Body

Combination checkpoint blockade before surgery (neoadjuvant therapy) produced a high response rate among patients with high-risk stage 3 melanoma, with nearly half having no sign of disease at surgery, but a high incidence of side effects caused the trial to be closed early.

The phase II study was led by researchers at The University of Texas MD Anderson Cancer Center. Results of the study, the first randomized neoadjuvant clinical trial of immune checkpoint blockade for melanoma patients, are reported in Nature Medicine.

Patients received either the PD-1 inhibitor nivolumab or the combination of nivolumab and the CTLA-4 checkpoint inhibitor ipilimumab. Each drug blocks a separate off-switch on T cells, freeing the immune system to attack cancer. All patients received nivolumab after surgery.

On the combination arm, 8 of 11 (73 percent) patients had their tumors shrink, 5 (45 percent) had no evidence of disease at surgery (pathological complete response), and 73 percent had grade 3 side effects, causing dose delays in 64 percent and delaying surgery for some. There were no grade 4 side effects.

In the nivolumab arm, 3 of 12 (25 percent) had their tumors shrink and had pathological complete response, only 8 percent had grade 3 side effects. Two patients progressed to stage 4 metastatic disease before they could get to surgery.

"In this trial, treatment with single-agent anti-PD-1 was associated with modest response rates, and we were concerned that two patients on that arm progressed and could not go to surgery," said co-first author Rodabe Amaria, M.D., assistant professor of Melanoma Medical Oncology. "Treatment with combined checkpoint blockade was much more effective, but at the expense of significant toxicity. It is clear from this trial that we need to further optimize this treatment approach."

All of those who achieved pathological complete response in either arm remain without evidence of disease recurrence. Overall survival was 100 percent at 24 months in the combination arm and 75 percent in the nivolumab arm.

"The advantage of a neoadjuvant approach in this setting is that it enables an interval evaluation of the tumor cells after therapy to determine the extent to which those tumor cells responded to the therapy in real time and predict which patients are likely to experience durable responses going forward. It also provides us the tissue resources to determine why tumors may not respond to therapy and thus tailor therapies going forward as we learn more about resistance," said co-senior author on the study, Michael Tetzlaff, M.D. Ph.D., associate professor of Pathology and Translational and Molecular Pathology.

Checkpoint blockade has been effective against metastatic melanoma and in reducing the risk of relapse after surgery for high-risk stage 3 disease. However, there is evidence in preclinical models that treatment before surgery may be superior to giving these agents in the adjuvant setting (after surgery).

Amaria and senior author Jennifer Wargo, M.D., associate professor of Surgical Oncology and Genomic Medicine, launched the investigator-initiated trial through MD Anderson's Moon Shots Program™, a collaborative effort to accelerate the development of scientific discoveries into clinical advances that save patients' lives.

Due to the results of this study, the team re-designed the study to explore the safety and efficacy of nivolumab plus relatlimab, an inhibitor of the LAG3 immune checkpoint, a combination that Amaria notes thinks may be more effective than nivolumab alone with a better side effect profile than treatment with combined CTLA-4 and PD-1 blockade.

Identifying biomarkers of response and resistance

"This presurgical platform provides an ideal setting to study biomarkers of response, mechanisms of resistance, and differential effects of these two commonly used treatment regimens," said co-first author Sangeetha Reddy, M.D., instructor in Cancer Medicine. "In this study we confirmed known biomarkers of response and observed novel biomarkers of therapeutic response that we are now studying further".

Analysis of biopsies and blood samples taken at multiple time points during the trial revealed:

Baseline infiltration of tumors by lymphoid cells and total mutational burden were associated with response to therapy.

Early on-treatment biopsies were better predictive of who would respond to both therapies compared to baseline biopsies.

Molecular analyses using a novel spatial profiling technology identified differential abundance of multiple immune markers that correlated with response and/or resistance to neoadjuvant immune checkpoint blockade.

T cell receptor sequencing identified differential patterns in responders versus non-responders to anti-PD-1 therapy versus combined CTLA-4 and PD-1 blockade. Responders to PD-1 monotherapy showed evidence of a pre-existing but inhibited T cell repertoire that further expanded during treatment, while treatment with combination therapy was associated with more variable changes in the T cell repertoire.

This trial was performed in parallel to a trial co-led by Christian Blank, M.D., Ph.D., and Ton Schumacher, Ph.D. of the Netherlands Cancer Institute - who tested the use of neoadjuvant versus adjuvant (post-surgical) treatment with combined CTLA-4 and PD-1 blockade in a similar patient population.

"The findings in their trial are provocative, demonstrating that a higher number of tumor-resident TCRs expanded in the peripheral blood of patients receiving neoadjuvant as opposed to adjuvant checkpoint blockade - supportive of what was seen in preclinical models - and suggests that the neoadjuvant approach may be superior." Wargo said.

This MD Anderson-led team is now working with others worldwide in an international neoadjuvant melanoma consortium to harmonize these efforts.

Philadelphia, Oct. 8, 2018--For the first time, scientists have performed prenatal gene editing to prevent a lethal metabolic disorder in laboratory animals, offering the potential to treat human congenital diseases before birth. Published today in Nature Medicine, research from the Perelman School of Medicine at the University of Pennsylvania and the Children's Hospital of Philadelphia (CHOP) and offers proof-of-concept for prenatal use of a sophisticated, low-toxicity tool that efficiently edits DNA building blocks in disease-causing genes.

Using both CRISPR-Cas9 and base editor 3 (BE3) gene-editing tools, the team reduced cholesterol levels in healthy mice treated in utero by targeting a gene that regulates those levels. They also used prenatal gene editing to improve liver function and prevent neonatal death in a subgroup of mice that had been engineered with a mutation causing the lethal liver disease hereditary tyrosinemia type 1 (HT1).

HT1 in humans usually appears during infancy, and it is often treatable with a medicine called nitisinone and a strict diet. However, when treatments fail, patients are at risk of liver failure or liver cancer. Prenatal treatment could open a door to disease prevention, for HT1 and potentially for other congenital disorders.

"Our ultimate goal is to translate the approach used in these proof-of-concept studies to treat severe diseases diagnosed early in pregnancy," said study co-leader William H. Peranteau, MD, a pediatric and fetal surgeon in CHOP's Center for Fetal Diagnosis and Treatment. "We hope to broaden this strategy to intervene prenatally in congenital diseases that currently have no effective treatment for most patients, and result in death or severe complications in infants."

"We used base editing to turn off the effects of a disease-causing genetic mutation," said study co-leader Kiran Musunuru, MD, PhD, MPH, an associate professor of Cardiovascular Medicine at Penn. "We also plan to use the same base-editing technique not just to disrupt a mutation's effects, but to directly correct the mutation." Musunuru is an expert in gene-editing technology and previously showed that it can be used to reduce cholesterol and fat levels in the blood, which could lead to the development of a "vaccination" to prevent cardiovascular disease.

In this study, the scientists used base editor 3 (BE3), which takes clustered regularly interspersed short palindromic repeats (CRISPR), joins it with a modified CRISPR-associated protein 9 to form a partially active version of the CRISPR-Cas 9 tool, and harnesses it as a homing device to carry an enzyme to a highly specific genetic location in the liver cells of fetal mice. The enzyme chemically modified the targeted genetic sequence, changing one type of DNA base to another. BE3 is potentially safer than CRISPR-Cas9, because it does not fully cut the DNA molecule and leave it vulnerable to unanticipated errors when the cut is repaired, as has been seen with the CRISPR-Cas9 tool.

After birth, the mice in the study carried stable amounts of edited liver cells for up to three months after the prenatal treatment, with no evidence of unwanted, off-target editing at other DNA sites. In the subgroup of the mice bioengineered to model HT1, BE3 improved liver function and preserved survival. The BE3-treated mice were also healthier than mice receiving nitisinone, the current first-line treatment for HT1 patients.

To deliver CRISPR-Cas9 and BE3, the scientists used adenovirus vectors, which have often been used in gene therapy experiments. Because previous gene therapy research has shown that adenovirus vectors may cause unintended and sometimes deleterious responses from the host's immune system, the team is investigating alternate delivery methods such as lipid nanoparticles, which are less likely to stimulate unwanted immune responses.

A future direction for the team, in addition to using base editing to directly correct disease-causing mutations, will be to investigate its application to other diseases, including those based in organs beyond the liver.

"A significant amount of work needs to be done before prenatal gene editing can be translated to the clinic, including investigations into more clinically relevant delivery mechanisms and ensuring the safety of this approach," said Peranteau, who added, "Nonetheless, we are excited about the potential of this approach to treat genetic diseases of the liver and other organs for which few therapeutic options exist."

PHILADELPHIA - A new method for sequencing the chemical groups attached to the surface of DNA is paving the way for better detection of cancer and other diseases in the blood, according to research from the Perelman School of Medicine at the University of Pennsylvania published today in Nature Biotechnology. These chemical groups mark one of the four DNA "letters" in the genome, and it is differences in these marks along DNA that control which genes are expressed or silenced.

To detect disease earlier and with increased precision, researchers have a growing interest in analyzing free-floating DNA in settings in which there is a limited amount, such as that extruded from tumors into the bloodstream.

"We're hopeful that this method offers the ability to decode epigenetic marks on DNA from small and transient populations of cells that have previously been difficult to study, in order to determine whether the DNA is coming from a specific tissue or even a tumor." said co-senior author Rahul Kohli, MD, PhD, an assistant professor of Biochemistry and Biophysics, and Medicine.

Researchers from Penn and elsewhere have investigated these DNA modifications over the last two decades to better understand and diagnose an array of disorders, most notably cancer. For the last several decades, the major methods used to decipher the epigenetic code have relied on a chemical called bisulfite. While bisulfite has proven useful, it also presents major limitations: it is unable to differentiate the most common modifications on the DNA building block cytosine, and more significantly, it destroys much of the DNA it touches, leaving little material to sequence in the lab.

The new method described in this paper builds on the fact that a class of immune-defense enzymes, called APOBEC DNA deaminases, can be repurposed for biotech applications. Specifically, the deaminase-guided chemical reaction is able to achieve what bisulfite could do, but without harming DNA.

"This technological advance paves the way to better understand complex biological processes such as how the nervous system develops or how a tumor progresses," said co-senior author Hao Wu, PhD, an assistant professor of Genetics. Kohli's graduate student Emily Schutsky is first author on the study.

Using this method, the team showed that determining the epigenetic code of one type of neuron used 1,000-times less DNA than required by the bisulfite-dependent methods. From this, the new method could also differentiate between the two most common epigenetic marks, methylation and hydroxmethylation.

"We were able to show that sites along the genome that appear to be modified are in fact very different in terms of the distribution of these two marks," Kohli said. "This finding suggests important and distinctive biological roles for the two marks on the genome."

Annals of Internal Medicine Tip Sheet

Below please find summaries of new articles that will be published in the next issue of Annals of Internal Medicine. The summaries are not intended to substitute for the full articles as a source of information.

1. Evidence does not support statin use for conditions other than heart disease

Abstract: http://annals.org/aim/article/doi/10.7326/M18-0808
URLs go live when the embargo lifts

Despite studies suggesting benefits for conditions beyond cardiovascular disease (CVD), the evidence does not support revising current statin prescribing guidelines. Findings from an evidence review and meta-analysis are published in Annals of Internal Medicine.

Statins are a group of medicines commonly used to lower cholesterol levels in the blood and their benefits for reducing the risk of heart disease and stroke are well-established. Some studies have suggested that statins may help patients with non-CVD conditions, but the evidence is not as clear.

Researchers led by the University of Edinburgh analyzed results from 256 studies that had investigated the benefits of taking statins for 278 non-CVD conditions. They found that statins can help to prevent deaths from kidney disease, which is already recognized in clinical guidelines, but there is no clear evidence that statins can help improve kidney function. Researchers also found evidence that statins can help slow cancer progression, but further investigation is needed. Further investigation is also needed to determine how statins affect COBD disease progression and Alzheimer's disease.

According to the study authors, the lack of convincing evidence of an association between statins and non-CVD outcomes supports leaving the current recommendations unchanged.

Media contact: For an embargoed PDF, please contact Lauren Evans at laevans@acponline.org. To interview the lead author Evropi Theodoratou, PhD, please contact Jen Middleton at Jen.Middleton@ed.ac.uk.

2. Fragmented prescribing associated with higher risk for opioid and benzodiazepine overlap

Abstract: http://annals.org/aim/article/doi/10.7326/M18-0852
URLs go live when the embargo lifts

Receiving medications from both the U.S. Department of Veterans Affairs and Medicare Part D, compared to receiving medications from either VA or Medicare alone, is associated with much higher risk of potentially dangerous overlapping of opioid and benzodiazepine prescriptions. Findings from a cross-sectional study are published in Annals of Internal Medicine.

Concurrent use of prescription opioids and benzodiazepines is associated with increased risk for overdose and death. This type of overlap is now cautioned against by opioid product labeling, VA guidelines, and opioid prescribing guidelines from the Centers for Disease Control and Prevention (CDC). It is also measured and tracked by the Pharmacy Quality Alliance. Still, veterans that receive medications from both the VA and Medicare may be at higher risk this type of overlapping.

Researchers from the VA Pittsburgh Health Care System and the University of Pittsburgh studied health records for all veterans (over 360,000 individuals) enrolled in both VA and Medicare Part D who filled at least two opioid prescriptions in 2013 to assess the association between dual use of drug benefits and the receipt of overlapping opioid and benzodiazepine prescriptions. The researchers found that receiving prescription medications from both the VA and Medicare was associated with a 27 percent increased risk for overlapping opioid and benzodiazepine prescriptions and more than twice the risk for overlapping high-dose opioids and benzodiazepines, compared with receiving prescriptions from the VA alone. The more fragmented the prescription use (the more evenly split medications are between VA and Part D), the greater the risk. Receipt of prescriptions from both the VA and Medicare was also associated with greater risk for opioid-benzodiazepine overlap compared with Medicare alone, although the magnitude of the difference was smaller.

According to the researchers, these findings suggest that receipt of medications from more than one health care system is a key risk factor for unsafe prescribing practices.

Media contact: For an embargoed PDF, please contact Lauren Evans at laevans@acponline.org. To interview the lead author, Gellad, Walid, MD, MPH, please contact Allison Hydzik at hydzikam@upmc.edu.

3. About 1.9 million current vapers have never smoked cigarettes

Geographically, Michigan had the highest prevalence of sole e-cigarette users and Alaska had the lowest
Abstract: http://annals.org/aim/article/doi/10.7326/M18-1826
Editorial: http://annals.org/aim/article/doi/10.7326/M18-2581
URLs go live when the embargo lifts

Approximately 1.9 million adults who currently use e-cigarettes have never smoked tobacco cigarettes. Of note, 60 percent of sole e-cigarette users were younger than 25 years old. A brief research report is published in Annals of Internal Medicine. Cigarette smoking is the leading cause of preventable death in the United States. As such, e-cigarette use has increased as a way for people to quit smoking. However, public health authorities worry that the uptake of e-cigarette use among people who have never smoked tobacco may overtake the potential utility of e-cigarettes as smoking cessation aids. Researchers from the American Heart Association used data from the Behavioral Risk Factor Surveillance System 2016 to examine the age distribution, state-level prevalence, health perceptions, and behaviors of U.S. adults who were sole-e-cigarette users. The researchers found that about 1.4 percent of the U.S. adult population were sole e-cigarette users and about 17.7 percent of them vaped daily. Michigan had the highest prevalence of sole e-cigarette users and Alaska had the lowest.

Sole e-cigarette users had a higher prevalence of high-risk lifestyle factors (binge drinking, high risk sexual behaviors, and marijuana use) had worse self-rated mental and physical health compared to nonusers. This is the first study to describe other lifestyle habits of sole e-cigarette users. Prior research has suggested that sole e-cigarette use might serve as a gateway to combustible cigarette smoking or illicit drug user - however, this could be not assessed in this study. Media contact: For an embargoed PDF, please contact Lauren Evans at laevans@acponline.org. To interview the lead author, Michael Blaha, MD MPH, please contact Vanessa McMains, Ph.D. at vmcmain1@jhmi.edu.

4. Lung cancer rates projected to drop dramatically over the next 50 years due to long-standing tobacco control efforts
Abstract: http://annals.org/aim/article/doi/10.7326/M18-1250

URLs go live when the embargo lifts

Tobacco control efforts implemented in the 1960s will continue to reduce lung cancer rates well into the next half-century. Since smoking will also continue to be an important determinant of lung cancer risk, continued policies and measures discouraging the uptake of smoking in youth and to promote cessation among current users will be needed. Findings from a comparative modeling study are published in Annals of Internal Medicine.

Researchers from the Cancer Intervention and Surveillance Modeling Network (CISNET) and the University of Michigan developed four computer models using U.S. data on smoking (1964 to 2015) and lung cancer mortality (1969 to 2010) to project reductions in tobacco use and lung cancer mortality from 2015 to 2065 attributable to existing tobacco control efforts. The models suggest that while lung cancer mortality due to smoking is expected to decrease overall, lung cancer will remain a significant health problem in the United States. Specifically, the number of annual deaths from lung cancer will decrease from 135,000 in 2015 to 50,000 in 2065. Still, 4.4 million deaths from lung cancer are still projected to occur over that same timeframe, with a majority occurring in those who had never smoked.

According to the researchers, these findings suggest that maintaining existing tobacco control efforts will result in considerable reductions in the lung cancer burden in the United States.

Media contact: For an embargoed PDF, please contact Lauren Evans at laevans@acponline.org. To interview the lead author, Rafael Meza, please contact Nardy Baeza Bickel at nbbickel@umich.edu.

Philadelphia, October 8, 2018 - Non-small-cell lung carcinoma (NSCLC) is often fatal because most cases are not diagnosed until they are so advanced that surgical intervention is no longer possible. To improve outcomes researchers are developing a blood test to detect lung cancer earlier in the disease. A report in The Journal of Molecular Diagnostics describes a new technology, electric field-induced release and measurement (EFIRM) that is both highly sensitive and specific in detecting two epidermal growth factor receptor (EGFR) mutations associated with lung cancer in the blood of NSCLC patients with early-stage disease. This platform is relatively inexpensive and capable of high-throughput testing.

Despite advances in chemotherapy, five-year survival for patients diagnosed with unresectable NSCLC is less than 10 percent. The ability to diagnose NSCLC in stages 1 and 2, when surgical resection and potential cure are still possible, could significantly reduce the mortality from NSCLC worldwide. "The revolutionary EFIRM technology is the most exciting development in noninvasive liquid biopsy in recent years. The potential to detect early-stage lung cancer patients with an affordable blood or saliva test could save thousands to tens of thousands of lives annually worldwide," stated Charles M. Strom, MD, PhD, co-director of the Center for Oral/Head and Neck Oncology Research at the UCLA School of Dentistry, Los Angeles, CA, USA, and Senior Vice President and Chief Medical Officer of EZLife Bio, USA, Woodland Hills, CA, USA. The EFIRM technology can also be used to monitor treatment and detect recurrence in patients already diagnosed with NSCLC.

Previously, the investigators had successfully measured two actionable EGFR mutations (p.L858R and Exon 19del) in blood samples from patients with late-stage NSCLC using EFIRM technology. In the current study, they investigated whether the mutations could be found in samples from patients with early-stage disease.

The researchers collected plasma samples from 248 patients with radiographically-determined pulmonary nodules. Of those, 44 were diagnosed with Stage I or Stage II NSCLC (23 with biopsy-proven benign pulmonary nodules and 21 with Stage I or Stage II adenocarcinoma). EFIRM was able to detect the p.L858R mutation in 11 of 12 samples and the Exon 19del mutation in seven of nine samples, resulting in greater than 90 percent sensitivity and 80 percent specificity.

"Currently, the clinical sensitivity of EFIRM to detect patients with NSCLC is limited by the percentage of tumors containing either or both of the two variants, which is estimated at 27 percent of NSCLC tumors," explained co-investigator Wu-Chou Su, MD, of the Department of Internal Medicine, National Cheng Kung University Hospital and College of Medicine of the National Cheng Kung University, Tainan, Taiwan. "We are presently developing a 10-variant panel that contains detecting mutations expressed in 50 percent of all lung malignancies."

Investigators emphasize that this study does not present direct evidence that detecting EGFR mutations in the plasma of an individual is predictive that the patient has cancer. Future work will explore whether finding an EGFR mutation in the circulation has any predictive value. Currently, the EFIRM liquid biopsy may be helpful for guiding treatment selection in patients for whom biopsy material is not available.

"We are gratified by the performance of the EFIRM platform in patients whose tumors were still small enough to qualify for surgical care. Work is underway to increase the number of mutations analyzed and to automate the process to increase sensitivity and facilitate mass screening," commented Dr. Strom.

For the first time, scientists have performed prenatal gene editing to prevent a lethal metabolic disorder in laboratory animals, offering the potential to treat human congenital diseases before birth. Published today in Nature Medicine, research from Children's Hospital of Philadelphia (CHOP) and the Perelman School of Medicine at the University of Pennsylvania offers proof-of-concept for prenatal use of a sophisticated, low-toxicity tool that efficiently edits DNA building blocks in disease-causing genes.

Using both CRISPR-Cas9 and base editor 3 (BE3) gene-editing tools, the team reduced cholesterol levels in healthy mice treated in utero by targeting a gene that regulates those levels. They also used prenatal gene editing to improve liver function and prevent neonatal death in a subgroup of mice that had been engineered with a mutation causing the lethal liver disease hereditary tyrosinemia type 1 (HT1).

HT1 in humans usually appears during infancy, and it is often treatable with a medicine called nitisinone and a strict diet. However, when treatments fail, patients are at risk of liver failure or liver cancer. Prenatal treatment could open a door to disease prevention, for HT1 and potentially for other congenital disorders.

"Our ultimate goal is to translate the approach used in these proof-of-concept studies to treat severe diseases diagnosed early in pregnancy," said study co-leader William H. Peranteau, MD, a pediatric and fetal surgeon in CHOP's Center for Fetal Diagnosis and Treatment. "We hope to broaden this strategy to intervene prenatally in congenital diseases that currently have no effective treatment for most patients, and result in death or severe complications in infants."

"We used base editing to turn off the effects of a disease-causing genetic mutation," said study co-leader Kiran Musunuru, MD, PhD, MPH, an associate professor of Cardiovascular Medicine at Penn. "We also plan to use the same base-editing technique not just to disrupt a mutation's effects, but to directly correct the mutation." Musunuru is an expert in gene-editing technology and previously showed that it can be used to reduce cholesterol and fat levels in the blood, which could lead to the development of a "vaccination" to prevent cardiovascular disease.

In this study, the scientists used base editor 3 (BE3), which takes clustered regularly interspersed short palindromic repeats (CRISPR), joins it with a modified CRISPR-associated protein 9 to form a partially active version of the CRISPR-Cas 9 tool, and harnesses it as a homing device to carry an enzyme to a highly specific genetic location in the liver cells of fetal mice. The enzyme chemically modified the targeted genetic sequence, changing one type of DNA base to another. BE3 is potentially safer than CRISPR-Cas9, because it does not fully cut the DNA molecule and leave it vulnerable to unanticipated errors when the cut is repaired, as has been seen with the CRISPR-Cas9 tool.

After birth, the mice in the study carried stable amounts of edited liver cells for up to three months after the prenatal treatment, with no evidence of unwanted, off-target editing at other DNA sites. In the subgroup of the mice bioengineered to model HT1, BE3 improved liver function and preserved survival. The BE3-treated mice were also healthier than mice receiving nitisinone, the current first-line treatment for HT1 patients.

To deliver CRISPR-Cas9 and BE3, the scientists used adenovirus vectors, which have often been used in gene therapy experiments. Because previous gene therapy research has shown that adenovirus vectors may cause unintended and sometimes deleterious responses from the host's immune system, the team is investigating alternate delivery methods such as lipid nanoparticles, which are less likely to stimulate unwanted immune responses.

A future direction for the team, in addition to using base editing to directly correct disease-causing mutations, will be to investigate its application to other diseases, including those based in organs beyond the liver.

"A significant amount of work needs to be done before prenatal gene editing can be translated to the clinic, including investigations into more clinically relevant delivery mechanisms and ensuring the safety of this approach," said Peranteau, who added, "Nonetheless, we are excited about the potential of this approach to treat genetic diseases of the liver and other organs for which few therapeutic options exist."

A pilot study has found that pregnant women who have suffered from depression or bipolar disorder (i.e. both mania and depression) recognise babies' faces and how babies laugh or cry, differently to healthy controls. This happens even if they are not currently experiencing depressive or manic symptoms and may represent an early risk-factor for children of these women, although the authors stress that research would be needed to confirm any long-term effects. This work is presented at the ECNP Congress in Barcelona.

Figures show that nearly 8% of Europeans (EU) have suffered from depression in the previous 12 months, with the rate of depression in women (9.7%) being around 50% higher than the rate in men. Around 1% of Europeans have suffered from bipolar disorder in the previous 12 months*. With over 5.1 million births in the EU every year, a significant number of the women who become pregnant will suffer from depression or bipolar disorder.

Researchers compared 22 pregnant women, currently well but with a history of depression, and 7 with bipolar disorder who were also currently well, against 28 healthy pregnant women. They also tested 18 non-pregnant women, as controls.

Between the 27th and 39th weeks of pregnancy, all the women were tested for how they responded to a series of happy or sad faces, and to laughter and crying, of both babies and adults. Specifically, the women were asked to rate how happy or distressed the infants were based on infants' facial and vocal displays of emotion (including smiles, laughter and cries). They were also asked to identify adult facial expressions of emotion (including happiness, sadness, fear and disgust) across varying intensity levels

According to lead researcher, Dr Anne Bjertrup (Rigshospitalet, Copenhagen), "In this study, we found that pregnant women with depression or bipolar disorder process infants' facial and vocal signals of emotion differently even when they are not currently experiencing a depressive or manic episode. These differences may impair these women's ability to recognise, interpret and respond appropriately to their future infants' emotional signals".

The researchers found that, compared to healthy pregnant women:

Pregnant women with bipolar disorder had difficulty with recognising all facial expressions and showed a "positive face processing bias", where they showed better recognition of happy adult faces and more positive ratings of happy infant faces.

In contrast, pregnant women with previous depression showed a negative bias in the recognition of adult facial expressions and rated infant cries more negatively.

Anne Bjertrup continued:
"This is a pilot study, so we need to replicate the findings within a larger sample. We know that depression and bipolar disorder are highly heritable, with up to 60% of children of parents with these affective disorders more likely to develop a mental disorder themselves. Genes play a role, but it is also likely that the quality of the early interaction with the mother is important. The different cognitive response to emotional infant signals in pregnant women with a history of mania and/or depression may make it more difficult for them to relate to their child and could thus confer an early environmental risk for the child.

It's worth emphasizing that this work does not say that the affected women are "bad mothers". It simply means that because of their health history, they may experience difficulties interpreting and responding appropriately to their infants' emotional needs and that we as clinicians need to be more aware of these possible difficulties. These are early days; this is the first research to show this link in both depression and bipolar disorder, so we need further studies to design and test early screening and intervention programs possibly involving ways which will train mothers to interpret the signals from their children better.

But above all, we need evidence of any effect on children; our group have an ongoing study of mothers with affective disorders and their infants, to see if what we have found does indeed make a difference to the mother-infant interaction, which has an impact on the child's psychological development - this is something the work presented here does not address".

Commenting, Professor Eduard Vieta (Institute of Neuroscience, University of Barcelona) said: "This study adds to the growing scientific literature showing emotional bias in people with mood disorders, even when they are in remission, and for the first time shows the difficulties mothers have in identifying emotions in their own newborns. The results, however, do not imply at all that women with such conditions would not be able to raise a child properly and it does not prove any risk for their children since longitudinal data are lacking. This work may help us identify targets for pharmacological and psychological treatments, which in turn may help people with depression and bipolar disorder".

Data from a clinical trial has shown that how people respond to treatment for Bipolar Disorder may be influenced by their weight and the overall quality of their diet, including whether they are eating a diet high in foods thought to contribute to general inflammation. These are early results, but if replicated may mean that treatment of some mental health problems could benefit from the inclusion of dietary advice. This is presented at the ECNP Conference in Barcelona.

Bipolar Disorder (which used to be called 'manic depression') is characterised by episodes of mood swings, between being very up or very down with periods in between the two extremes. The fact that there are two opposite sets of symptoms means that finding an effective treatment is difficult. While current medications are useful, they are better at targeting mania symptoms (the 'up' phase), leaving a lack of effective treatment for people experiencing depressive episodes. Now a group of Australian, German and American scientists have shown those who have a high quality diet, a less inflammatory diet, and/or a low BMI (Body Mass Index) may respond better to an add-on nutraceutical treatment provided as part of a clinical trial.

"If we can confirm these results, then it's good news for people with Bipolar Disorder, as there is a great need for better treatments for the depressive phase of Bipolar Disorder" said lead researcher Melanie Ashton of Deakin University in Australia.

A total of 133 participants were randomly assigned to take a combination of nutraceuticals (compounds derived from foods such as vitamins or minerals that treat or prevent a disease or disorder) including the anti-inflammatory amino acid n-acetylcysteine (NAC), or NAC alone, or a placebo (a dummy pill) for 16 weeks. Participants received the study medication in addition to any stable treatments they were already receiving. Researchers measured BMI at the beginning of the study, and then measured depression and how a person is able to function in their day to day life. Researchers also rated whether a participant was improving and, if so, how much, over the next 20 weeks. Participants filled in a questionnaire about what they usually eat over the year and researchers calculated a diet quality score, where good diets included a healthy diet with lots of fruit and vegetables, whereas poorer-quality diets had more saturated fat, refined carbohydrates and alcohol. These types of diets were then categorised as either anti-inflammatory or pro-inflammatory based on foods that affect inflammation.

Melanie Ashton continued, "We found that people who had a better-quality diet, a diet with anti-inflammatory properties, or a lower BMI, showed better response to add-on nutraceutical treatment than did those who reported a low-quality diet, or a diet including foods that promote inflammation, or who were overweight.

What this means, if these results can be repeated in a larger trial, is that treatment for Bipolar Disorder would need to take into account what a person eats and their weight.

There are some points we need to note about this study. This is a randomised, controlled trial, but what we found were exploratory outcomes; in other words, it wasn't the main result that we were testing. Our result is statistically significant, but because the study wasn't specifically designed to test the effect of diet quality,

inflammatory diets and BMI on drug response in general, it is necessary to see the work replicated in a larger study before any firm conclusions can be formed".

Commenting, Professor Eduard Vieta (Barcelona) said:

"This is interesting work, which holds out the possibility that patients with Bipolar Disorder may benefit from a balanced diet. However, it is an early study, and we need more research before we can think whether this might affect clinical practice".

Professor Vieta was not involved in this work, it is an independent comment.

SAN FRANCISCO - Clinicians prescribed antibiotics without an infection-related diagnosis nearly half of the time and one in five prescriptions were provided without an in-person visit, according to research being presented at IDWeek 2018. The study, which is the first to look at overall outpatient antibiotic prescribing, analyzed more than half a million prescriptions from 514 outpatient clinics.

Previous research has found antibiotics often are prescribed for certain symptoms (such as a sore throat or cough) when they shouldn't be.

Most of these types of illnesses are caused by viruses and therefore don't benefit from antibiotics, which only treat bacterial infections.

"We looked at all outpatient antibiotic prescribing and results suggest misuse of these drugs is a huge problem, no matter the symptom," said Jeffrey A. Linder, MD, MPH, lead author of the study and chief of the Division of General Internal Medicine and Geriatrics at Northwestern University Feinberg School of Medicine, Chicago. "We found that nearly half the time, clinicians have either a bad reason for prescribing antibiotics, or don't provide a reason at all. When you consider about 80 percent of antibiotics are prescribed on an outpatient basis, that's a concern."

The research, which was funded by the Agency for Healthcare Research and Quality (AHRQ), analyzed 509,534 outpatient antibiotic prescriptions given to 279,169 patients from November 2015 through October 2017 by 2,413 clinicians at 514 clinics. The prescribers included physicians, attending physicians, nurse practitioners, and physician assistants in specialties including primary care internal medicine, obstetrics/gynecology, family medicine, dermatology, cardiology, and gastroenterology. Researchers determined 46 percent of antibiotics were prescribed without an infection-related diagnosis: 29 percent noted something other than an infection diagnosis (such as high blood pressure or annual visit) and 17 percent were written without a diagnosis indicated. Researchers hypothesize that some of that is related to sloppy diagnosis coding, but much of it reflects antibiotic prescribing for vague or inappropriate reasons, such infections that are caused by viruses, said Dr. Linder.

Of the 20 percent of antibiotics that were prescribed outside of an in-person visit, most were by phone (10 percent). Others were via an electronic health record system that allows prescription writing but there is no opportunity to gather information about symptoms or testing (4 percent), refill (4 percent) and online portal (1 percent). There are some cases where that may be appropriate, such as for women who suffer from recurrent urinary tract infections or teens taking antibiotics for acne. Researchers will analyze which of those prescriptions were appropriate in the next phase of research.

"Despite 40 years of randomized controlled trials showing antibiotics don't help for most coughs and sinus infections, many people are convinced they will not get better without an antibiotic and specifically call the doctor requesting one," said Dr. Linder. "At busy clinics, sadly the most efficient thing to do is just call in an antibiotic prescription. We need to dig into the data more, but we believe there is a lot of antibiotic prescribing for colds, the flu and non-specific symptoms such as just not feeling well, none of which are helped by antibiotics."

GALVESTON, Texas - Researchers at The University of Texas Medical Branch at Galveston have developed less expensive way to produce vaccines that cuts the costs of vaccine production and storage by up to 80 percent without decreasing safety or effectiveness. The findings are currently available in EBioMedicine.

Vaccines are the most effective way to prevent and eradicate infectious diseases. Currently, many vaccines have to be manufactured in cell culture or eggs, which is expensive and carries the risk of contaminations. In addition, most vaccines must be kept refrigerated during the transportation from manufacturers to health care clinics. In tropical and subtropical regions, such cold storage requirements could contribute to more than 80 percent of the vaccine cost.

"The ability to eliminate cell culture or eggs and cold storage will change the process of vaccine development," said UTMB's Pei-Yong Shi, professor in the department of biochemistry and molecular biology. "Importantly, this vaccine technology could potentially serve as a universal platform for development of live-attenuated vaccines for many viral pathogens."

To achieve these goals, the UTMB team engineered a live-attenuated Zika vaccine in the DNA form. Once the DNA is delivered into our body, it launches the vaccine in our cells, leading to antibody production and other protective immunity. With this production method, there is no need to manufacture the vaccine in cell culture or eggs at factories. Because DNA molecules are shelf stable, the vaccine will not expire at warm temperatures and could be stockpiled at room temperature for years.

Using UTMB's Zika vaccine as a model, the research group showed that the DNA platform worked very efficiently in mice. After a single low dose, the DNA vaccine protected mice from Zika virus infection, mother-to-fetus transmission during pregnancy and male reproductive tract infection and damage.

"This is the first study to demonstrate that, after a single low dose, a DNA vaccine could induce saturated protective immunity," Shi said. "We will continue testing this promising Zika vaccine platform and then apply the platform to other viruses."

Following a review of the latest evidence --including a range of recent trials of drug and lifestyle interventions -- the European Association for the Study of Diabetes (EASD) and the American Diabetes Association (ADA) have produced an updated consensus statement on how to manage hyperglycaemia (high blood sugar) in patients with type 2 diabetes. The consensus paper is being co-published in Diabetologia, the journal of EASD, and Diabetes Care, the journal of the ADA, during the annual meeting of EASD in Berlin, Germany.

The new recommendations from the expert panel from both societies, which update their previous 2015 guidance, include:

Providers and healthcare systems should prioritise the delivery of patient-centred care

Facilitating medication adherence should be specifically-considered when selecting glucose-lowering medications. (Ultimately, patient preference is a major factor driving the choice of medication. Even in cases where a patient's clinical characteristics suggest the use of a particular medication based on the available evidence from clinical trials, patient preferences regarding route of administration, injection devices, side effects or cost may prevent their use by some individuals)

All patients should have ongoing access to diabetes self-management education and support

Medical nutrition therapy (healthy eating advice and strategies) should be offered to all patients

All overweight and obese patients with diabetes should be advised of the health benefits of weight loss and encouraged to engage in a programme of intensive lifestyle management, which may include food substitution

Increasing physical activity improves glycaemic control and should be encouraged in all people with type 2 diabetes.

Metabolic surgery is a recommended treatment option for adults with type 2 diabetes and (1) a BMI of 40 or over (or 37.5 or over in people of Asian ancestry) or (2) a BMI of 35.0 to 39.9 (32.5-37.4 kg/m2 in people of Asian ancestry) who do not achieve durable weight loss and improvement in comorbidities with reasonable non-surgical methods.

Metformin continues to be the first-line recommended therapy for almost all patients with type 2 diabetes

The selection of medication added to metformin is based on patient preference and clinical characteristics, including presence of cardiovascular disease, heart failure and kidney disease. The risk for specific adverse medication effects, particularly hypoglycaemia and weight gain; as well as safety, tolerability, and cost, are also important considerations.

Regarding medication management, for patients with clinical cardiovascular disease, a sodium-glucose cotransporter 2 (SGLT2) inhibitor or a glucagon-like peptide 1 (GLP-1) receptor agonist with proven cardiovascular benefit is recommended. Individual agents within these drug classes have been shown to have cardiovascular benefits.

For patients with chronic kidney disease (CKD) or clinical heart failure and atherosclerotic cardiovascular disease, an SGLT2 inhibitor with proven benefit should be considered

GLP-1 receptor agonists are generally recommended as the first injectable medication, except in settings where type 1 diabetes is suspected

Intensification of treatment beyond dual therapy to maintain glycaemic targets requires consideration of the impact of medication side-effects on comorbidities, as well as the burden of treatment and cost

The panel say that the lack of evidence over specific combinations of glucose-lowering therapies remains an issue, and more research is needed. The say: "As the cost implications for these various approaches is enormous, evidence is desperately needed. Different models of care are being implemented globally. Defining optimal cost-effective approaches to care, particularly in the management of patients --including those with multi-morbidity --is essential."

They add: "New questions arise from the recent cardiovascular outcomes studies. Do the cardiovascular and renal benefits of SGLT2 inhibitors and GLP-1 receptor agonists demonstrated in patients with established CVD extend to lower-risk patients? Is there additive benefit of use of GLP-1 receptor agonists and SGLT2 inhibitors for prevention of cardiovascular and renal events? If so, in what populations? Addressing these and other vital clinical questions will require additional investment in basic, translational, clinical and implementation research."

They conclude: "The management of hyperglycaemia in type 2 diabetes has become extraordinarily complex with the number of glucose-lowering medications now available. Patient-centred decision making and support and consistent efforts to improve diet and exercise remain the foundation of all glycaemic management. Initial use of metformin, followed by addition of glucose-lowering medications based on patient comorbidities and concerns is recommended as we await answers to the many questions that remain."

Traumatic head injury can have widespread effects in the brain, but now scientists can look in real time at how head injury affects thousands of individual cells and genes simultaneously in mice. This approach could lead to precise treatments for traumatic brain injury (TBI). The study, reported in Nature Communications, was supported by the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health.

"Instead of clustering responses according to categories of cells in TBI, we can now see how individual cells in those groups react to head injury," said Patrick Bellgowan, Ph.D., program director at NINDS.

University of California, Los Angeles professors Fernando Gomez-Pinilla, Ph.D. and Xia Yang, Ph.D., along with their colleagues, used a novel method known as Drop-seq to closely look at individual brain cells in the hippocampus, a region involved in learning and memory, after TBI or in uninjured control animals. Drop-seq allows thousands of cells and genes to be analyzed simultaneously. Its creation was in part funded by the NIH's Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative.

"These tools provide us with unprecedented precision to pinpoint exactly which cells and genes to target with new therapies," said Dr. Yang. "Another important aspect to this study was the highly collaborative and multidisciplinary nature of the work. Lots of people, from many different scientific areas, made this study possible."

In one set of experiments the team looked at TBI's effects on gene expression activity in individual cells. They found that certain genes were upregulated or downregulated across many different cell types, suggesting these genes may play important roles in TBI. Some of these genes are also known to be involved in diseases, such as Alzheimer's disease, which may help explain how TBI can be a risk factor for other disorders. For example, Drs. Yang and Gomez-Pinilla's groups observed altered activity in genes that are involved in regulating the amyloid protein, which builds up in Alzheimer's.

In particular, the genomic analysis revealed that the activity of the Ttr gene, which is involved in both thyroid hormone transport and scavenging of amyloid protein in the brain, was increased in many cells following TBI, suggesting the thyroid hormone pathway may be a potential target for therapy. Drs. Gomez-Pinilla and Yang's teams treated animals with the thyroid hormone thyroxine (T4) 1 and 6 hours after brain injury and saw that they performed much better on learning and memory tasks compared to animals that received a placebo.

The team identified 15 clusters of cells based on gene activity, including two clusters, named Unknown1 and Unknown2, the cells of which had not been described previously in the hippocampus. Further analysis of these clusters revealed that the cells in the Unknown1 group were involved in cell growth and migration and the cells in Unknown2 were involved in cell differentiation during development. The findings in this study also reveal that although two cells may have similar structure and shape, their functions, as suggested by the analysis of gene activity, may differ.

"We now know the secret life of single cells, including how they coordinate with other cells and how vulnerable they are to injury," said Dr. Gomez-Pinilla. "In addition, seeing which types of genes, including genes involved in metabolism, were involved across many cell types helps identify processes that may be critical in TBI."

Future studies will examine how TBI affects cells in areas other than the hippocampus. In addition, more research is needed to learn about long-term effects of TBI. Analyzing individual cells and genes may identify potential therapies for TBI.

A summit convened by The Gerontological Society of America (GSA) National Adult Vaccination Program (NAVP) has resulted in a roadmap for advancing immunization efforts in long-term care (LTC) facilities. A dozen recommendations -- including five priority actions -- have been outlined in a new white paper, "Charting a Path to Increase Immunization Rates in the Post-Acute and Long-Term Care Settings."

The summit and white paper were developed by GSA with the support of Sanofi Pasteur. The summit, held in Washington, DC, in May, welcomed stakeholders from the government, immunization advocacy organizations, and professional societies representing those who work in long-term care.

"Immunization in long-term care is critical as we are dealing with individuals at great risk for getting the flu, pneumonia, shingles, and associated complications," said GSA Past President Barbara Resnick, PhD, RN, CRNP, FGSA, who sits on the NAVP Workgroup and participated in the summit.

Moreover, she added that residents in long-term care are living in close proximity to other individuals and can easily share/pass infections.

"In addition to immunizing residents, it is necessary to immunize staff so that they do not increase resident exposure to viruses and so that staff are not missing days of work," Resnick said. "The white paper developed by GSA has recommendations for how to best motivate and engage staff in getting immunized themselves and making sure that all residents are immunized."

As identified by the summit's expert attendees, the top five recommended focus areas for future consideration in long-term care are:

1. Increase use of mandatory staff vaccination policies.
2. Make vaccination a condition of hire.
3. Implement mandatory resident vaccination policies across all long-term care settings.
4. Create financing tip sheets (e.g., roster billing, best practices, algorithms, calculator of outbreak costs).
5. Examine tools and resources for opportunities to weave immunizations into other priorities for post-acute and long-term care facilities.

The other recommended actionable items included: increase use of renewable consent documents; publish resident vaccination rates on facility websites; compile and share state law best practices; create sample score cards/dashboards/standing orders for facilities; work with legal consultants to clarify the why and how of consent; develop tips on staff incentives and processes (e.g., visual performance gauge, survey) and how to combine educational messages with strategy; and develop infomercials for staff and residents -- use consistent messaging for all.

The recommendations and white paper will be used as the basis for future efforts in partnership with the National Adult and Influenza Immunization Summit.

New study suggests ketone supplement more effective than low-carbohydrate, high-fat ketogenic diets at reducing body weight in mice

A study published in The FASEB Journal found that ketone supplementation decreased body fat and body weight in mice placed on a high-fat diet. The findings could have implications for an alternative to low-carbohydrate, high-fat ketogenic diets to help lower body fat and weight.

To conduct the study, researchers fed all mice in the study a high-fat diet for 12 weeks. After 12 weeks, they placed the obese mice in three random groups and observed them for another 12 weeks. During this time, the first group (which served as the control group) remained on the high-fat diet. The second group remained on the high-fat diet but were given a ketone supplement that replaced 30 percent of their prior caloric intake. The third group remained on the high-fat diet but were given approximately 25 percent fewer calories to closely match the caloric intake produced by the ketone supplement.

The study showed that the mice in the second group that received ketone supplementation experienced greater weight loss than the mice in the third group that received similar caloric intake. The novel findings suggest that the ketone supplementation used in this study either increased calories expended or decreased calories available for storage.

"The difficulties of losing and keeping off weight are well known," said Eric P. Plaisance, PhD, an assistant professor of exercise science and nutrition at The University of Alabama at Birmingham's Department of Human Studies. "This study forms the basis for developing human studies to explore how ketone supplements could help people lose and keep off weight."

"This new lead is a welcome development," said Thoru Pederson, PhD, Editor-in-Chief of The FASEB Journal.

UCLA researchers have discovered a common process in the development of late-stage, small cell cancers of the prostate and lung. These shared molecular mechanisms could lead to the development of drugs to treat not just prostate and lung cancers, but small cell cancers of almost any organ.

The key finding: Prostate and lung cells have very different patterns of gene expression when they're healthy, but almost identical patterns when they transform into small cell cancers. The research suggests that different types of small cell tumors evolve similarly, even when they come from different organs.

The study, led by Dr. Owen Witte, founding director of the UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research and professor of microbiology, immunology and molecular genetics, was published in the journal Science. Witte collaborated with scientists from UCLA's Crump Institute for Molecular Imaging and the UCLA Jonsson Comprehensive Cancer Center.

Cancers that become resistant to treatment often develop into small cell cancers -- also known as small cell neuroendocrine carcinomas, or SCNCs -- which generally have extremely poor prognoses. Certain cancers can evade treatment in part by changing cell types -- from aggressive adenocarcinoma to small cell carcinoma, for example.

Previous research hinted that small cell cancers from different organs may be driven by common mechanisms, but the UCLA study is the first to so clearly describe the steps in their evolution.

"Small cell cancers of the lung, prostate, bladder, and other tissues were long thought to be similar in name alone -- and they were treated by oncologists as different entities," Witte said. "Over the past few years, though, researchers have increasingly begun to realize that there are similarities in the cancers, and that's what our work confirms."

Dr. Jung Wook Park, the study's first author, and UCLA collaborators explored the potential parallels between the cancer types by transplanting human prostate cells with five genes, known collectively as PARCB, into mice. When those cells grew in the mice, they displayed unique features of human small cell neuroendocrine carcinomas.

The team also identified that for small cell neuroendocrine carcinomas to develop in the prostate, two tumor suppressor genes, TP53 and RB1, which are known for protecting normal cells from transforming into cancer cells, had to be simultaneously inactivated when PARCB was introduced.

Additional tests confirmed striking similarities between the PARCB-SCNC cells and small cell prostate cancer cells from humans. In particular, RNA expression and the turning on and off of certain genes were nearly identical.

"The similarities between the PARCB-SCNC cancers and human small cell prostate cancer samples were extraordinary," Witte said. "If you blindly gave the data sets to any statistician, they would think they were the same cells."

The team also looked at large databases of gene expression, to compare the patterns of gene expression in their PARCB-SCNC cells to cancers of other organs. They found that the pattern of gene expression in PARCB-SCNC cells was extremely similar to those of both prostate and lung small cell cancers.

Next, they tested whether PARCB genes could alter healthy cells from human lungs into small cell lung cancers, and the scientists found that they could.

The team now is working on mapping which genes control the entire cascade of events that underlies the transition to small cell cancer.

"Our study revealed shared 'master gene regulators' -- the key proteins that control expression of multiple genes in small cell cancer cells," Witte said. "Studying the network of the master gene regulators could lead to a new way of combating deadly cancers."