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Excess weight at age 3 years was associated with a higher risk of being overweight or obese at age 15 years in a study of adolescents in Japan.

In the Pediatric Obesity study of 1,581 mother-child pairs, pre-pregnancy overweight/obesity in mothers was also a strong predictor of overweight/obesity at age 15 years in children.

After adjustments, being overweight or obese at age 3 years was linked with a more than 4.2-times higher risk of overweight/obesity at age 15 years, and overweight/obesity in mothers was linked with a more than 2.4-times higher risk. Investigators did not find an association between birth weight and overweight/obesity during adolescence.

"Because family members often share a common lifestyle, interventions for parents and children may be necessary to prevent obesity in adolescents," said first author Satomi Yoshida, PhD, of Kyoto University.

Overweight and obesity were associated with higher risks of several common cancers in a 40-year, nationwide Danish study.

In the Journal of Internal Medicine study, there were 20,706 cancers among 313,321 adults diagnosed with overweight and obesity compared with 18,480 cancers that were expected based on information from the general population. This corresponds to a 12% higher risk associated with overweight and obesity.

Having type 2 diabetes or alcoholism-related diseases in addition to overweight or obesity was linked with even higher risks.

The increased risk was seen for cancers previously identified as obesity-related, including pancreatic and postmenopausal breast cancers, as well as for blood and neurological cancers.

Use of antipsychotic medications was associated with an increased risk of head injuries in a study of individuals with Alzheimer's disease. The findings are published in the Journal of the American Geriatrics Society.

The nationwide study of individuals in Finland who were diagnosed with Alzheimer's disease from 2005 to 2011 included 21,795 patients who started taking antipsychotic medications and 21,795 patients who did not. Use of antipsychotic medications was linked with a 29% higher risk of head injuries--the "event rate" was 1.65 vs. 1.26 per 100 person-years in users vs. non-users. (This means there would be an average of 1.65 vs. 1.26 injuries among 100 people over one year. This translates to 165 vs. 126 injuries per 10,000 people.) Also, use of antipsychotic medications was linked with a 22% higher risk of traumatic brain injuries--0.90 vs. 0.72 per 100 person-years.

When comparing antipsychotic medications, quetiapine users had 60% higher risk of traumatic brain injuries compared with risperidone users.

"Persons with Alzheimer's disease have a higher risk of falling, head injuries, and traumatic brain injuries and worse prognosis after these events in comparison to those without Alzheimer's disease.Therefore, it is important to avoid further increasing risk with antipsychotics in this vulnerable population, if possible," said lead author Vesa Tapiainen, MD, of the University of Eastern Finland.

HOUSTON -- A study at The University of Texas MD Anderson Cancer Center demonstrated a potential new approach to treating two of the most common subtypes of lymphoma through manipulation of molecular programs controlled by the cAMP-response element binding protein (CREBBP). Mutations of CREBBP are frequently found in follicular lymphoma and diffuse large B-cell lymphomas (DLBCL), and allow malignant cells to hide from the immune system.

Study results were published in the Jan. 8 online issue of Cancer Discovery. Co-lead investigators, Michael Green, Ph.D., assistant professor of Lymphoma & Myeloma at MD Anderson and Ari Melnick, M.D., of Weill Cornell Medical School, reported on how inhibition of a protein called histone deacetylase 3 (HDAC3) restores immune programs lost as a result of CREBBP mutations, paving the way for potential immunotherapy approaches for common forms of non-Hodgkin lymphoma.

CREBBP is the second most frequently mutated chromatin-modifying gene in both follicular lymphoma and DLBCL. It encodes a protein that alters the activity of genes by modifying the histone proteins around which DNA is wrapped.

"CREBBP mutations are highly recurrent in B-cell lymphomas and either inactivate its histone acetyltransferase (HAT) domain or truncate the protein," said Green." We showed that these two classes of mutations yield different degrees of disruption of the epigenome, with HAT mutations being more severe and associated with inferior clinical outcome."

Through CRISPR/Cas9 gene editing of cell lines and using mouse models, the research team also showed that HDAC3 selective inhibitors reverse aberrant epigenetic programming caused by CREBBP resulting in growth inhibition of lymphoma cells and restoration of immune surveillance.

"Our study characterized the molecular consequences of CREBBP mutations and identified key cellular pathways silenced as a result of unopposed HDAC3 activity," said Green. "We demonstrated how inhibition of HDAC3 restores these pathways, suppressing growth and most critically enabling T cells to recognize and kill lymphoma cells."

HDAC3 inhibitors appear to affect expression of major histocompatibility molecular class II (MHC class II), molecules, which are antigen presentation proteins crucial for initiating adaptive immune responses.

"The frequency of MHC class II loss in DLBCL exceeds the frequency of CREBBP mutations in this disease through unknown mechanisms," said Green. "The ability of HDAC3 inhibition to induce MHC class II expression may have potentially broad implications for immunotherapy. We believe that inhibition of HDAC3 represents a novel mechanism-based immune-epigenetic therapy for CREBBP- mutant lymphomas."

Aurora, Colo. (Jan. 8, 2020) - The Lancet Infectious Diseases recently published the results of an observational study led by researchers on Children's Hospital Colorado Infectious Disease and Neurology teams, along with counterparts at the Centers for Disease Control and Colorado Department of Public Health and Environment. The study was conducted from March 1 to November 30, 2018, and led to a discovery of the largest outbreak of enterovirus A71 (EV-A71) in the United States.

Since the 1990s, every 1 to 3 years, EV-A71 has caused large-scale, and sometimes deadly epidemics in the Asia-Pacific region, which has prompted the development of EV-A71 vaccines. In the United States, detections of this virus have been small-scale and sporadic. However, the unique symptoms, unusually high number of cases, and the geographic clustering of children who were observed during this study, indicated an outbreak.

"We need to watch this very closely," said Kevin Messacar, MD, pediatric infectious disease physician and researcher at Children's Hospital Colorado and University of Colorado Anschutz Medical Campus . "Enhanced surveillance is needed in order to determine whether this outbreak was an isolated event, or a warning of impending cyclic outbreaks of EV-A71 neurological disease in the U.S."

In addition to highlighting the need to improve enterovirus surveillance, the observational study also helped identify what other medical providers should be looking for. Children with EV-A71 disease were best differentiated from children with other enteroviruses by the neurological findings of myoclonus (quick, involuntary muscle jerks), ataxia (dizziness), weakness and autonomic instability (dysregulation of heart rate, blood pressure and perfusion). Often times these symptoms can be misunderstood or misattributed to other diagnoses - especially among young children.

Finally, it's important to note that these viruses tend to appear in seasonal waves. If through additional surveillance efforts, the United States continues to see enteroviruses circulating that cause neurological illness, the development of antivirals and vaccines may need to become a priority.

"Were it not for Children's Hospital Colorado's ongoing interest and commitment to the study of enteroviruses, this outbreak would probably not have been detected," noted Drs. Carol Glaser and Mike Wilson in a commentary published alongside the Lancet study. "The USA has yet to have large-scale epidemics of enteroviruses as are seen in Asia and other countries, but it should take steps to become better prepared."

Washington (January 8, 2020) - Parents who worry their child with celiac disease may be exposed to gluten at school might be able to strike two common school substances -- Play Doh and dry, uncooked pasta -- from the exposure risk list, as long as children don't consume them. A study from Children's National Hospital published in the Journal of Pediatric Gastroenterology and Nutrition found no significant gluten transfer on hands or surfaces after children used these items for classroom and sensory play.

Other common school supplies and activities such as paper mache and baking projects with flour-based dough were associated with gluten transfer. However, gluten residue was not detected when hands and play surfaces were cleaned through basic hygiene including handwashing and routine surface cleaning.

"We've coached families for many years to avoid kids touching any gluten containing school supply, which can be challenging, especially for young children, including my own," says Vanessa Weisbrod, executive director of the Celiac Disease Program at Children's National Hospital, who conceived and led the study. "These findings make an easy distinction--school supplies that are dry and not sticky show very low gluten transfer, while those that were wet and pasty cling heavily to hands and table surfaces. In all cases, good hand hygiene and cleaning surfaces after using gluten-containing materials can prevent most gluten transfer."

The authors tested five scenarios commonly taking place in schools where it was thought gluten transfer could be high enough to pose a risk for someone with celiac disease. Gluten transfer was quantified by measuring the amount of gluten in an entire slice of gluten-free bread handled by the child or wiped on the play surfaces, both before and after cleaning. In general, products containing greater than 20 parts per million (ppm) or .002% gluten are considered unsafe for patients with celiac disease.*

The study found negligible gluten transfer in two scenarios:

Play-Doh: After five minutes of play, none of the samples rubbed on the hands of children had gluten transfers above the 20ppm threshold. Only two slices of bread tested above the 20 ppm threshold when rubbed on table surfaces. Both of these slices had visible pea-sized pieces of Play-Doh adhered to them.

Dry pasta in a sensory table: All samples (hands and surfaces) contained less than 20 ppm gluten, and 9 out of 10 samples were under 5 ppm after five minutes of play.
School scenarios where significant gluten transfer was detected included:

Home economics baking project: Both hands and workspaces used to roll out flour-containing cookie dough transferred potentially clinically significant amounts of gluten to bread --well above the assay's upper limit quantification of 84 ppm.

Paper mache balloon art: Even after hands and surfaces dried, gluten transfer after this activity was high, mostly above 84 ppm.

Cooked, dyed pasta in a sensory table: After five minutes of play with cooked pasta gluten transfer resulted in concentrations of more than 20ppm gluten, with most samples exceeding 84 ppm.

*U.S. Food and Drug Administration regulations allow foods with less than 20 parts per million of gluten to be labeled "gluten-free." It is not possible to detect zero ppm--the lowest detected level is 3 ppm (.0003%).

"These methods provide a realistic estimate of the risk to children with celiac disease using gluten-containing school supplies," notes Jocelyn Silvester, M.D., Ph.D., director of Research for the Celiac Disease Program at Boston Children's Hospital and a co-author on the study. "Now we can give evidence-based recommendations to families and schools, so that they can focus on what is most important to keep children with celiac disease safe."

"Educators are very aware of our additional responsibility to keep students safe during every learning experience at school," says Amy Damast, Ph.D., Director of Early Childhood Education and Family Engagement at the Temple Sinai Early Childhood Education Program and study co-author. "These study findings should reassure us all that routine, careful handwashing and surface-cleaning methods will keep children with celiac disease safe and healthy, while allowing them to participate in more activities that may involve gluten-containing materials. This study is a win for the students and their schools."

Clean hands and surfaces matter most

Following the Play-Doh and home economics baking project, the team also tested the effectiveness of three cleaning methods at removing gluten particles. All three--handwashing with just water, handwashing with soap and water, or thorough wiping with an antibacterial hand wipe--demonstrated the ability to effectively remove gluten.

"Whether you're protecting from bacteria or gluten, handwashing and surface hygiene are key," says Weisbrod. "As parents we want to do everything we can to keep our kids safe and healthy, and this study definitely shows that the number one thing we can do is teach our kids to wash their hands!"

"The presence of gluten in schools poses a potentially serious health concern for students with celiac disease, both in long-term health complications and in debilitating acute symptoms at the time of exposure, seriously inhibiting a student's ability to succeed at school," says Marilyn G. Geller, chief executive officer of the Celiac Disease Foundation, which funded the study. "The Celiac Disease Foundation is proud to partner with Children's National Hospital and sponsor research that defines the risk of gluten contamination in everyday school supplies."

Offering HIV screening to new patients in general practice on a routine basis increases testing rates and improves detection and earlier diagnosis, research co-led by Queen Mary University of London and UCL suggests.

HIV testing rates in general practice are low, despite testing being recommended in UK and international guidelines. Lack of testing leads to later HIV diagnosis, poorer clinical outcomes and higher care and treatment costs. It can also increase the chances of an individual passing on the virus.

A paper published in EClinicalMedicine today examines the impact of implementing HIV screening using one-off training for staff, reflecting 'real-world' conditions in 13 east London GP practices.

It compares outcomes with those recorded in the same team's earlier randomised control trial in which staff from 20 practices received initial training plus regular support. The initial trial, which ran between 2010 and 2012, found the approach increased both the number of HIV tests and the number of diagnoses. CD4 counts at diagnosis were high - suggesting that the infection was picked up when the immune system was still healthy.

The study team believes this new analysis is the first comparing results of 'real-world' implementation of nurse-led HIV screening in routine primary care with those of a trial, as well as with practices that received no intervention (the comparator group).

This analysis showed outcomes achieved from routine implementation were comparable to those achieved in the randomised control trial: increased HIV testing rates, resulting in more and earlier diagnoses. The rise in new diagnoses in both practice groups was higher than in a comparator group of ten practices that received no training or support.

All the practices were within the City and Hackney Clinical Commissioning Group area.

People diagnosed during the 'routine implementation' period had average CD4 scores at diagnosis of 425 cells/micro litre - higher than the 351 recorded during the initial trial period and the 327 recorded for newly-diagnosed patients of the comparator group of practices.

HIV testing was 55% higher in implementation practices than comparator practices, diagnosis rates were 106% higher and CD4 count at diagnosis was typically 35% up. The researchers caution that the wide range in confidence levels around data, mean the results on the latter two outcomes are suggestive but not conclusive.

Importantly, most of the new diagnoses were among people in groups at the highest risk of late diagnosis - heterosexuals, and black African and Caribbean adults. Both those groups are under-represented at sexual health services where they would be offered HIV testing - which can mean they are diagnosed later.

The 13 practices did not receive the regular support from the research team enjoyed by the trial practices so the team could study the impact when practices made screening part of their routine registration of new patients.

Study co-lead Dr Werner Leber, a GP and clinical lecturer in primary care at Queen Mary University of London, said the 'implementation phase' confirmed that practices could successfully integrate HIV screening - particularly of new patients - into business as usual.

Dr Leber said: "During our initial research study we found that offering HIV tests to new patients did pick up previously undiagnosed cases of HIV. The data collected outside the clinical trial environment and published today shows that the intervention is effective in routine care within modern GP practices."

The study was funded by the National Institute for Health Research through the NIHR Applied Research Collaboration (ARC) North Thames (formerly NIHR CLAHRC North Thames).

Study co-lead Dr Jasmina Panovska-Griffiths, a Senior Research Fellow and Lecturer at UCL, said: "Our study shows that implementation of nurse-led HIV screening in general practices can be delivered effectively, leading to increased HIV testing that may be associated with increased and earlier HIV diagnosis. It also appears that most of the new diagnoses are amongst people who are less likely to attend sexual health services where they would be offered HIV testing."

Professor Chris Griffiths, Director of the Institute of Population Health Sciences at Queen Mary, said: "General practices across London and in urban areas with higher HIV prevalence in the UK and beyond need urgently to implement HIV screening in routine care. Screening is a key tool which can help realise the goal of eradicating HIV."

Professor Rosalind Raine from UCL and Director of NIHR ARC North Thames, said: "We were delighted to be able to fund this research, which has important implications for people, populations and health care systems internationally. People, particularly those from at risk key populations, are likely to benefit from increased access to testing in a familiar primary care setting with links to prompt treatment and care for those testing positive."

SEATTLE - Road injuries have become more frequent but less fatal over the past three decades, according to a new scientific study.

The probability of dying from a road accident increased in only five nations since 1990 - Central African Republic, Jamaica, Somalia, Swaziland, and United Arab Emirates.

Disability from road injuries is multifactorial, and largely driven by injuries such as lower limb fracture, traumatic brain injury, open wounds, digit amputations, and muscle and tendon injuries. These conditions often require medical treatment to prevent long-term disability, which is not always available in areas with high rates of road injuries.

"Many factors affect the risk of road injuries, including vehicle and road safety and engineering; enforcement of speeding, seatbelt, and alcohol laws; and access to medical care," said Dr. Spencer James, senior author on the study and Lead Research Scientist at the Institute for Health Metrics and Evaluation (IHME) at the University of Washington School of Medicine. "It's encouraging to find improvements globally in road injury mortality over the past three decades, though there is still considerable progress to be made since road injuries should be considered preventable."

In 2017, 54 million people worldwide were injured in road accidents, leading to 1.2 million deaths. Regions with the highest incidence rates in 2017 were Central Europe, Australasia, and Eastern Europe.

Road injuries become more burdensome as countries transition to more stable economies, according to James. He and the study's coauthors found middle-income nations experienced the greatest increases in incidence between 1990 and 2017.

Men ages 25-29 are most likely to be injured, with a global incidence rate that is more than double the rate for women in the same age group.

Published today in the international medical journal BMJ Injury Prevention, the study is part of the annual Global Burden of Disease (GBD). The analysis provides comparable estimates of road-injury-related mortality and morbidity across 195 countries and territories. Road injuries were defined as involving motor vehicles, pedestrians, motorcyclists, and cyclists.

"While individuals injured in road accidents today are less likely to die, their injuries can still result in short- and long-term disability," said James. "This places a substantially higher burden on both individuals and health systems, with especially dramatic increases in costs related to care."

Additional findings include:

Globally, the incidence rate for road injuries for all ages combined increased by 15.7% from 1990 to 2017.

The greatest increases in the all-ages incidence rate during the time period were observed in Sri Lanka (143.3%), China (130.3%), and Marshall Islands (121.5%).

By comparison, Portugal, Ethiopia, and South Korea saw the largest declines in the all ages incidence rate, at -40.9%, -38.3%, and -35.9%, respectively.

In 2017, the probability of dying from a road injury was highest in Haiti (15.6% of those injured, or about one in seven), Central African Republic (10.4%), El Salvador (7.3%), Afghanistan (7.2%), and Guatemala (7.0%).

For males aged 20-24 and 25-29, global incidence rates were double those for females.

Among females ages 20-24, the rate was 585.8 new cases of road injury per 100,000, versus 1,229.2 for males. Among 25-29 year-olds, the female rate was 660.5, versus 1,354.0 for males.

At 261,802 deaths in 2017, China ranked highest globally in number of total deaths, but 48th out of 195 countries in terms of death rate for all ages combined.

ROAD INJURY DEATH RATES, 195 COUNTRIES AND TERRITORIES, 2017

Highest death rates:

1. Central African Republic: 75.6 deaths per 100,000 people (all ages combined)

2. Oman: 43.0

3. Lesotho: 41.2

4. Haiti: 37.9

5. United Arab Emirates: 37.5

6. Saudi Arabia: 35.0

7. Swaziland: 33.0

8. Tunisia: 32.1

9. Yemen: 31.4

10. Papua New Guinea: 30.7

Lowest death rates:

1. Singapore: 3.53 deaths per 100,000 people (all ages combined)

2. Ireland: 3.86

3. Sweden: 3.88

4. Switzerland: 3.89

5. Malta: 3.97

6. United Kingdom: 4.02

7. Norway: 4.09

8. Iceland: 4.24

9. Greenland: 4.28

10. Andorra: 4.67

RISK OF DEATH GIVEN A ROAD INJURY, 2017

Highest risk of death given a road injury:

1. Haiti: 15.6% of road injuries resulted in death

2. Central African Republic: 10.4%

3. El Salvador: 7.3%

4. Afghanistan: 7.2%

5. Guatemala: 7.0%

6. Bolivia: 6.8%

7. Ecuador: 6.7%

8. Burkina Faso: 6.5%

9. Guyana: 6.4%

10. Dominican Republic: 6.1%

Lowest risk of death given a road injury:

1. Slovenia: 0.44% of road injuries resulted in death

2. New Zealand: 0.45%

3. Switzerland: 0.49%

4. Czech Republic: 0.51%

5. Ireland: 0.52%

6. Singapore: 0.52%

7. Iceland: 0.55%

8. Andorra: 0.56%

9. Croatia: 0.57%

Starting HIV antiretroviral therapy (ART) within hours of birth has been hypothesized to have positive effects raising the possibility of remission in some children with HIV. To test the hypothesis, researchers at Columbia Mailman School of Public Health and Columbia University Irving Medical Center designed a trial in a group of newborns with HIV who started ART within 14 days of birth. The results showed that about 75 percent of infants attained viral suppression on ART; but only 52 percent attained and sustained viral suppression on ART. The success of attaining and sustaining viral suppression was similar in the 46 infants starting ART less than two days old (51 percent) and the 27 infants starting therapy between 2 and 14 days after birth (54 percent). The findings are published online in E-Clinical Medicine.

"The results of our trial suggest that very early treatment in newborns may not have to mean within hours of birth," said Louise Kuhn, PhD, Columbia Mailman School professor of epidemiology (in the Sergievsky Center). "We learned that we must be more attune to basing decisions about how quickly to start ART on optimizing maternal adherence with treatment rather than with just focusing on speed. While we certainly do not want to introduce undue delay, starting ART within the first two weeks of life led to similar outcomes to starting within the first two days of life."

The study was designed shortly after the report of the infant in Mississippi who started antiretroviral treatment within 30 hours of birth and who was able to maintain viral suppression off treatment for over two years. This case report led to optimism that ART started within hours of birth may lead to protection of critical immune processes and smaller viral amounts, making possible remission in a sizable minority of infants treated in this way. "The outcome in Mississippi raised the tantalizing possibility that we may be able to facilitate remission in infants if we start ART very early in life," noted Kuhn.

To yield the target population for the trial, clinical protocols were established at Rahima Moosa Mother and Child Hospital (RMMCH), Johannesburg, South Africa. The analysis included 73 children who were born between March 1, 2015 and September 30, 2017 with confirmed HIV infection and ART initiated within 14 days. The initial ART regimen consisted of nevirapine, lamivudine and zidovudine; nevirapine was replaced with lopinavir-ritonavir once the child reached 42 weeks post-menstrual age, usually about 4 weeks of age in calendar time. ART was initiated based on results of the first round of diagnostic testing and was continued throughout the study.

Of those surviving during the study, 75 percent attained viral load

"Viral suppression rates, especially to more stringent cut-offs than required by our protocol were lower than expected, and we concluded that very early ART on its own, with routinely-available regimens, is unlikely to lead to remission in a sizable minority of early-treated infants," said Kuhn. This is most likely explained by the significant challenges of adequate maternal adherence with ART for neonates and infants including major practical difficulties of sustaining adherence with twice-daily, poorly-palatable liquids for infants. Moreover, most of the study participants' caregivers live in impoverished economic circumstances with complex social problems and experience a high degree of HIV-related stigma.

"We need to find interventions to treating newborns that are reasonable for mothers to fully adhere to," said Kuhn. Long-acting formulations and/or alternative interventions may be more adherence-friendly and need to be investigated. These may enable more rapid and sustained viral control and immune recovery in a larger proportion of early treated infants as a stepping stone to achieve remission.

What The Study Did: This randomized clinical trial examined the effects of daily folic acid and zinc supplementation in men on semen quality and live births among 2,300 couples planning infertility treatment.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

Authors: Enrique F. Schisterman, Ph.D., of the Eunice Kennedy Shriver National Institute of Child Health and Human Development in Bethesda, Maryland, is the corresponding author.

(doi:10.1001/jama.2019.18714)

Editor's Note: The article includes conflict of interest and funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

What The Study Did: This study assessed changes between 2008 and 2018 in the rate of cesarean deliveries in China.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

Authors: Jian-meng Liu, Ph.D., of the Peking University Health Science Center in Beijing, is the corresponding author.

(doi:10.1001/jama.2019.17595)

Editor's Note: The article includes funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

CHAMPAIGN, Ill. -- Scientists have developed new drug compounds that thwart the pro-cancer activity of FOXM1, a transcription factor that regulates the activity of dozens of genes. The new compounds suppress tumor growth in human cells and in mouse models of several types of human breast cancer.

The researchers report their findings in the journal NPJ Breast Cancer.

FOXM1 is a naturally occurring protein that ramps up the expression of genes that are important to cell proliferation and development. It plays an important role during early development, but normally is present only at very low levels in adult tissues.

The researchers focused on FOXM1 because it is found in higher abundance in cancer cells than in healthy human cells, said Benita Katzenellenbogen, a University of Illinois professor of molecular and integrative physiology who led the study with U. of I. chemistry professor John Katzenellenbogen and life sciences research specialist Yvonne Ziegler.

"FOXM1 is a key factor that makes breast cancer and many other cancers more aggressive and more difficult to treat," Benita Katzenellenbogen said. "Because it is a master regulator of cancer growth and metastasis, there has been great interest in developing compounds that would be effective in blocking it."

So far, no successful drug agents have been developed to reduce the effects of FOXM1, John Katzenellenbogen said.

"There are reports of other inhibitors of FOXM1, but these are generally less potent and do not work well in the body," he said. "Our compounds have good anti-tumor activity in animal models. They behave well in vivo and have long half-lives in the blood. Some work well when given orally, which is desirable for ultimate patient use."

The researchers developed the new drugs by analyzing the properties of various compounds in a chemical library of potentially therapeutic agents. They selected those that reduced breast cancer cell proliferation and inhibited the expression of genes known to be regulated by FOXM1.

The team then modified the compounds to enhance their inhibition of FOXM1 and increase their cellular potency. Three of the tested compounds performed best.

"We found that these compounds inhibit the growth of breast cancer cells that represent the major subtypes of breast cancers, including estrogen receptor-positive, HER2-positive and triple-negative breast cancers," Benita Katzenellenbogen said. "They also block the growth of human breast tumors in mouse models."

The research is promising, but preliminary, the scientists said. Full development of new anti-cancer drug agents can take more than a decade from this stage of discovery.

"Because cancers are often treated with a combination of drugs, we are exploring how our FOXM1 inhibitors might be combined with other standard-of-care agents to improve cancer treatment," Benita Katzenellenbogen said.

A risk-management program set up in 2012 by the U.S. Food and Drug Administration to curb improper prescribing of extended-release and long-acting opioids may not have been effective because of shortcomings in the program's design and execution, according to a paper from researchers at the Johns Hopkins Bloomberg School of Public Health. Extended-release and long-acting opioids, which include oxycontin, account for a significant proportion of the prescription opioid market and are among the most misused.

The paper was published online December 30, 2019 in JAMA Internal Medicine.

For their analysis, the researchers reviewed more than 9,000 pages of internal FDA documents, obtained through a Freedom of Information Act (FOIA) request, on the agency's Risk Evaluation and Mitigation Strategies program for extended-release and long-acting opioids. The authors concluded that the program never had proper evaluation procedures in place--essentially leaving the FDA without critical information about whether the program was working.

In their review, the authors found a number of critical design flaws in the evaluation program, including an over-reliance on surveys rather than other sources of health care information such as clinical records; use of non-representative and self-selected patient and prescriber populations; and a failure to directly link prescribing behaviors with program participation.

"The FDA's Risk Evaluation and Mitigation Strategies program is a primary way to promote the safe use of these medicines, but we found that the mechanisms for assessing the program's effectiveness were deficient from the start," says the paper's senior author Caleb Alexander, MD, professor in the Bloomberg School's Department of Epidemiology and former chair of the FDA's Peripheral and Central Nervous System Drugs Advisory Committee.

The current opioid crisis in the U.S. originated largely from the wide availability and misuse risks of prescribed opioid painkillers. The crisis has now expanded to 50,000 opioid-related overdoses per year and millions of cases of opioid-use disorder. Among the more dangerous prescription opioids are extended-release and long-acting versions of oxycodone, morphine, and other painkillers, designed to deliver opioids into the body over longer periods of time than immediate-release forms of these drugs. Studies suggest that compared to immediate-release forms, extended-release and long-acting opioids are more likely to be used non-medically, and more likely to lead to opioid use disorder as well as overdoses.

To reduce the risks of extended-release and long-acting opioids, the FDA set up a Risk Evaluation and Mitigation Strategies program for these drugs in 2012. It required extended-release and long-acting opioid manufacturers to provide FDA-approved educational materials to both prescribers and patients in order to instruct them on the safe and appropriate use of these products. During the program, extended-release and long-acting opioid manufacturers also were required to monitor and report annually on prescriber knowledge and behavior associated with these drugs, as well as on data related to patient access and safety.

For their study, Alexander and his colleagues obtained via a FOIA request access to over 9,700 pages of internal FDA documents, including annual Risk Evaluation and Mitigation Strategies assessments by manufacturers during 2012-2017 and the FDA reviews of those assessments. The team performed a narrative review, archiving and coding the documents and extracting both quantitative and qualitative information relevant to the design of the Risk Evaluation and Mitigation Strategies program.

The FDA documents suggested that Risk Evaluation and Mitigation Strategies' educational materials were consistent with FDA guidelines. However, the FDA documents also suggested that assessments of the impact of the program were for the most part inadequate. For example, to evaluate whether their prescriber education program was working, FDA conducted cross-sectional surveys of some prescribers that provided snapshots of prescriber awareness of safe extended-release and long-acting practices. Yet, these surveys of select, non-representative groups of prescribers were snapshots and were not designed in a way that could have shown how prescriber awareness changed due to their participation in the Risk Evaluation and Mitigation Strategies educational programs.

Similarly, patient surveys were not representative of individuals using extended-release and long-acting products. Moreover, evaluations of extended-release and long-acting prescribing trends and adverse events associated with these drugs were not tied to Risk Evaluation and Mitigation Strategies program prescribers and patients in a way that could have enabled FDA to gauge the program's influence on these trends.

"Opioid manufacturers could have linked participation in the Risk Evaluation and Mitigation Strategies program with information on prescribing and health care utilization in order to understand precisely how the program was affecting prescriber behavior. It's unclear why they never did so," Alexander says. "Such information would have allowed the FDA to better understand how the program was performing and, if needed, make changes to strengthen it."

The FDA itself highlighted several of these problems in their own annual reviews, yet did little to fix them over five years of follow-up, the authors note. In some cases, the agency reacted by scaling back their Risk Evaluation and Mitigation Strategies assessment goals so that they no longer focused on determining the precise impact of the program on measures such as extended-release and long-acting prescribing or adverse events.

"In some cases the FDA identified deficiencies that should have been apparent earlier," Alexander says. "We hope our analyses can serve as the basis for improving the design and conduct of these programs by opioid manufacturers and the FDA to yield accurate and insightful findings regarding both patient and prescriber behavior."

New Rochelle, NY, January 7, 2020--In a radical new approach to treat cocaine addition, researchers at the Mayo Clinic are seeking approval for first-in-human studies of a single-dose gene therapy. To support the safety and efficacy of this approach they have demonstrated the successful delivery of a gene coding for an enzyme that metabolizes cocaine into harmless byproducts in mice. The study is published in Human Gene Therapy, a peer-reviewed journal from Mary Ann Liebert, Inc., publishers. Click here to read the full-text article free on the Human Gene Therapy website through February 7, 2020.

Stephen Brimijoin and colleagues from Mayo Clinic, Rochester, MN, coauthored the article entitled "Systemic Safety of a Recombinant AAV8 Vector for Human Cocaine Hydrolase Gene Therapy: A Good Laboratory Practice Preclinical Study in Mice." In advance of filing for an Investigational New Drug Application with the U.S. Food and Drug Administration, which would allow for human testing, the researchers needed to show the systemic safety of their recombinant adeno-associated viral (AAV) 8 vector, which targets its therapeutic gene payload to the liver. They showed a total lack of viral vector-related adverse effects in both cocaine-experienced and cocaine-naïve mice at different doses. In fact, mice who received the gene therapy followed by daily cocaine injections had much less tissue pathology than those mice who received daily cocaine injections but did not have the gene therapy.

"Substance use disorders present an immense public health problem in the US and other industrialized countries," says Editor-in-Chief Terence R. Flotte, MD, Celia and Isaac Haidak Professor of Medical Education and Dean, Provost, and Executive Deputy Chancellor, University of Massachusetts Medical School, Worcester, MA. "Putting the power of an innovative gene therapy to work on this problem presents an exciting new approach."

London, UK: A meta-analysis published in the journal Cephalalgia, the official journal of the International Headache Society, highlights the predictors of chronic migraine. The study, entitled "Predictors of episodic migraine transformation to chronic migraine: A systematic review and meta-analysis of observational cohort studies", was coordinated by Dr. Dawn Buse, from the Department of Neurology at Albert Einstein College of Medicine, New York, USA.

Chronic migraine is defined by the International Classification of Headache Disorders - ICHD-3 as having headaches for ≥ 15 days per month, for ≥ 3 months, which ≥ 8 days/month are linked to migraine. Several factors have been associated with migraine chronification, such as depression, anxiety, sleep disorders, obesity, other pain disorders comorbidities, allodynia, female sex, medication overuse, coffee, major life events, and low income. However, these studies are not devoid of biases and limitations that may underestimate or overestimate these factors.

In this meta-analysis, Dr. Dawn Buse and colleagues pointed out the main factors contributing to the evolution of episodic migraine to the chronic form. Excluding biases and poor-quality studies, Dr. Buse and her co-authors showed that, significantly, only the following factors were associated with chronic migraine:

Depression

Suffering from depression increases the chances of progressing to chronic migraine by 58 %. This is, in fact, a psychiatric comorbidity widely observed in many other migraine studies.

High Frequency of Attacks

Having ≥ 5 attacks per month increases 3.1 times, while ≥ 10 attacks per month lead to a 5.9-fold increase in the risk for chronic migraine. In fact, these findings raise a permanent debate surrounding the chronic migraine diagnostic criteria. In a comment also published in Cephalalgia (When Does Chronic Migraine Strike?), Dr. Patricia Pozo-Rosich, from the Headache Unit, Neurology Department, Vall d'Hebron University Hospital, Barcelona, Spain, underscores that from the functional and emotional disability perspective, patients with ≥ 10 attacks per month show no difference from chronic migraine patients. In this sense, Dr. Buse also affirms: "An average monthly headache day frequency of 10 days/month is usually considered high frequency episodic migraine, which looks in many ways similar to people with chronic migraine and may be managed in similar ways such as considering preventive therapy and behavioral therapies to treat or prevent poor outcomes in functional and emotional disability."

Medication Overuse

Medication overuse increases the odds of developing chronic migraine by 8.8 times. At this point, the authors stress the need for more vigilance by clinicians on failures of acute medications and medication overuse.

Allodynia

Allodynia is a sensory disorder where innocuous (harmless) stimuli turn out to cause pain. The best-known example is cutaneous allodynia on the scalp when combing becomes a painful act because of scalp sensitivity. In Dr. Buse's study, having allodynia increased the chances of progressing from episodic migraine to chronic migraine by 40%.

Allodynia results from a neurophysiological process called central sensitization, where 2nd and 3rd order neurons in the central nervous system are activated producing exaggerated sensory stimuli, which can make normal stimuli such as touch into painful sensations. Although the magnitude of the allodynia effect was small in this meta-analysis, it makes sense from the pathophysiological viewpoint.

Income

Having an income of ≥ US$ 50,000 reduces the chances of progressing to chronic migraine by 35%. A likely explanation for this fact is that a higher income allows access to information and treatments that prevent migraine chronification.

A final remark from the study's authors addresses the clinical implication of these findings: " Healthcare professionals should remain vigilant for factors that may increase risk the risk of progression to CM among people with EM, including high frequency headache, medication overuse, and depression, and treat these conditions when they encounter them."