Aggression neurons identified

High activity in a relatively poorly studied group of brain cells can be linked to aggressive behaviour in mice, a new study from Karolinska Institutet in Sweden shows. Using optogenetic techniques, the researchers were able to control aggression in mice by stimulating or inhibiting these cells. The results, which are published in the scientific journal Nature Neuroscience, contribute to a new understanding of the biological mechanisms behind aggressive behaviour.

Aggression is a behaviour found throughout the animal kingdom that shapes human lives from early schoolyard encounters to armed, global conflict. Like all behaviour, aggression originates in the brain. However, the identity of the neurons involved, and how their properties contribute to the stereotyped expression of interpersonal conflicts, remains largely a mystery. Researchers at Karolinska Institutet now show that a previously relatively unknown group of neurons in the ventral premammillary nucleus (PMv) of the hypothalamus, an evolutionarily well-preserved part of the brain that controls many of our fundamental drives, plays a key role in initiating and organising aggressive behaviour.

Studying male mice, the researchers found that the animals that displayed aggression when a new male was placed in their home cage also had more active PMv neurons. By activating the PMv through optogenetics, whereby neurons are controlled using light, they were able to initiate aggressive behaviour in situations where animals do not normally attack, and by inhibiting the PMv, interrupt an ongoing attack.

The mapping of the PMv neurons also showed that they, in turn, can activate other brain regions such as the reward centres.

“That could explain why mice naturally make their way to a place where they have experienced an aggressive situation,” says the study’s lead author Stefanos Stagkourakis, doctoral student at the Department of Neuroscience, Karolinska Institutet. “We also found that the brief activation of the PMv cells could trigger a protracted outburst, which may explain something we all recognise—how after a quarrel has ended, the feeling of antagonism can persist for a long time.”

Aggression between male mice is often ritualised and focused less on causing harm than on establishing a group hierarchy by determining the strongest member. This can be studied experimentally in the so-called tube test, wherein two mice encounter each other in a narrow corridor, from which observations can be made about submission and dominance. By inhibiting the PMv cells in a dominant male and stimulating the same cells in a submissive male, the researchers were able to invert their mutual hierarchical status.

“One of the most surprising findings in our study was that the role-switch we achieved by manipulating PMv activity during an encounter lasted up to two weeks,” says study leader Christian Broberger, associate professor at the Department of Neuroscience, Karolinska Institutet.

The researchers hope that the results can contribute to new strategies for managing aggression.

“Aggressive behaviour and violence cause injury and lasting mental trauma for many people, with costly structural and economic consequences for society,” says Dr. Broberger. “Our study adds fundamental biological knowledge about its origins.”

 Explore further: Unexpected discovery gives new model for studying brain networks

More information: Stefanos Stagkourakis et al, A neural network for intermale aggression to establish social hierarchy, Nature Neuroscience (2018). DOI: 10.1038/s41593-018-0153-x

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VA turns to foster care for veterans instead of putting them in nursing homes

Ralph Stepney’s home on a quiet street in north Baltimore has a welcoming front porch and large rooms, with plenty of space for his comfortable recliner and vast collection of action movies. The house is owned by Joann West, a licensed caregiver who shares it with Stepney and his fellow Vietnam War veteran Frank Hundt.

“There is no place that I’d rather be. . . . I love the quiet of living here, the help we get. I thank the Lord every year that I am here,” Stepney, 73, said.

It’s a far cry from a decade ago, when Stepney was homeless and “didn’t care about anything.” His diabetes went unchecked and he had suffered a stroke — a medical event that landed him at the Baltimore Veterans Affairs Medical Center.

After having part of his foot amputated, Stepney moved into long-term nursing home care at a Department of Veterans Affairs medical facility, where he thought he’d remain — until he became a candidate for a small VA effort that puts aging veterans in private homes: the Medical Foster Homeprogram.

The $20.7 million-per-year program provides housing and care for more than 1,000 veterans in 42 states and Puerto Rico, serving as an alternative to nursing home care for those who cannot live safely on their own. Veterans pay their caregivers $1,500 to $3,000 a month, depending on location, saving the government about $10,000 a month in nursing home care. It has been difficult to scale up, though, because VA accepts only foster homes that meet strict qualifications.

For the veterans, it’s a chance to live in a home setting with caregivers who treat them like family. For VA, the program provides an option for meeting its legal obligation to care for ailing, aging patients at significantly reduced costs, because the veterans pay room and board directly to their caregivers.

Cost-effectiveness is but one of the program’s benefits. Stepney and Hundt, 67, are in good hands with West, who previously ran a home health-care services company. And they’re in good company, watching television together in the main living room, going twice a week to a center that offers daytime care and sitting on West’s porch chatting with neighbors.

West, who considers caring for older adults “her calling,” also savors the companionship and finds satisfaction in giving back to those who spent their young lives in military service to the United States.

“I took care of my mother when she got cancer and I found that I really had a passion for it. I took classes and ran an in-home nursing care business for years. But my dream was always to get my own place and do what I am doing now,” West said. “God worked it out.”

The Medical Foster Home program has slightly more than 700 licensed caregivers who live full time with no more than three veterans and provide round-the-clock supervision and care, according to VA. Akin to a community residential care facility, each foster home must be state-licensed as an assisted-living facility and submit to frequent inspections by VA as well as state inspectors, nutritionists, pharmacists and nurses.

Unlike typical community care facilities, foster home caregivers are required to live on-site and tend to the needs of their patients themselves 24/7 — or supply relief staff.

“It’s a lot of work, but I have support,” West said. “I try to make all my personal appointments on days when Mr. Ralph and Mr. Frank are out, but if I can’t, someone comes in to be here when I’m gone.”

VA medical foster home providers also must pass a federal background check, complete 80 hours of training before they can accept patients, plus 20 hours of additional training each year, and allow VA to make announced and unannounced home visits. They cannot work outside the home and must maintain certification in first aid, CPR and medicine administration.

But one prerequisite cannot be taught — the ability to make a veteran feel at home. West has grown children serving in the military and takes pride in contributing to the well-being of veterans.

“It’s a lot of joy taking care of them,” she said of Stepney and Hundt. “They deserve it.”

To be considered for the program, veterans must be enrolled in VA health care; have a serious, chronic disabling medical condition that requires a nursing home level of care; and need care coordination and access to VA services. It can take up to a month to place a veteran in a home once they are found eligible, according to VA.

The veterans also must be able to cover their costs. Because medical foster homes are not considered institutional care, VA is not allowed to pay for it directly. The average monthly fee, according to VA, is $2,300, which most veterans cover with their VA compensation, Social Security and savings, said Nicole Trimble, Medical Foster Home coordinator at the Perry Point VA Medical Center in Maryland.

Pilot program takes off

Since 1999, the Department of Veterans Affairs has been required to provide nursing home services to veterans who qualify for VA health care and have a service-connected disability rating of 70 percent or higher, or are considered unemployable and have a disability rating of 60 percent or higher.

VA provides this care through short- or long-term nursing home facilities, respite care, community living centers on VA hospital grounds, private assisted living facilities and state veterans homes.

Shortly after, the VA Medical Center in Little Rock launched an alternative — a pilot program that placed veterans in individual homes, at an average cost to VA of about $60 a day, including administration and health-care expenses, compared with upward of $500 a day for nursing home care.

And because veterans who are enrolled in the Medical Foster Care program must use VA’s Home Based Primary Care program, which provides an interdisciplinary team of health professionals for in-home medical treatment, the program saves VA even more. One study showed that the home-based care has yielded a 59 percent drop in VA hospital inpatient days and a 31 percent reduction in admissions among those who participate.

More than 120 VA medical centers now oversee a Medical Foster Home program in their regions, and VA has actively promoted the program within its health system.

It also has attracted bipartisan congressional support. In 2013, Sen. Bernie Sanders (I-Vt.) introduced a bill to allow VA to pay for medical foster homes directly.

In 2015, former House Veterans’ Affairs Committee chairman Rep. Jeff Miller (R-Fla.) introduced similar legislation that would have allowed VA to pay for up to 900 veterans under the program.

And this month , Rep. Clay Higgins (R-La.) raised the issue again, sponsoring a bill similar to Miller’s. “Allowing veterans to exercise greater flexibility over their benefits ensures that their individual needs are best met,” Higgins said in support of the program.

A guardian ‘angel’

Foster care has been a blessing for the family of Hundt, who suffered a stroke shortly after his wife died and was unable to care for himself. Hundt’s daughter, Kimberly Malczewski, lives nearby and often stops in to visit her dad, sometimes with her 2-year-old son.

“I’m not sure where my father would be if he didn’t have this,” she said. “With my life situation — my husband and I both work full time, we have no extra room in our house, and we have a small child — I can’t take care of him the way Miss Joann does.”

Trimble, whose program started in 2012 and has five homes, said she hopes to expand by two to three homes a year. VA will remain meticulous about selecting homes.

“There is a strict inspection and vetting process to be a medical foster home,” Trimble said. “We only will accept the best.”

It also takes a special person to be an “angel,” as the caregivers are referred to in the program’s motto, “Where Heroes Meet Angels.”

Stepney and Hundt agree West has earned her wings. On a recent cruise to Bermuda, she brought Stepney and Hundt along.

For Hundt, it was the first time he’d been on a boat. And Stepney said it was nothing like the transport ships he and his fellow troops used in the late 1960s: “Well, I’ve gotten to travel, but it was mainly two years in Vietnam, and there weren’t any women around.”

When asked why she brought the pair along, West said caregiving is “a ministry, something you really have to like to do.”

“And you know how the saying goes,” she said. “When you like what you do, you never work a day in your life.”

https://wapo.st/2IVMDvV

Research during Ebola vaccine trial: It’s complicated

During an outbreak of the deadly Ebola virus like the one underway in the Democratic Republic of the Congo (DRC), research necessarily takes a back seat to proven containment strategies, including isolation of infected people, identification and testing of their contacts, and safe burial of the dead. But the DRC has approved one vaccine trial, and a second study piggy backed on it to assess immune response to the vaccine, in the hope that the “experimental” intervention might help curb the outbreak and offer some insights for the future.

The unlicensed vaccine, made by Merck, performed exceptionally well in a large clinical trial held in Guinea during the 2015 outbreak, but it came as that epidemic already was winding down and had little impact on bringing it to an end. At last count in the DRC, 52 cases were confirmed, probable, or suspected; 22 deaths had been reported; and the outbreak had spread to three locations in Équateur province, including a city of 1.2 million people on the heavily trafficked Congo River.

The new trial will mirror the strategy used in Guinea and vaccinate “rings” of people around cases: contacts (there are more than 600 already), contacts of contacts, and front-line responders. The study will follow vaccinated people to see whether they develop disease and to monitor for adverse events to assess safety. For ethical reasons, there is no control group, however, so the study will yield limited data about efficacy. “The vaccine is just one part of the big response,” explains Yap Boum, a microbiologist with Doctors Without Borders who lives in Yaoundé and is helping the DRC’s Ministry of Public Health run the study. (Studies of other experimental treatments like monoclonal antibodies and drugs may take place, but none has yet been approved by the DRC government.)

The second study will try to extract more data from the vaccine trial. Since 2015, a group led by epidemiologist Anne Rimoin from the University of California, Los Angeles, has been working with colleagues in the DRC on an Ebola study that has taken blood samples from more than 1000 health care workers, as well as about 100 survivors and their contacts. Now, in collaboration with Boum and the vaccine team, the group is expanding that work to collect samples from the new volunteers who are participating in the vaccine trial. “Usually during outbreaks you’re scrambling to get these protocols in place and luckily we already have one that matches up quite nicely with the objective of the government and everyone who is wondering how well these vaccines might work,” Rimoin says.

The blood work could clarify whether people have pre-existing immunity to Ebola, in which case the vaccine would be boosting an existing response. Analyses of various immune responses triggered by the vaccine in people who do and don’t develop Ebola also could help clarify why the vaccine succeeds or fails.

To properly collect and store blood samples, Rimoin’s team travels to remote areas of the DRC with freezers that go down to –80°C, which they power with their own generators and batteries. They also cart in thousands of test tubes, pipettes, and other equipment to create their field lab. “When we’re doing this work we spend a lot of time on logistics of how we keep samples cold,” Rimoin says.

Although the Guinea trial found that the vaccine offered an astonishing 100% protection in vaccinated clusters, it did not take blood from participants. Rimoin points out that the Guinea population differs both genetically and immunologically from that of the DRC. In particular, she notes, Ebola had never been seen in Guinea before that epidemic, whereas this is the ninth outbreak in the DRC. “It’s very important to get as much data as you can to understand how the vaccine works in different populations,” Rimoin says.

Some investigators who worked on the Guinea study question the practicality and value of taking blood samples in the DRC. “Blood draws would complicate significantly field operations in communities affected by the disease, where blood is not just a fluid but is charged with symbolism,” says Marie-Paule Kieny, who helped run the study when she worked for the World Health Organization. She is now director of research at INSERM, the French biomedical research agency, in Paris. At the time of the Guinea study, communities reacted violently to some outreach workers, and there initially was much concern that many people would not even volunteer to participate in a vaccine study—but nearly 8000 people did.

Mark Feinberg, who heads the International AIDS Vaccine Initiative in New York City and who worked for Merck during the trial in Guinea, also questions the value of Rimoin’s study. Merck’s vaccine was tested in many other studies, and several of those did blood draws to help clarify the relationship between the vaccination and various immune responses. Merck says it plans to use data from some 18,000 vaccinated people in those trials to support its application for licensure next year. “I am not sure that having additional data on immune responses in the current outbreak in DRC would add significantly to this data package,” Feinberg says.

To Anthony Fauci, who heads the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, more data are always good. “It’s always better to have material that you can examine than to not have any material,” he says. Linda Venczel, an epidemiologist with international health nonprofit PATH in Seattle, Washington, who works in the DRC agrees. The study is “fantastic,” she says, and Rimoin’s group has the trust of public health leaders in the country. “Their serosurveys are very important,” Venczel says. “This is the kind of quantitative data that we need.”

Rimoin expects that their studies will uncover surprises. Indeed, in the 30 January issue of The Journal of Infectious Diseases, Rimoin and colleagues describe how they found Ebola antibodies in hundreds of people in the DRC who live in areas that have never had a documented outbreak of the disease. “There are more questions to answer than just licensure,” she says.

https://bit.ly/2IV88x7

Smiths Group, ICU Medical reported in talks on healthcare merger

British engineering firm Smiths Group Plc and U.S.-based ICU Medical Inc are in talks about a merger of their medical device businesses, a person familiar with the discussions told Reuters.

The talks are at a very early stage, according to the person.

Sky News and the Financial Times had reported earlier on Sunday that the two companies were in talks.

The FT said Smiths Group had been exploring options for some time for its medical business.

https://bit.ly/2kvq07i

Iterum Therapeutics Files for $92 Million IPO to Advance Antibiotics

Iterum Therapeutics, with headquarters in Dublin, Ireland and locations in Chicago and Old Saybrook, Connecticut, filed with the U.S. Securities and Exchange Commission (SEC) to initiate an initial public offering (IPO). The company hopes to raise $92 million.

Iterum is a clinical-stage drug company focused on developing anti-infectives for multi-drug resistant (MDR) pathogens.

The company recently gave a presentation and published two posters at the European Congress of Clinical Microbiology held in Madrid, Spain, April 21 to 24. The oral presentation of ePoster 0736 was, “Impact of Initial Inappropriate Antibiotic Therapy on Outcome for Uncomplicated Urinary Tract Infection Due to Antibiotic Non-Susceptible Enterobacteriaceae.” The study reviewed the records of 3,792 patients given oral antibiotics for urinary tract infections and concluded that more than 20 percent of patients with an outpatient UTI were given an antibiotic to bacteria that were resistant.

The posters were “Antimicrobial Activity of Sulopenem in the Urine of Healthy Volunteers” and “Impact of ESBL-Positivity and Quinolone Non-Susceptibility on Outcome for Inpatients with Complicated Urinary Tract Infections: A Multicenter Evaluation in the US.”

Sulopenem is the company’s lead compound, a novel penem anti-infective with oral and IV formulations. It has shown in vitro activity against a wide range of gram-negative, gram-positive and anaerobic bacteria that are resistant to other antibiotics. The compound has been designated a Qualified Infectious Disease Product (QIDP) under the U.S. Food and Drug Administration (FDA)’s Generating Antibiotics Incentives Now (GAIN) Act.

Iterum was founded in 2015 and brought in around $0.5 million in revenue in 2017. It expects to list on the Nasdaq under the symbol ITRM. Leerink Partners and RBC Capital Markets are the joint bookrunners on the IPO.

The funds will be used to advance the Phase III clinical trials of both oral and IV formulations of sulopenem.

Iterum acquired sulopenem, which is in the same class of antibiotics as penicillin, from Pfizer in 2015. Pfizer received an upfront payment, a stake in Iterum, and a shot at additional equity, milestones and royalties in the future.

Pfizer published information about the synthesis of sulopenem in the early 1990s and eventually evaluated it in a Phase II clinical trial. It presented results in 2010, showing cure rates of 90 percent and 88 percent in patients with community-acquired peneumonia requiring hospitalization. This compared to patients receiving ceftriaxone followed by an amoxicillin-clavulanate suspension, who had a cure rate of 63 percent.

The trial only had 33 patients, smaller than planned, and 10 didn’t complete the trial. The patients who dropped out came from both trial arms. The control arm had more side effects-related dropouts, and as many serious side effects as the sulopenem arms combined.

Technically, the data failed to show a statistically significant difference between the sulopenem and control arms, but it showed promise. The trial size wasn’t large enough to support definitive conclusions. But Pfizer apparently lost interest and didn’t prioritize the drug until Corey Fishman and Michael Dunne, who were part of the management team of Durata Therapeutics. Durata received approval for Dalvance, an antibiotic, which was then acquired by Actavis for $675 million in 2014. Durata bought its antibiotic from Pfizer as well.

Fishman is Iterum’s chief executive officer. At Durata, he was chief financial and chief operating officer. Dunne is Iterum’s chief scientific officer. He was Durata’s chief medical officer.

https://bit.ly/2kveIjq

National experts and state lawmaker react to diabetes amputation increase

A state legislator who is leading an inquiry into the escalating rates of diabetes and heart disease highlighted inewsource data in his campaign to provide more money to diabetes prevention through a soda tax.

Assemblymember Richard Bloom said he was surprised by data in our story that documented skyrocketing diabetes-related amputations in California. Our analysis found the population-adjusted rate of amputations increased by 31 percent from 2010 to 2016 statewide, with a 66 percent increase in San Diego County.

The Santa Monica Democrat cited the data at a hearing on diabetes in Los Angeles last week and plans to continue asking questions at upcoming hearings in Fresno and Sacramento. These are part of the Assembly Select Committee on Diabetes and Heart Disease Prevention, convened by Bloom.

He characterizes diabetes as an epidemic because it is diagnosed in approximately 9 percent of California residents.

The amputation rate increase “did surprise me,” Bloom said of the inewsource data in a phone interview. “As a legislator, I don’t want to step out and point a finger at anyone before I have more information” about the reasons behind it. “We need more information.”

The California Department of Public Health’s one-sentence response to inewsourceconcerned Bloom. When asked about the data, a spokesman for the department, which has a dedicated program for diabetes prevention, responded that it “does not have information related to possible reasons for increases in diabetes-related amputations.”

Bloom said that after his initial surprise at the data, in retrospect, growing populations of homeless and people with diabetes make the amputation rates “start to make more sense.”

In an email, he said “I am anxious to hear experts postulate why we are seeing a dramatic increase in amputations.”

Bloom said during the interview the state’s diabetes prevention program receives no state money, which he hopes to change with revenue from soda taxlegislation he has introduced. That bill has failed so far and is now on a two-year track.

“It’s pretty shocking that our funding level is as low as it is,” Bloom said.

inewsource “uncovering this information – that amputations are significantly higher than we thought – is helpful because I think it helps us get closer to the place where I think we can start funding these programs.”

Our findings prompted reactions across the country.

Dr. David Armstrong, a diabetes specialist, podiatrist and surgeon at the Keck School of Medicine at the University of Southern California, called the story a “call to action,” which is how he said various health officials and academic faculty members at UCLA and the Los Angeles Veteran’s Administration hospital reacted to the story he distributed.

Armstrong, who authors a blog for diabetes foot specialists, said his colleagues believe a partial solution to the increase in amputations is to expand the number of foot specialty clinics and podiatry services throughout the state to more rapidly detect and treat foot wounds that may otherwise go unnoticed. Too often, he said, people with diabetes-related neuropathy lack “the gift of pain” that would alert them to ulcers that then get infected.

The story prompted numerous comments from physicians and patients across the country suggesting a variety of other reasons for the increase in lower limb amputations. Among those was the theory, expressed in comments on a version of the story published by inewsource’s partner, MedPage Today, that people with diabetes don’t understand the gravity of their condition and don’t appreciate the necessity of curtailing carbohydrates to prevent progression of their disease.

The story also prompted physician comments critical of their fellow providers, saying that in the rush to see patients on daily schedules, they too frequently fail to conduct proper foot exams on their patients.

https://bit.ly/2hKPqj2

Weekend Sleep-in May Lower Mortality Risk

New research is trying to put to bed the idea that too little sleep during weekdays can’t be counteracted by a longer sleep during weekends.

A prospective cohort study of nearly 40,000 participants showed that, at least in those younger than 65 years, sleeping an average of 5 hours or fewer per night over the weekend increased mortality risk by 52% compared with sleeping 7 hours.

Having short sleep on both the weekdays and weekend, as well as having long sleep at both times, also increased the risk in this age group.

However, the mortality rate among participants with shorter sleep hours during weekdays and longer sleep hours during weekends did not differ significantly from those who averaged 7 hours per night consistently (the reference group).

“Possibly, long weekend sleep may compensate for short weekday sleep,” write the investigators, led by Torbjörn Åkerstedt, PhD, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden. But they note that more research is needed.

There were no significant associations between sleep and mortality risk in the participants aged 65 years or older.

The findings were published online May 22 in the Journal of Sleep Research.

No U-Shape?

“Previous studies have found a U-shaped relationship between mortality and (weekday) sleep duration,” the investigators write. This means that “both short and long sleep is associated with higher mortality,” they add.

However, they note that published findings have been inconsistent, especially when it comes to measuring weekday or weekend sleep specifically.

In the current study, the researchers assessed 43,880 participants in the Swedish National March Cohort, all of whom filled out a 36-page questionnaire on lifestyle and medical history. After exclusion criteria were applied, the final cohort of 38,015 individuals was followed for 13 years (October 1997 through December 2010) through linkage with databases, such as the Swedish National Register of Death.

The participants were also placed into subgroups based on average sleep duration at baseline, from “short” (≤5 hours/night) to “long” (≥9 hours/night). The reference group received 7 hours of sleep consistently.

“Speculative” Results?

In the younger than 65 years age group, the hazard ratio (HR) was 1.52 for those who slept an average of 5 hours or fewer per weekend night at baseline compared with those who slept an average of 7 hours per weekend night (95% confidence interval [CI], 1.15 – 2.02).  There were no significant links between mortality risk and 9 hours or more of weekend sleep.

A 65% higher mortality rate was shown for those who consistently slept fewer than 5 hours on all nights (HR, 1.65; 95% CI, 1.22 – 2.23) compared with those who consistently slept 6 to 7 hours per night; and there was a 25% higher mortality rate for those who averaged 8 hours or more of sleep on all nights (HR, 1.25; 95% CI, 1.05 – 1.50).

As mentioned, no significant associations were found in the participants aged 65 years or older.

The suggestion that sleeping more hours over the weekend may compensate for staying up late during the week, at least in the younger age group, appears to diverge from past research, note the investigators. But they point out that this is probably because “previous work has focused on weekday sleep only.” Also, the two types of sleep differ over causes, consequences, duration, and effect from age, they add.

Still, the “interpretation of results on sleep duration in terms of sufficient or insufficient recovery or compensatory sleep is speculative,” the researchers write.

“It needs confirmation in studies that link changes in sleep duration…in a longitudinal approach across many weeks,” they add.

The study was funded by AFA Insurance and the Italian Institute of Stockholm, Sweden. The study authors have disclosed no relevant financial relationships.

J Sleep Res. Published online May 22, 2018. Abstract

https://wb.md/2LzbjfD