menopause. We know that after pregnancy, there's a sharp drop in the levels of key sex hormones, and that this could influence vocal fold dynamics and vocal control.

"This effect could also be behavioural. Research has already shown that people with low-pitched voices are typically judged to be more competent, mature, and dominant, so it could be that women are modulating their own voices to sound more authoritative, faced with the new challenges of parenting. Additionally, new mums often experience increased mental and physical fatigue, as well as changes in mood and self-perception. This could be reflected in their voices, although given all we know about the impact of hormones and social context on vocal pitch, it's unlikely that this effect is due just to tiredness alone.

"Our results show that, despite some singers noticing that their voices get lower while pregnant, the big drop actually happens after they give birth.

"We analysed voice recordings of natural, free speech during interviews between the mothers and other adults rather than direct speech to their babies, as we know that parents often artificially raise the pitch of their voice when talking to newborns."

The study sample included 20 mothers (and 20 age-matched controls who had never given birth), whose voice recordings were obtained from archives. This allowed the researchers to analyse free speech before, during and after pregnancy. The University of Sussex psychologists analysed 634 interview clips - equivalent to 277 minutes of audio.

Taking an average, the study found that women's mean voice pitch dropped by over five percent, equivalent to more than one piano note. That's about 15 Hz, or 1.3 semitones. The 'highest' (maximum) pitch of their voices also dropped, by 44 Hz or 2.2 semitones on average. That's more than two piano notes. The researchers also found that there was less variation in voice pitch after childbirth, meaning that the new mothers' voices became both lower pitched, and more monotonous.

Given that a person's voice pitch can affect how they are perceived by others, and can even predict how successful they are in social situations - from a job interview to a first date - postpartum changes in women's voices could influence their social interactions. The academics were inspired to undertake this study after hearing anecdotally that the voices of singers and actresses lower after pregnancy. The next step in this line of research is to test whether postpartum voice changes influence listeners' social judgments of new mothers.

Among women planning to conceive after a pregnancy loss, those who had sufficient levels of vitamin D were more likely to become pregnant and have a live birth, compared to women with insufficient levels of the vitamin, according to an analysis by researchers at the National Institutes of Health. This study appears in The Lancet Diabetes & Endocrinology.

"Our findings suggest that vitamin D may play a protective role in pregnancy," said the study's principal investigator Sunni L. Mumford, Ph.D., in the Epidemiology Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).

The authors note that a few studies have shown that women who have higher levels of vitamin D before undergoing in vitro fertilization have higher pregnancy rates than those with lower levels. However, little research has been done on pregnancy rates and pregnancy loss in women attempting to conceive without assisted reproductive technologies.

The researchers analyzed data collected as part of the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial, which sought to determine if daily low-dose aspirin (81 milligrams) could prevent miscarriage in women with a history of pregnancy loss. Blood levels of vitamin D were tested for roughly 1,200 women before pregnancy and again at the eighth week of pregnancy. Researchers defined a vitamin D level of below 30 nanograms per milliliter as insufficient.

Women who had sufficient preconception vitamin D concentrations were 10 percent more likely to become pregnant and 15 percent more likely to have a live birth, compared to those with insufficient concentrations of the vitamin. Among women who became pregnant, each 10 nanogram per milliliter increase in preconception vitamin D was associated with a 12-percent lower risk of pregnancy loss. Vitamin D levels in the eighth week of pregnancy were not linked to pregnancy loss.

The authors note that the study does not prove cause and effect. Additional studies are needed to determine whether providing vitamin D to women at risk for pregnancy loss could increase their chances for pregnancy and live birth.