A viable vaccine for tough tumors

Biomaterial-based cancer vaccine combines chemo and immunotherapy to treat triple-negative breast cancer in mice

WYSS INSTITUTE FOR BIOLOGICALLY INSPIRED ENGINEERING AT HARVARD

Research News

 

Patients with cancer have multiple treatment options available to them today, but each has its drawbacks. Chemotherapy kills rapidly dividing cancer cells, but it also damages healthy cells in the body and often does not effectively prevent tumor metastasis or disease recurrence. Immunotherapies avoid those problems by acting on a patient's immune system to generate a sustained anti-cancer response, but frequently have trouble accessing tumors due to the immunosuppressive local environment that tumors create.

Now, a new, best-of-both-worlds approach packages the cancer-killing power of chemotherapy and the long-term efficacy of immunotherapy into a biomaterial-based cancer vaccine that can be injected adjacent to a tumor site. When mice with aggressive triple-negative breast cancer (TNBC) were given the vaccine, 100% of them survived a subsequent injection of cancer cells without relapsing. This research is reported in Nature Communications.

"Triple-negative breast cancer does not stimulate strong responses from the immune system, and existing immunotherapies have failed to treat it. In our system, the immunotherapy attracts numerous immune cells to the tumor while the chemotherapy produces a large number of dead cancer cell fragments that the immune cells can pick up and use to generate an effective tumor-specific response," said co-first author Hua Wang, Ph.D., a former Postdoc and Technology Development Fellow at Harvard's Wyss Institute for Biologically Inspired Engineering and John A. Paulson School for Engineering and Applied Sciences (SEAS) who is now an Assistant Professor in the Department of Materials Science and Engineering at University of Illinois, Urbana-Champaign.

Personalized vaccines without the wait

First developed in 2009, the injectable cancer vaccine has shown great promise in treating multiple types of cancer in mice, and has been explored in clinical trials for treating melanoma at Dana Farber Cancer Institute. In the original formulation of the vaccine, molecules found in cancerous cells called tumor-associated antigens (TAAs) were incorporated together with adjuvants inside the aspirin-sized scaffold so that arriving dendritic cells could recognize them as "foreign" and mount an immune response targeted against the tumor. These TAAs can be isolated from harvested tumors or identified by sequencing the genome of cancerous cells and subsequently manufactured, but both of these processes to create personalized cancer vaccines can be long, tedious, and expensive.

"One of the critical limiting factors in the development of cancer vaccines is the selection of TAAs, because currently we only have a very small library of known antigens for a few specific tumor cell lines, and it's difficult to predict which can mount an effective immune response," said co-first author Alex Najibi, a graduate student in the lab of Wyss Core Faculty member David Mooney. "Implanting chemotherapy drugs inside the vaccine scaffold creates a burst of cancer cell death that releases TAAs directly from the tumor to the dendritic cells, bypassing the long and costly antigen development process."

Wang, Najibi, and their colleagues set out to apply this new cancer vaccine tactic to TNBC, a disease in which the tumors aggressively suppress immune activity in their local area, limiting the efficacy of immunotherapy. The team first loaded their alginate hydrogel scaffold with a protein molecule called Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF). GM-CSF stimulates the development and concentration of dendritic cells, which take up antigens from tumors and other invaders and present them to T cells in the lymph nodes and spleen to initiate an immune response. They also added the chemotherapy drug doxorubicin (Dox) attached to a peptide called iRGD. iRGD is known to penetrate tumors, and helps target the Dox to tumors upon release.

When mice with TNBC tumors were injected with the new vaccine, those that received a scaffold loaded with GM-CSF and the Dox-iRGD conjugate showed significantly better penetration of the drug into tumors, increased cancer cell death, and fewer metastatic tumors in the lungs than those that received gels containing Dox conjugated to a scrambled peptide molecule, unmodified Dox, or were untreated. Analysis of the scaffolds showed that they had accumulated a large number of dendritic cells, indicating that both the immunotherapy and chemotherapy components of the vaccine were active.

Encouraged by these results, the team then experimented with adding a third component to the vaccine called CpG, a synthetic bacterial DNA sequence that is known to enhance immune responses. Mice that received vaccines with this addition displayed significantly slower tumor growth and longer survival times than mice that received vaccines without it. To evaluate the strength and specificity of the immune response generated by this three-part vaccine, the researchers extracted and analyzed cells from the animals' lymph nodes and spleens. Strikingly, 14% of the T cells taken from lymph nodes reacted against the tumor cells, indicating that they had been "trained" by the dendritic cells to target the cancer, compared with only 5.3% of the mice that received the two-part vaccine and 2.4% of the T cells from untreated mice. In addition, giving a "booster" dose of the vaccine 12 days post-injection increased their survival time even further.

Localized action, long-term protection

While these results revealed the vaccine's effect on activating the immune system, the team also wanted to understand how it affected the local tumor microenvironment. Analysis of the vaccines and their nearby tumors revealed that cells in tumors treated with gels containing GM-CSF, Dox-iRGD, and CpG had an increased amount of the protein calreticulin on their surfaces, which is an indicator of cell death. Mice that received the three-part vaccine also displayed higher numbers of pro-inflammatory macrophages: white blood cells that are associated with improved anticancer activity and longer survival.

The researchers also discovered that their treatment caused an increase in the expression of the cell-surface protein PD-L1 on tumor cells, which is used by cancer to evade immune detection. They had a hunch that co-administering an anti-PD-1 checkpoint inhibitor treatment that blocks this immune evasion with their vaccine would increase its effectiveness. They implanted the three-part vaccine into mice, then injected anti-PD-1 separately. Mice treated with the combination of gel vaccine and anti-PD-1 showed significantly reduced tumor size and number, and survived for a median of 40 days compared to 27 days for untreated mice and 28 days for mice that received anti-PD-1 alone. This synergy suggested that the vaccine might best be used in combination with checkpoint inhibitor therapies.

To imitate how the cancer vaccine might be administered to human patients, the team tested its ability to prevent cancer recurrence after a primary tumor is removed. They surgically excised TNBC tumors from mice, then injected either their three-part hydrogel vaccine or a liquid vaccine containing all the components in a suspension near the original tumor site. Both treated groups had significantly lower tumor recurrence, but the gel vaccine produced significantly slower tumor growth and improved survival. Mice were then re-challenged with an injection of cancer cells and, strikingly, 100% of the mice that had received the gel vaccine survived with no metastasis, while all of the untreated mice succumbed to the disease.

"The ability of this vaccine to elicit potent immune responses without requiring the identification of patient-specific antigens is a major advantage, as is the ability of local chemotherapy delivery to bypass the severe side effects of systemic chemotherapy, the only treatment currently available for the disease," said corresponding author Mooney, Ph.D., who leads the Immuno-Materials platform at the Wyss Institute and is also the Robert P. Pinkas Family Professor of Bioengineering at SEAS. "Not only does this vaccine activate dendritic cells with tumor-specific TAAs in situ, it also reshapes the tumor microenvironment to allow the immune system greater access to the tumor, and creates an immune memory that prevents further recurrences."

The team is continuing to explore the combination of chemotherapy with cancer vaccines, and hopes to improve their antitumor efficacy for other difficult-to-treat tumor models. The team hopes that future studies to better understand and optimize the system will allow it to move into preclinical trials and, eventually, human patients.

"The team's newest version of their cancer vaccine is a novel multifunctional anticancer therapy that offers new hope for the treatment of a wide range of cancers. It is essentially an entirely new form of combination chemotherapy that can be administered through a single injection and potentially offer greater efficacy with much lower toxicity than conventional treatments used today," said Wyss Institute Founding Director Don Ingber, M.D., Ph.D. Ingber is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and the Vascular Biology Program at Boston Children's Hospital, as well as Professor of Bioengineering at SEAS.

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Additional authors of the paper include Wyss and SEAS members Miguel Sobral, Bo Ri Seo, Ph.D., David Wu, D.M.D., and Catia Verbeke, Ph.D., and former members Jun Yong Lee, Ph.D., who is now an Assistant Professor at the Catholic University of Korea, and Aileen Li, Ph.D., who is now a Postdoctoral Fellow at the University of California, San Francisco.

This work was supported by the National Institutes of Health, the Wyss Technology Development Fellowship, and the National Science Foundation.

Researchers discover enzyme suppressing immune response to viral infections

Findings could lead to targeted therapy for persistent infections and other diseases

UNIVERSITY OF MISSOURI-COLUMBIA

Research News

 

Viruses such as HIV, hepatitis B and hepatitis C evade or disrupt the immune system to create persistent infections. These viruses remain a serious health threat, but researchers from the University of Missouri School of Medicine have discovered how an enzyme that regulates several cellular processes might be a key target to preventing viruses from disarming the human immune response.

"There is very little research on how the sphingosine kinase 2 (SphK2) enzyme affects the immune responses to viral infections," said senior author Bumsuk Hahm, PhD, associate professor of surgery and molecular microbiology and immunology. "We hypothesized that this enzyme suppresses the T cells that fight infections and allows viruses to persist."

Hahm and his team tested their hypothesis by infecting mice with the lymphocytic choriomeningitis virus, a common rodent-borne virus. Mice in the study that received an oral therapy that briefly inhibited the SphK2 enzyme experienced a robust immune response and an accelerated destruction of the virus.

"SphK2 is shown to regulate immune cell responses during a viral infection, and inhibition of this enzyme is effective in clearing a persistent viral infection," Hahm said. "We believe targeting SphK2 may provide a promising route for developing a drug to elicit protective immunity against viral infections that have a devastating impact on human health."

Another key finding from the study demonstrated that SphK2 plays a role in preventing the immune system from attacking the kidneys during an infection. Hahm's team found SphK2 deficient mice died within two weeks of infection from kidney failure. All showed evidence of immune cell infiltration in the kidneys.

Hahm's team also discovered SphK2 inhibition may also treat some types of cancer by promoting activation of the immune system. Other clinical trials are already exploring the idea that SphK2 inhibition can slow cancer cell growth by directly blocking cancer cell proliferation.

"Our study suggests that SphK2 can be targeted for restoring T cell immunity to circumvent an immune suppressive environment," Hahm said. "This finding may be applicable to cancer studies as well as other diseases caused by immune disruption."

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In addition to Hahm, the study authors include current MU graduate students Caleb Studstill and Jennifer Wolf; Curtis Pritzl, PhD, from the surgery and molecular microbiology and immunology departments; Ravi Nistala, MD, associate professor of clinical medicine; and Dae Young Kim, PhD, clinical associate professor of veterinary medicine.

Their study, "Sphingosine kinase 2 restricts T cell immunopathology but permits viral persistence," was recently published in the Journal of Clinical Investigation. The authors of the study declare that they have no conflicts of interest.

Rapid test can ID unknown causes of infections throughout the body

All-in-one 'metagenomic' test advances efforts to eliminate lengthy diagnosis

UNIVERSITY OF CALIFORNIA - SAN FRANCISCO

Research News

 

UC San Francisco scientists have developed a single clinical laboratory test capable of zeroing in on the microbial miscreant afflicting patients hospitalized with serious infections in as little as six hours -- irrespective of what body fluid is sampled, the type or species of infectious agent, or whether physicians start out with any clue as to what the culprit may be.

The test will be a lifesaver, speeding appropriate drug treatment for the seriously ill, and should transform the way infectious diseases are diagnosed, said the authors of the study, published November 9, 2020 in Nature Medicine.

"The advance here is that we can detect any infection from any body fluid, without special handling or processing for each distinct body fluid," said study corresponding author Charles Chiu, MD, PhD, a professor in the UCSF Department of Laboratory Medicine and director of the UCSF-Abbott Viral Diagnostics and Discovery Center. "It's a simple procedure."

Conventional diagnostic tests are designed to detect only one or sometimes a small panel of potential pathogens. In contrast, the new protocol employs powerful "next-generation" DNA-sequencing technology to account for all DNA in a sample, which may be from any species -- human, bacterial, viral, parasitic, or fungal. Clinicians do not need to have a suspect in mind. To identify a match, the new test relies on specially developed analytical software to compare DNA sequences in the sample to massive genomic databases covering all known pathogens.

Chiu and colleagues at the UCSF Center for Next-Gen Precision Diagnostics first developed this method to identify infectious agents in spinal fluid in cases of encephalitis and meningitis, notably helping to save a long-sick boy's life, and later validating the protocol for use as a clinical test that is now being ordered by physicians at hospitals nationwide.

Chiu and collaborators also developed a similar blood test for sepsis, a leading killer of hospital patients, while other tests use respiratory fluid to diagnose infectious causes of pneumonia.

But each of these tests is designed to work only with specific body fluids, not all. Unfortunately, physicians are often uncertain of the origin of a patient's infection and must send off samples of several different body fluids simultaneously for lab analysis.

In the new study, the UCSF researchers, including Center for Next-Gen Precision Diagnostics co-founders Joe DeRisi, PhD, and Steve Miller, MD, PhD, compared performance of their new single-protocol "metagenomic" DNA test to gold-standard laboratory culture-based tests and now-standard PCR-based DNA tests, using two high-powered DNA sequencing technologies to diagnose bacterial or fungal infection. One was a portable, pocket-sized sequencer made by Oxford Nanopore Technologies, which can complete sequencing within six hours and to date has been used almost exclusively by research labs. The other was Illumina sequencing, which can simultaneously handle many samples in parallel and which already is used in some clinical labs (including at UCSF), but which requires more than 24 hours to complete.

The researchers analyzed body fluids -- 180 samples from in and around the lungs, the peritoneal cavity, pus-filled abscesses, the spinal cord, joints, and other sites such as tonsillar fluid and even vitreal (eye) fluid-- from 160 patients, 144 of whom were hospitalized.

Compared with gold-standard culture and PCR, the researchers diagnosed 79% of bacterial and 91% of fungal infections by Illumina sequencing, and 75% of bacterial and 91% of fungal infections by nanopore sequencing.

Using the metagenomic DNA test, Chiu and colleagues were also able to diagnose infections in seven of 12 patients whose illnesses had remained undiagnosed after standard culturing or PCR-based DNA testing.

"We think this one metagenomic test can potentially replace all PCR-based DNA tests now being used to detect hundreds of organisms that can't be adequately cultured," Chiu said.

The researchers are now moving towards FDA regulatory approval in hopes of making this test a standard part of clinical practice at UCSF and elsewhere.

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Scientists use bacteria as micro-3D printers

Technique creates highly customized structures that could be used in regenerative medicine

AALTO UNIVERSITY

Research News

 

IMAGE: THE NANOCELLULOSE FIBRES CREATED BY THE BACTERIA ARE ABOUT A THOUSAND TIMES THINNER THAN THE WIDTH OF A HUMAN HAIR. view more 

CREDIT: IMAGE: LUIZ GRECA

A team at Aalto University has used bacteria to produce intricately designed three-dimensional objects made of nanocellulose. With their technique, the researchers are able to guide the growth of bacterial colonies through the use of strongly water repellent - or superhydrophobic - surfaces. The objects show tremendous potential for medical use, including supporting tissue regeneration or as scaffolds to replace damaged organs. The results have been published in the journal ACS Nano.

Unlike fibrous objects made through current 3D printing methods, the new technique allows fibres, with a diameter a thousand times thinner than a human hair, to be aligned in any orientation, even across layers, and various gradients of thickness and topography, opening up new possibilities for application in tissue regeneration. These kinds of physical characteristics are crucial for support materials in the growth and regeneration of certain types of tissues found in muscles as well as in the brain.

'It's like having billions of tiny 3D printers that fit inside a bottle,' explains Luiz Greca, a doctoral student at Aalto University. 'We can think of the bacteria as natural microrobots that take the building blocks provided to them and, with the right input, create complex shapes and structures.'

Once in a superhydrophobic mould with water and nutrients --sugar, proteins and air -- the aerobic bacteria produce nanocellulose. The superhydrophobic surface essentially traps a thin layer of air, which invites the bacteria to create a fibrous biofilm replicating the surface and shape of the mould. With time, the biofilm grows thicker and the objects become stronger.

Using the technique, the team has created 3D objects with pre-designed features, measuring from one-tenth the diameter of a single hair all the way up to 15-20 centimetres. The nano-sized fibres do not cause adverse reactions when placed in contact to human tissues. The method could also be used to grow realistic models of organs for training surgeons or improving the accuracy of in-vitro testing.

'It's really exciting to expand this area of biofabrication that takes advantage of strong cellulose nanofibres and the networks they form. We're exploring applications for age-related tissue degeneration, with this method being a step forward in this and other directions,' says research group leader Professor Orlando Rojas. He adds that the strain of bacteria used by the team, Komagataeibacter medellinensis, was discovered in a local market in the city of Medellin, Colombia, by previous collaborators from Universidad Pontificia Bolivariana. In both nature and engineering, superhydrophobic surfaces are designed to minimise the adhesion of dust particles as well as microorganisms. This work is expected to open new possibilities for using superhydrophobic surfaces to precisely produce naturally manufactured materials.

As the bacteria can be removed or left in the final material, the 3D objects can also evolve as a living organism over time. The findings provide an important step towards harnessing full control over bacterially fabricated materials.

'Our research really shows the need to understand both the fine details of bacteria interaction at interfaces and their ability to make sustainable materials. We hope that these results will also inspire scientists working on both bacteria-repelling surfaces and those making materials from bacteria,' says Dr. Blaise Tardy.

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E-cigarettes can be 'gateway' to cigarettes for teens with no prior intention to smoke

CHILDREN'S NATIONAL HOSPITAL

Research News

 

Cigarette smoking remains a leading preventable cause of morbidity and mortality in the United States. And while adolescent cigarette smoking has declined over the past several decades, e-cigarette use presents a new risk for nicotine use disorder. a new study, published Nov. 9 in the journal Pediatrics, finds that e-cigarette use is associated with a higher risk of cigarette smoking among adolescents who had no prior intention of taking up conventional smoking. These findings have strong implications for practice and policy, researches say.

"Research is showing us that adolescent e-cigarette users who progress to cigarette smoking are not simply those who would have ended up smoking cigarette anyway," says Olusegun Owotomo, M.D., Ph.D., M.P.H., the study's lead author and a pediatric resident at Children's National Hospital. "Our study shows that e-cigarettes can predispose adolescents to cigarette smoking, even when they have no prior intentions to do so."

In one of the first theory-guided nationally representative studies to identify which adolescent e-cigarette users are at most risk of progressing to cigarette smoking, Researchers looked at data of more than 8,000 U.S. adolescents, ages 12-17, who had never smoked. The data was collected by the Population Assessment of Tobacco and Health (PATH) study, an NIH and FDA collaborative nationally representative prospective cohort study of tobacco use, from 2014-2016. Among adolescents who did not intend to smoke cigarettes in the future, those who used e-cigarettes were more than four times more likely to start smoking cigarettes one year later compared to those who did not use e-cigarettes.

E-cigarette use constitutes a relatively new risk factor for nicotine use disorder among U.S. adolescents. A 2019 study from the Centers for Diseases Control and Prevention found that 28% of high school students and 11% of middle school students were current e-cigarette users. With the recent emergence of newer and potentially highly addictive e-cigarette products, adolescents who use e-cigarettes are at increased risk of developing nicotine use disorder and progressing to smoke conventional cigarettes.

"Abstinence from e-cigarettes can protect teens from becoming future smokers and should be framed as a smoking prevention strategy by all concerned stakeholders," says Dr. Owotomo. "Pediatricians are best positioned to educate patients and families on the clinical and psychosocial consequences of e-cigarette use and should support education campaigns and advocacy efforts geared to discourage adolescent e-cigarette use."

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Frugal science--a low-cost way to decontaminate PPE equipment

UD researchers develop scalable method to help address PPE supply chain issues, help hospitals with limited resources

UNIVERSITY OF DELAWARE

Research News

 

IMAGE: WIDELY AVAILABLE MATERIALS FOUND IN HARDWARE STORES, LIKE THOSE SHOWN HERE, CAN BE COMBINED WITH ULTRAVIOLET LIGHTS FOUND IN SHUTTERED RESEARCH LABS TO ENABLE LOW-COST DECONTAMINATION OF PERSONAL PROTECTIVE EQUIPMENT,... view more 

CREDIT: PHOTO BY EVAN KRAPE

As the weather turns cooler and people move activities indoors, the number of new coronavirus (COVID-19) cases being reported in the United States is rising. This mirrors COVID-19 activity already seen in Europe and elsewhere across the globe.

Meanwhile, supply-chain problems are likely to cause limited supplies of filtering facepiece respirators, such as N95 masks. Yet strategies to decontaminate personal protective equipment, or PPE, remain unresolved in many hospitals with limited resources, both in the United States and abroad.

University of Delaware researchers, led by biomedical engineer Jason Gleghorn, have devised a system for decontaminating N95 masks using off-the-shelf materials available at any hardware store combined with ultraviolet type C (UV-C) lights found in shuttered research laboratories.

The UD-developed method offers comparable decontamination to more expensive methods at an affordable cost of about $50 in materials.

"We focused on frugal science -- how do you decontaminate PPE in a very simple way that is easily scalable for high throughput so that any health care facility can use it globally," said Gleghorn, an associate professor of biomedical engineering at UD.

A simple solution

The project was inspired earlier this year by Rachel Gilbert, a doctoral candidate in the Gleghorn lab, after she learned that friends in the medical field were repeatedly donning the same N95 mask day after day.

"This is more widely known today, of course, thanks to media publicity around this issue, but it got me thinking," said Gilbert.

She knew that UV-C light was routinely used for sterilization of various materials and equipment found in research labs. She wondered if this technique could be repurposed to decontaminate specialized masks, specifically for front line workers, in a low-cost, scalable way.

Ultraviolet germicidal irradiation (UVGI) has been validated as an effective method to decontaminate masks between use. UVGI systems are routinely used to decontaminate work environments and surgical suites, equipment and ambulances, but not all healthcare facilities have access to this expensive commercial sterilization equipment. That said, many UV-C bulbs are sitting idle in biosafety cabinets in university labs and research facilities that may be empty due to restrictions arising from the pandemic.

"Being able to provide something that can be on-site, as opposed to other methods that require surgical-suite UV systems costing tens of thousands of dollars or shipping masks out for decontamination and relying on them coming back in a timely manner, was important," added Gilbert.

When she discussed the idea with Gleghorn, a former firefighter and critical care medic, he immediately agreed. Gilbert called the effort a "huge, collaborative team effort" with many lab members collectively reading the literature, figuring out a solution and then going to the hardware store and creating the setup in the peak of the pandemic in April, all while working from home.

It only took a few weeks to solve the problem and put the system together, but securing peer-review took longer.

"Peer-review is an important part of the process. And while we wish it could move faster, there is a reason that innovations are rigorously examined in the scientific community," said Gleghorn. "We need to make sure the science is sound and the methods we develop are safe for people."

Using basic resources

Now, more about how the method works.

Lay two N95 masks side-by-side and it is impossible to tell which mask, if either, is contaminated with the novel coronavirus SARS-CoV-2 that causes the disease COVID-19. It's not like dirt, which you can see.

The system the research team constructed modifies common fluorescent light fixtures to hold and power the specialized UVGI light bulbs. That, in addition to specific light placement arrangements and tin foil covered cardboard for reflectors, creates multiple decontamination arrangements people can make. To confirm the UV-C lights were effective, the researchers did copious mathematical calculations and modeling to make sure the intensity of UV radiation that the repurposed lights emit was correct and the N95 masks received the correct UV exposure to decontaminate the masks.

The team developed freely downloadable build instructions in simple, easy-to-understand language with a lot of pictures and made them freely available on the Gleghorn lab website. The directions emphasize UV safety and focus on use in healthcare because of the need for specialized equipment, like a UV-C intensity meter. They also include precautions to measure UV-C intensity to ensure confidence the system is delivering the correct degree of UV intensity for enough time to decontaminate.

The detailed setup instructions include granular information, too, such as how far apart to space the masks for maximum effectiveness. This is critical because placing them too close together can create shadows that prevent comprehensive UV-C decontamination.

It is important to note that this is not an at-home device.

"You need proper personal protective equipment to work with UV light, which can disrupt DNA and pose safety concerns," said Gilbert.

This disruptive feature, however, is exactly what makes the UV-C light useful for decontaminating PPE.

"The UV light causes the virus DNA to break up and become ineffective," explained Gleghorn.

"So, the virus -- that little spiky thing you've seen by now -- might still stick to you, but the genetic material inside will be fragmented and will not have the correct machinery to replicate."

The research team enlisted Kim Bothi, former global engineering director and now executive director of UD's Center for Hybrid, Active, and Responsive Materials, to help think through ways to scale the project. She, too, has firefighting and emergency medical technician experience, not to mention expertise in integrating new ideas across a global spectrum.

Bothi used her global expertise and relationships to recruit volunteers across the world to translate the build instructions into multiple languages with regional-specific information. So far, the directions have been translated in French, Spanish, Portuguese, Russian and German. To-date, the build plans have been accessed over 1,060 times from users in 52 countries.

She also is working on a policy brief to share the research team's method with Delaware's congressional delegation. Additionally, Bothi is passing information along to colleagues working with the Kenya Medical Research Institute and in other nongovernmental organizations across the world.

"Like any other technology or innovation, our off-the-shelf decontamination method will only have impact if people are aware of it," she said.

The researchers concede that mask re-use is not ideal, but they also recognize that not all hospitals or other patient care facilities are equipped with enough PPE to meet demand in a crisis, so first responders may be required to reuse masks in emergency situations.

This includes doctors, nurses and emergency response personnel, but also extends to staff behind-the-scenes who may be cleaning, disinfecting or preparing spaces for patient care. Beyond hospitals, PPE is worn in residential facilities and rural clinics around the globe that may have limited access to resources.

In a perfect world, Bothi would like to see academic and research institutions working hand-in-hand with hospital systems to collaboratively put these off-the-shelf systems in place where they are needed.

Kenya, for example, is a country in sub-Saharan Africa that has a fairly robust system for healthcare. Yet, the country is still facing incredible shortages of PPE just like here in the United States.

"The bigger benefit will be translating this to other areas of the world, where they don't have the resources," said Gleghorn.

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The team published their method in a paper in the journal Global Health: Science and Practice.

Other co-authors on the work include Gleghorn's multidisciplinary team of graduate students and staff whose fields of study range from biomedical engineering to biological sciences, chemistry and biochemistry, and chemical and biomolecular engineering. In addition to Gilbert (the paper's lead author), the graduate student team includes Allyson M. Dang, Michael J. Donzati, Christine L. Hatem, Brielle Hayward-Piatkovskyi, Daniel J. Minahan, Katherine M. Nelson and Jasmine Shirazi. For more information about the decontamination system, visit the Gleghorn Lab website.

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Two genes regulate social dominance

University of Houston researcher uses Nobel Prize-method to make discovery

UNIVERSITY OF HOUSTON

Research News

 

IMAGE: BEAU ALWARD, ASSISTANT PROFESSOR OF PSYCHOLOGY AT THE UNIVERSITY OF HOUSTON WITH A JOINT APPOINTMENT IN BIOLOGY AND BIOCHEMISTRY, HAS DISCOVERED TWO GENES IN THE CICHLID FISH REGULATE SOCIAL DOMINANCE. view more 

CREDIT: UNIVERSITY OF HOUSTON

Rank in social hierarchy is a condition not solely claimed by humans. In the animal kingdom, male peacocks exhibit brightly colored plumes to illustrate dominance, and underwater, male fish show pops of bright colors to do the same. Despite the links identified between social status, physiology and behavior, the molecular basis of social status has not been known, until now.

"We discovered that two paralogous androgen receptor genes control social status in African cichlid fish," reports Beau Alward in the Proceedings of the National Academy of Sciences. Alward is an assistant professor of psychology at the University of Houston with a joint appointment in biology and biochemistry. Paralogs are duplicate genes; androgens are hormones like testosterone necessary for male sexual development.

"Testosterone binds to androgen receptors to exert its effects. What we found through genome editing is that the two genes encoding these receptors are required for different aspects of social status," said Alward. "This type of coordination of social status may be fundamental across species that rely on social information to optimally guide physiology and behavior."

To make his discovery, Alward used CRISPR/Cas9 gene editing, often referred to as "genetic scissors." The developers of the CRISPR method recently won the Nobel Prize in Chemistry for their invention. The technique allowed Alward to test what regulates physiological and behavioral changes.

Alward found that the two androgen-receptor (AR) paralogs - AR alpha (ARα) and AR beta (ARβ) that exist in cichlid fish - regulate traits that determine their survival and mating opportunities.

"We've shown that ARβ controls coloration, a super key function because females prefer to mate with those that are brightly colored, and that ARα controls behavior, which can change rapidly due to social cues and also determines mating success," said Alward.

This independent regulation of changes in color and behaviors by two receptors suggests there are independent mechanisms in the brain, and that allows Alward and his team to study them in isolation.

"The fact that these are independent implies that this is how flexible social status could be regulated by similar independent mechanisms in other species, including humans," said Alward.

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Group size and makeup affect how social birds move together

Scientists have used high-resolution GPS tracking methods to provide new insights into how differently sized animal groups move and interact with their environment

ELIFE

Research News

 

IMAGE: THIS PHOTO SHOWS SOME OF THE VULTURINE GUINEAFOWL FROM THE STUDY BY DANAI PAPAGEORGIOU AND DAMIEN FARINE view more 

CREDIT: DAMIEN R FARINE (CC BY 4.0)

Scientists have shown that the size and makeup of groups of social birds can predict how efficiently they use and move through their habitat, according to new findings published today in eLife.

The study suggests that intermediate-sized groups of vulturine guineafowl - a ground-dwelling social bird found in east African savannahs - exhibit the most effective balance between a decreased ability to coordinate movements and increased accuracy of navigation.

These findings add to our understanding of a key question in animal sociality - namely, whether groups have an optimal size - by showing that the number of individuals in a group determines the ability of that group to make the most effective use of their environment.

"For many social animals, larger groups benefit from information pooling, where inputs from multiple individuals allow for more accurate decisions about navigation," explains first author Danai Papageorgiou, IMPRS Doctoral Student at the Department of Collective Behaviour, Max Planck Institute of Animal Behavior, and at the Centre for the Advanced Study of Collective Behaviour, University of Konstanz, Germany. "However, as groups become larger they start to face challenges in coordinating their actions, such as reaching a consensus about where to go next or maintaining cohesion as they move through vegetation."

Papageorgiou and her PhD advisor, Professor Damien Farine, investigated the relationship between the size and collective movement of groups of vulturine guineafowl. They predicted that the optimal group size of these birds would be determined by the balance between their ability to coordinate movement and their ability to make accurate decisions when navigating.

The team fitted individual birds from 21 distinct social groups with GPS tags and collected movement data over five two-month-long seasons. They used these data to calculate the groups' habitat use, including their home-range size, the distance that they travelled each day and their movement speed while 'on the go'. By observing the groups each week, they could also measure the size of each group and record their makeup. Specifically, they recorded the number of chicks in each group, as they predicted that the birds' movement abilities may be restricted when there are more chicks because they are slower and much more vulnerable to predators.

The researchers found that intermediate-sized groups, consisting of 33-37 birds, ranged over larger areas and achieved this by travelling shorter distances each day, compared to smaller and larger groups. They also explored the most new areas. These results suggest that intermediate-sized groups were more efficient in using the space, potentially encountering more resources while spending less energy and lowering their chances of being tracked by predators. Additionally, data collected on the birds' reproductive success reinforced the fact that intermediate-sized groups benefited from these movement characteristics, as they also had more chicks.

However, the study also found interesting consequences of having a beneficial group size for movements. Groups with many chicks, despite being the optimal size, had more restricted home ranges. This was likely because the chicks needed more protection from predators, and therefore stayed in the protected vegetation for longer periods of time, and their small sizes slowed down the group while moving.

As a result, the study showed that intermediate-sized groups were in fact rarer than smaller and larger groups. Papageorgiou and Farine suggest this is because the benefits of being in an optimal-sized group makes the size of these groups less stable. For example, higher reproductive success inevitably pushes the group past its optimal group size.

"Our study highlights how all groups are not equal, with the effects of group size and composition playing a major role in shaping how social species use their habitat," Farine says. "What is particularly interesting is that optimally sized groups are not expected to be common. Future studies should investigate whether these relationships change across different environmental conditions, and how animal groups cope with the different challenges that each season brings."

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Reference

The paper 'Group size and composition influence collective movement in a highly social terrestrial bird' can be freely accessed online at https://doi.org/10.7554/eLife.59902. Contents, including text, figures and data, are free to reuse under a CC BY 4.0 license.

Media contact

Emily Packer, Media Relations Manager
eLife
e.packer@elifesciences.org
01223 855373

About eLife

eLife is a non-profit organisation created by funders and led by researchers. Our mission is to accelerate discovery by operating a platform for research communication that encourages and recognises the most responsible behaviours. We work across three major areas: publishing, technology and research culture. We aim to publish work of the highest standards and importance in all areas of biology and medicine, including Ecology, while exploring creative new ways to improve how research is assessed and published. We also invest in open-source technology innovation to modernise the infrastructure for science publishing and improve online tools for sharing, using and interacting with new results. eLife receives financial support and strategic guidance from the Howard Hughes Medical Institute, the Knut and Alice Wallenberg Foundation, the Max Planck Society and Wellcome. Learn more at https://elifesciences.org/about.

To read the latest Ecology research published in eLife, visit https://elifesciences.org/subjects/ecology.

Treating opioid addiction in primary care helps patients and cash-strapped medical practices

AMERICAN ACADEMY OF FAMILY PHYSICIANS

Research News

 

Buprenorphine-based treatment for opioid addiction is in short supply in many areas of the United States. And while many physicians want to offer it, clinics are unsure how to offer buprenorphine therapy in a financially sustainable way. A team of researchers at Harvard Medical School conducted financial cost and revenue analysis for four different approaches to delivering buprenorphine-based treatment in primary care practices. The approaches differed based on who in the clinic delivered the majority of face-to-face care, the presence of nurse care managers, and whether care was delivered in traditional one-on-one or group settings.

Microsimulation modelling found that all four approaches to care produced positive net revenue after the first year, and net revenues were consistently highest for rural practices. Physician-led treatment and shared medical visits, both of which relied on nurse care managers, consistently produced the greatest net revenue gains. Additionally, net revenues were positive for all primary care practices that had at least nine patients in buprenorphine treatment per provider at any given time and no-show rates less than 34 percent. The findings suggest that in the current fee-for-service-dominated environment, offering office-based therapy for opioid addiction with buprenorphine can be a financially sustainable choice for cash-strapped primary care practices, despite hurdles.

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Financing Buprenorphine Treatment in Primary Care: A Microsimulation Model

Sanjay Basu, MD, PhD, et al
Harvard Medical School, Center for Primary Care, Boston, Massachusetts
https://www.annfammed.org/content/18/6/535

Taking a scalpel to opioid painkiller risks: New studies show progress and opportunity

Surgery studies show progress and opportunity to reduce prescribing and better support pain care across many types of operations

MICHIGAN MEDICINE - UNIVERSITY OF MICHIGAN

Research News

 

Having surgery means placing complete trust in a team of professionals, and counting on them to fix what's wrong while keeping surgical risks as low as possible.

But one of those risks, surgery experts have begun to realize, has nothing to do with what happens in the operating room. Instead, it has to do with treating post-surgery pain without raising the chance that the patient will get hooked, or more dependent, on opioids.

It's a risk that affects a minority of patients - maybe 1% to 10% at most, depending on the operation. But it's not easy to tell in advance which patients will continue to seek opioid painkiller refills months after their surgery pain should have subsided.

Meanwhile, patients who already took opioids for pain before their operation face other risks from increased doses taken after surgery.

A wave of new studies led by surgeons and trainees at Michigan Medicine, the University of Michigan's academic medical center, add to the understanding of these risks. They also show what happens when surgical teams work together to reduce the emphasis on, and supply of, opioid painkillers while still seeking to ease surgery patients' pain.

Sustained success

It's already been several years since a U-M team published some of the first evidence about the risks of long-term post-surgical opioid use. The team also took the novel step of contacting patients to find out how many opioid pills they had actually taken for their surgical pain, compared with what they'd been prescribed.

That led them to develop prescribing guidelines for sharp reduction in opioid prescribing, and use of other pain medications and patient education. They formed the Michigan Opioid Prescribing and Engagement Network, or Michigan OPEN, to help spread the word about the guidelines and about the need for proper disposal of leftover pain medicines to keep them from being diverted to recreational use.

A trial of the guidelines at Michigan Medicine's hospitals showed opioid prescribing declined without increasing patients' pain. That was enough to convince dozens of hospitals across the state of Michigan to adopt the guidelines, and work together to refine them, through the Michigan Surgical Quality Collaborative funded by Blue Cross Blue Shield of Michigan.

Now, a new paper published in BMJ Quality & Safety shows the long-term effects of that statewide effort. It includes data from 36,022 patients who received a prescription for an opioid painkiller to help them with the pain associated with one of 9 operations between February 2017 and May 2019 in 69 hospitals across Michigan.

In all, the average surgical opioid prescription size was cut in half over this time, from an average of 30 tablets to about 15. The amount of opioids patient took from those prescriptions also dropped, from an average of 13 tablets to an average of 6, and the percentage of patients who sought a refill for their opioid prescription went down.

Despite the reduction in prescribing and consumption, there was no increase in the amount of pain patients reported in follow-up surveys, or decrease in their satisfaction with their surgery experience. These follow-up data are available for more than 15,000 of the patients.

Prescribing was more in line with guidelines instead of varying greatly by surgeon and procedure, especially for less commonly performed operations that had previously varied widely.

"This project illustrates the power of engaging and empowering physicians, nurses, and other healthcare workers across the state to help improve care for all of our patients," says Craig Brown, M.D., the general surgery resident who is the first author of the new paper. "There's still room to improve opioid prescribing, but teamwork like that exhibited through this MSQC and M-OPEN partnership has made a lasting impact on post-operative prescribing and made a huge difference in our communities."

Surgery professor Michael Englesbe, M.D., who co-leads Michigan OPEN and leads MSQC, is the study's senior author. "We are fortunate in Michigan that our physicians, nurses, state policy makers, and major private payer are able to partner, coordinate efforts and rapidly improve care for patients in our State," he says.

Opioids and hernia surgery

Every year, nearly 800,000 Americans - most of them men - have surgery for the most common kind of hernia, called an inguinal hernia. And according to results of a new study, about 12,000 of them might end up using opioid painkillers long-term, months after the pain from their operation should have subsided.

The study led by U-M surgery resident Ryan Howard, M.D., and surgery associate professor Dana Telem, M.D., M.P.H., is published ahead of print in the Annals of Surgery. It looked at national data on hernia operations done from 2008 to 2016, on patients who got their insurance through a major private insurer including through jobs and Medicare Advantage plans. It only included patients who were "opioid-naïve," meaning they were not already using opioid at the time of surgery.

The team found that of all the patients who received an opioid prescription around the time of surgery, 1.5% of these patients continued refilling opioid prescriptions for at least 3 months after their hernia repair. This means that these patients are continuing to use opioids - medications that carry many risks -long after the surgical pain should have subsided. While this is a lower percentage than those seen in other studies of post-surgery chronic opioid use, it's still concerning because the operation is so common, the authors say.

A critical finding of this study was that patients who filled an opioid prescription in the month before their operation were four times more likely to become persistent opioid users after surgery. Importantly, over half of these preoperative prescriptions were provided by surgeons. The study team believes this may reflect the practice of "convenience prescribing," where a provider makes sure a patient has their prescription filled and ready before they even have their operation. Given that this dramatically increases the risk of persistent opioid use, it may be time for surgeons to abandon this practice.

Additionally, patients who had a major complication of their operation, or who had anxiety, disruptive mood disorder, alcohol or substance abuse disorders or pain disorders were more likely to go on to become chronic opioid users.

Opioids after cancer surgery

One of the key goals of surgical opioid prescribing research is to "right size" the painkiller prescriptions that patients receive before or immediately after their operations so that they have the pills they need to control their pain once they get home, but don't have so many that leftovers pose a risk to them or someone in their household.

A new study in the Journal of Surgical Oncology by a team led by U-M medical student Nicholas Eyrich, M.S., and general surgery chief resident Jay S. Lee, M.D., shows what breast cancer and melanoma surgery patients at a major medical center actually reported receiving and using.

They interviewed 439 patients within a few months of their operation, and found that on average patients took just two of the opioid tablets they were prescribed, no matter what operation they had or whether they received a prescription of 5, 10 or 20 tablets.

While the vast majority of patients said they received instructions for taking opioids, less than half said a member of the care team had talked with them about using non-opioids first or about the risk of addiction to opioids. Less than a third said they were told about the risks of having unused opioids in the home, and only a quarter said they had discussed safe disposal of unused opioids with a member of the care team.

Persistent use leads to higher costs

Another new paper, led by Lee and Michigan OPEN co-leader and plastic surgeon Jennifer Waljee, M.D., M.P.H., M.S., shows that patients who become persistent opioid users for the first time after surgery cost the health system more.

Writing in the Annals of Surgery, they report data from more than 133,000 people nationwide who did not take opioids before they had surgery, of whom 8,100 continued refilling opioid prescriptions for months after their operations.

The average health care bills for each of those patients were $2,700 higher than for those who didn't develop persistent use. The increased spending kept going for at least six months after surgery, at an average rate of $200 a month.

Outpatient surgery risks for those already taking opioids

Older patients who take high doses of opioids, and then go on to have outpatient operations, are more likely to die within a few months of surgery than those who weren't taking opioids, according to a recent study published in JAMA Surgery.

The team, led by Katherine Santosa, M.D., M.S., U-M chief resident in plastic surgery, and Waljee, looked at data from Medicare enrollees over 65 who had common outpatient procedures between 2009 and 2015. They included people who had gallbladder, thyroid, hernia, carpal tunnel, hemorrhoid, varicose vein and prostate surgery, among others.

The team did the study because opioid use is known to be associated with falls, fractures and breathing issues in older adults, especially those who also take medications called benzodiazepines for anxiety or sleep issues.

Although only a small percentage of patients died within 90 days of their outpatient operation - just 471 of the more than 99,000 studied, or 0.5% - the researchers were able to see a difference based on opioid use. It was visible even after adjusting the results for differences in age, sex, race, type of surgery, and multiple measures of health.

The authors call for more attention to be paid to the risks of surgery for people who take opioids on a long-term basis, especially those taking higher doses. Helping them reduce their opioid use before their operation could reduce their risk, and also help them respond better to any opioids prescribed for pain control after surgery. The authors also note that prescribing naloxone, a drug that can "rescue" someone from an opioid overdose, might be wise.

Englesbe, Telem and Waljee are faculty in the U-M Department of Surgery and members of the U-M Institute for Healthcare Policy and Innovation. Waljee directs the Center for Healthcare Outcomes and Policy, where Brown and Howard are current fellows and Lee is a former fellow.

Learn more about the full spectrum of opioid-related research and scholarship at U-M through the Opioid Solutions Initiative.

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