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DALLAS - April 30, 2021 - UT Southwestern scientists successfully employed a new type of gene therapy to treat mice with Duchenne muscular dystrophy (DMD), uniquely utilizing CRISPR-Cas9-based tools to restore a large section of the dystrophin protein that is missing in many DMD patients. The approach, described online today in the journal Science Advances, could lead to a treatment for DMD and inform the treatment of other inherited diseases.

"Thousands of different mutations causing Duchenne have been identified, but they tend to cluster into certain parts of the dystrophin gene," says study leader Eric Olson, Ph.D., professor and founding chair of molecular biology at UTSW. Some of these mutations cause muscle cells to produce short, less functional versions of the dystrophin protein. "The power of our method is that you don't need a new gene editing strategy for every patient with a new mutation; you can correct multiple different mutations with a consolidated approach."

Olson and his colleagues took advantage of the fact that the enormous dystrophin gene is composed of many different segments, called exons, some of which are dispensable. In about 8 percent of boys with DMD, nearly half of the dystrophin protein is missing due to mutations within exon 51 that cause the body to stop protein production. The researchers developed multiple successful CRISPR-Cas9 nucleotide gene editing strategies to skip the errant "stop" signal, restoring production of 97 percent of the protein. Some strategies worked by removing neighboring exons, while others utilized tiny genetic additions or subtractions to get protein production back on track.

When the researchers used the new approach in mice with dystrophin mutations, functioning copies of dystrophin returned to more than half of all leg muscle fibers within three weeks. Moreover, the group showed that they could use isolated cells from mice or humans with DMD to test whether the approach would be successful for a particular patient ahead of treatment. The isolated cells are coaxed to develop into induced pluripotent stem cells (iPS cells) and then heart cells. In a dish, researchers can observe whether the gene editing program helps the heart cells work better.

"Using iPS cell-derived cardiomyocytes from DMD patients, we rapidly tested our nucleotide gene editing approaches, demonstrating the recovery of the dystrophin protein," says Francesco Chemello, Ph.D., a postdoctoral researcher in the Olson lab and first author of the paper.

DMD affects about one in five thousand males at birth and leads to progressively worsening muscle weakness in early childhood. The disease is caused by one of more than 7,000 different mutations in the gene for dystrophin - a protein that normally acts as a scaffold to support muscle fibers. Without fully functional dystrophin, the skeletal and heart muscles of people with DMD degenerate over time, eventually leading to death.

The gene therapy reported in the study is not ready for humans with DMD yet. Additional safety studies in animals are needed first, as well as more work to optimize the virus that carries the gene editing machinery to muscle and heart cells. But by showing that multiple CRISPR-Cas9 strategies can correct a mutation, the researchers have expanded the toolbox of potential gene therapy options for DMD.

"Every cell in the human body has 3 billion letters of DNA sequence in its genome, and this method makes it possible to correct large deletions in the DMD gene by specifically swapping one of these letters," says Olson. "That level of specificity and efficiency is remarkable."

TAMPA, Fla. - A hallmark of cancer is its ability to evade the immune system. It is why researchers are focused on finding new strategies and targets to jumpstart the immune system so it can mount a response against tumors. One such target is the inhibitory receptor T-cell immunoglobulin and mucin domain 3 (TIM-3), a protein that is overexpressed in many different types of cancer and is associated with poor patient outcomes. It is known to block the activity of immune cells, such as dendritic cells, but how remains unclear. In a new article published in the journal Immunity, Moffitt Cancer Center researchers show that TIM-3 inhibits the STING signaling pathway in dendritic cells, thereby blocking their ability to elicit an immune response.

Dysregulation of the immune system is an important contributor to cancer development. Many new therapies target T cells to restimulate them to attack cancer cells. However, dysregulation of dendritic cells and other cells of the immune system can also contribute to the development of cancer. Dendritic cells are specialized cells that capture, process and display antigens, which are then recognized by T cells that become activated. Cancer patients often have dysregulated or lower dendritic cells levels, suggesting that approaches to augment their activity may be effective against cancer.

Previously, Moffitt researchers demonstrated that antibodies that block TIM-3 enhanced the activity of chemotherapy in mouse models of breast cancer, even though T cells in this model had very low levels of TIM-3. They also found that the effect of TIM-3 blocking antibodies was dependent on the presence of dendritic cells.

To further understand the role of TIM-3 in dendritic cells, the Moffitt team performed preclinical laboratory experiments in cell lines and mouse models. They discovered that TIM-3 inhibits activation of the cGAS-STING pathway and downstream immune cell activation. The cGAS-STING pathway is an important mediator of immune cell function and activators of STING can stimulate anti-tumor activity of immune cells. They found that TIM-3 was able to block activation of the STING pathway in dendritic cells by inhibiting the internalization of double-stranded DNA derived from tumor cell debris in the extracellular space. The researchers also confirmed that chemotherapy plus TIM-3 blockade effectively prevented tumor growth in mice, which was dependent on STING activity.

"Our results suggest that we can enhance T cell activity by targeting TIM-3 to activate the STING pathway in dendritic cells," said Brian Ruffell, Ph.D., associate member of the Department of Immunology at Moffitt. "While more research is needed, we believe understanding this process will help us develop combinations with anti-TIM-3 antibodies as a possible therapy for certain types of cancer."

Marie-Claude Bourgeois-Daigneault and her team at the CRCHUM are using mice to show how a combination of peptides and oncolytic viruses, used as an adjuvant, can provide effective immunization against cancer.

In her laboratoryat the University of Montreal Hospital Research Centre (CRCHUM), Marie-Claude Bourgeois-Daigneault and a team of scientists usually modify viruses to make them specific to the cells of a tumour.

Once in the patient's body, these viruses, called oncolytic viruses, infect and specifically destroy the cancer cells without touching healthy cells. These viruses can even stimulate the immune system so that it is better armed to recognize and kill malignant cells. This is immunotherapy.

In a study published in Nature Communications, the scientific team at the University of Montreal Hospital Research Centre (CRCHUM) show how they came to create an effective personalized vaccine by combining oncolytic viruses with small synthetic molecules (peptides) specific to the targeted cancer.

Bourgeois-Daigneault is a professor in Université de Montréal department of microbiology, infectious diseases and immunology), a member of the Institut du cancer de Montréal and the principal author of the study, led by Dominic Guy Roy.

Here, she explains her team's approach and findings.

In your study, you use oncolytic viruses as anti-cancer vaccine adjuvants to immunize mice. How do you do it?

For a vaccine to induce an immune response, it has to contain elements that stimulate the cells of the immune system--the famous white blood cells.

These elements, called adjuvants, are ingredients in all vaccines. They allow the human body to perceive potential danger and contain the threat by sending its army of immune cells.

Our approach consists of using oncolytic viruses to stimulate this immune response and direct it towards the cancer. To succeed, we create a vaccine by mixing viruses with synthetic peptides (antigens) that resemble the targeted cancer.

Because it's true that, to be effective, the vaccine has to be personalized for each patient, based on the mutations specific to each cancer cell. Thanks to the identification work done by other research teams, we can predict what peptides to use for each patient through the information obtained from a biopsy.

The advantage of our approach is that the oncolytic viruses themselves have the power to kill the cancer. We can thus attack the cancer on two fronts: kill it directly with the virus and induce an immune response, thanks not only to the virus, but to the vaccine as well.

On our mice, we were able to show the efficacy of the resulting immunization.

What sets your vaccine strategy apart from clinical trials currently being conducted by other teams?

The other clinically tested personalized anti-cancer vaccines don't use oncolytic viruses as vaccination adjuvants. Therefore, their adjuvant doesn't have direct anti-cancer effects whereas, in our case, our viruses can destroy the cancer.

An anti-cancer vaccine using oncolytic viruses is currently being tested in Canada and the U.S. However, it is not personalized. Instead, it targets certain specific cancers that have an antigen in common. By targeting this antigen, the vaccine induces an immune response.

In this case, the oncolytic viruses have to be genetically modified to allow for the insertion of the antigen into the genome of the viruses.

This is very different from our approach. We can target all cancers without genetic modification. A little like putting together Lego--it's a matter of mixing synthetic peptides resembling the cancer with the chosen virus. It will be a lot easier to implement in a clinical setting.

What challenges need to be addressed before your personalized anti-cancer vaccination approach can be translated to clinical practice?

The main challenge is to identify the mutations that we want to vaccinate against. Because a cancer is unique in its tens or hundreds of mutations, but only a few of them, once targeted, will have a therapeutic effect and allow us to eliminate it.

The identification of these mutations is the key step that still has to be optimized. Fortunately, many groups are working in this area.

Greater Presence of Family Physicians, Midwives May Be Key Component to Decreasing Cesarean Delivery Rates

Surgical cesarean births can expose new mothers to a range of health complications, including infection, blood clots and hemorrhage. As part of Healthy People 2020 and other maternal health objectives, the state of California exerted pressure to reduce cesarean deliveries, and statewide organizations established quality initiatives in partnership with those goals. In this study, researchers from Stanford University and the University of Chicago examined unit culture and provider mix differences on hospital and delivery units to identify characteristics of units that successfully reduced their cesarean delivery rates. The mixed-methods study surveyed and interviewed labor and delivery teams from 37 California hospitals that were participating sites in the California Maternal Quality Care Collaborative's Supporting Vaginal Birth initiative. Respondents at successful hospitals included more family physicians and midwives, and physicians who had been in practice for less time. The study identified a number of unit culture factors that also predicted success. The authors conclude, "Family medicine, a discipline that strongly identifies itself as valuing patient-centered care and shared decision-making, may be in a unique position to contribute positively to this aspect of culture change on labor and delivery units."

Culture That Facilitates Change: A Mixed Methods Study of Hospitals Engaged in Reducing Cesarean Deliveries
Emily C. White VanGompel, MD, MPH, et al
University of Chicago, Pritzker School of Medicine, Department of Family Medicine, Chicago, Illinois
https://www.annfammed.org/content/19/3/249

Psychotherapy, Paired With Pharmacotherapy, Is More Effective in Treating Depression Than When Kept Separate

Most patients with depression are treated in primary care, however, relatively few clinical trials for treating depression have focused on primary care. Researchers at the Vrije University Amsterdam examined the effects of the two major approaches to treating depression: psychotherapy and pharmacotherapy, as well as combined treatment and care-as-usual. The study integrated the results of 58 randomized controlled trials with a total of 9,301 patients. Results concluded that both psychotherapy and pharmacotherapy were significantly more effective than care-as-usual or waitlist control. However, they found no significant difference between psychotherapy and pharmacotherapy as stand-alone treatments. Combined treatment, particularly in studies that included cognitive behavioral therapy, was better than either pharmacotherapy or psychotherapy alone. Treatment in primary care should be organized to accommodate any of these treatments in response to patients' preferences and values, the authors write.

Psychologic Treatment of Depression Compared With Pharmacotherapy and Combined Treatment in Primary Care: A Network Meta-Analysis
Pim Cuijpers, PhD, et al
Vrije University, Amsterdam, Department of Clinical, Neuro and Developmental Psychology and Amsterdam Public Health Research Institute; The Netherlands
https://www.annfammed.org/content/19/3/262

Newer Class of Fluoroquinolone Antibiotics May Present Reduced Risk of Tendon Ruptures

It's widely understood that people taking a common class of antibiotics, like ciprofloxacin and levofloxacin, run the risk of tendonitis and tendon ruptures. However, a new analysis sheds light on newer, third-generation fluoroquinolones and suggests they may have a lower risk of Achilles tendon rupture. Researchers from Jichi Medical University in Tochigi, Japan, used health care administrative data to identify 504 patient cases of Achilles tendon ruptures with co-occurrence of antibiotics. They found that third-generation fluoroquinolones were not associated with an increase in Achilles tendon rupture. First- and second-generation fluoroquinolones, like ciprofloxacin and ofloxacin, were at elevated risk of tendon rupture, which was consistent with previous evidence. Third-generation fluoroquinolones include moxifloxacin, garenoxacin, sitafloxacin, prulifloxacin and pazufloxacin, some of which are not yet approved by the Food and Drug Administration in the United States. The authors note that further studies are required to determine the risks of third-generation fluoroquinolones for other rare adverse events, such as heart damage.

Association Between Third-Generation Fluoroquinolones and Achilles Tendon Rupture: A Self-Controlled Case Series Analysis
Takashi Chinen, MD, et al
Jichi Medical University, Department of Clinical Oncology, Tochigi, Japan
https://www.annfammed.org/content/19/3/212

Shared Medical Appointments Help Patients With Prediabetes

Researchers from the Cleveland Clinic and Takeda Pharmaceutical Company conducted a study to evaluate the effectiveness of shared medical appointments for people with pre-diabetes compared with a group of patients receiving usual care. Shared medical appointments are typically delivered in a medical clinic by physicians and other health care providers. Within the context of this study, shared medical appointments consisted of patients consulting with their doctors one-on-one and then joining a group of similar patients to set goals and review lab results with the same family physician and a diabetes educator. Researchers also assessed the impact of attending a shared medical appointment versus care-as-usual on chronic conditions such as high blood sugar, cholesterol and blood pressure.

Over 24 months, patients who took part in shared medical appointments lost more weight than those who received usual care. By the conclusion of the study period, patients who attended shared medical appointments showed better outcomes in managing the aforementioned chronic conditions than those patients who received usual care.

Researchers concluded that shared medical appointments may provide an effective model of treatment for patients with pre-diabetes. As the diabetic epidemic continues, the authors call for more research using shared medical appointments to manage prediabetes in health care systems.

Shared Medical Appointments and Prediabetes: The Power of the Group
Aphrodite Papadakis, MD, et al
Department of Family Medicine, Cleveland Clinic, Cleveland, Ohio
https://www.annfammed.org/content/19/3/258

Interdisciplinary Consults Can Help Primary Care Doctors Effectively Manage Patients Living with Chronic Pain and Addiction

Between 11% to 40% of adults in the United States experience chronic pain, and primary care physicians may feel ill-equipped to effectively and safely care for patients with chronic pain, addiction or both. Researchers from Tufts University conducted a study to evaluate the effectiveness of an interdisciplinary consultation service that supports primary care physicians who care for patients experiencing chronic pain and addiction. The goal was to identify new and effective strategies that clinics can use to support PCPs.

From that interdisciplinary consultation service, the researchers collected and thematically analyzed 66 referral questions and 14 interviews with PCPs to better understand the types of support physicians would find most beneficial.

PCPs' expressed needs included needing expertise in addiction, safe prescribing of opioids, non-opioid treatment options, communication strategies for difficult conversations, a comprehensive review of the case, and a biopsychosocial approach to management. Some additional needs were identified after interviews, including confirmation of their medical decision-making process, emotional validation, feeling more control, having an outside entity take the burden off the PCP for management decisions, boundary setting and reframing the visit to focus on the patient's function, values and goals.

The authors concluded that an interdisciplinary consultation service can effectively support primary care physicians who care for patients battling pain and addiction. They then offer some potential strategies that health systems can use to support PCPs in this important role.

Multidisciplinary Approach for Managing Complex Pain and Addiction in Primary Care: A Qualitative Study
Randi Sokol, MD, MPH, MMedEd, et al, Department of Family Medicine, Tufts University School of Medicine, Boston, Massachusetts
https://www.annfammed.org/content/19/3/224

Antibiotics: Patient Expectations and Doctors' Prescribing Habits May Contribute to Antimicrobial Resistance

Inappropriate antibiotic prescribing for upper respiratory tract infections contributes to antibiotic resistance, making some bacterial infections difficult to treat. This often leads to higher medical costs, prolonged hospital stays and increased mortality. Still, many physicians report prescribing antibiotics at their patients' request. To address patients' expectations for antibiotic prescribing for URTIs, researchers conducted an experiment in which study participants were assigned brief educational videos to watch on a tablet immediately prior to their appointment.

The authors randomized patients into three groups - one that viewed a presentation about the futility of antibiotic treatment of URTIs; a second group that viewed a presentation about the adverse effects associated with antibiotics; and a third control group that learned about the benefits of healthy diet/exercise. The researchers then measured the effects of the presentations on patients' beliefs that antibiotics are helpful for URTIs; their expectations to be prescribed an antibiotic; and whether they were actually prescribed antibiotics for their URTIs. Participants who viewed either the futility or adverse effects presentations had greater reductions in their expectations of receiving antibiotics compared to the group that viewed the video about the benefits of healthy/diet and exercise. However, there was no significant difference between the three groups when it came to doctors actually prescribing antibiotics to patients. Researchers concluded that a brief, tablet-based waiting room intervention significantly changes participants' expectations on receiving antibiotics for URTIs, but that future efforts to improve antibiotic prescribing need to involve both patients and their doctors.

Reducing Expectations for Antibiotics in Patients With Upper Respiratory Tract Infections: A Primary Care Randomized Controlled Trial
Anna Perera, MBChB, et al
University of Auckland, Department of Psychological Medicine, Auckland, New Zealand
https://www.annfammed.org/content/19/3/232

New Study Examines Connection Between Oral and General Health in Patients With Diabetes-Related Oral Health Issues

Individuals with diabetes are at greater risk of developing oral health issues, like gum disease, yet care for these linked health issues are usually disconnected, split between primary care and dental care. A research team from the University of Amsterdam developed an intervention that provided primary care-based oral health information and dental referrals for patients with diabetes. In a cluster randomized controlled trial, 764 patients from 24 primary care practices received either the oral health support or standard primary care. Participants were asked to rate their oral health quality of life, as well as their general health and any oral health complaints, at the start and end of the study. Analysis showed that individuals who received the primary care-based oral health support intervention had a significant increase in their self-reported oral health quality of life when compared with the control group. The authors conclude that, "patients with type 2 diabetes who attend primary diabetes care can benefit from extra attention to oral health." They add, "It also further reflects the concept of oral health and general health being connected."

Implementation of an Oral Care Protocol for Primary Diabetes Care: A Pilot Cluster-Randomized Controlled Trial
Martijn J.L. Verhulst, Ph.D., MSc, et al
Vrije Universiteit, Department of Periodontology, Academic Centre for Dentistry, Amsterdam, The Netherlands
https://www.annfammed.org/content/19/3/197

Improving Smoking Cessation Counseling and Blood Pressure Quality Metrics in Primary Care Requires Both Operational Changes and Consideration of Local Context

In order to make meaningful gains in cardiovascular disease care, primary care medical practices should adopt a set of care improvements specific to their practice size and type, according to a new study from the national primary care quality improvement initiative EvidenceNOW. High blood pressure and smoking are among the biggest risk factors associated with cardiovascular disease. Primary care physicians help patients manage high blood pressure and provide smoking cessation interventions.

Researchers found that there is no one central playbook for all types of practices, but they did identify combinations of practice characteristics, amount of practice facilitation, and operational changes linked with improved cardiovascular disease care. Smaller, solo and clinician-owned practices that changed routine aspects of their process, such as training medical assistants to perform accurate blood pressure readings; allowing staff to take repeated blood pressure measures and note second readings in electronic medical records; and equipping clinicians with the tools to perform smoking screening and cessation referrals, were able to make substantial improvements.

In addition, working with a practice facilitator helped. Smaller practices that participated in a moderate amount of facilitation were able to make these improvements. However, for larger hospital or health system-owned practices and Federally Qualified Health Centers more facilitation was necessary, leading researchers to conclude that "making operational changes alone--in certain clinical settings--was insufficient to achieve meaningful improvements." In practices that are part of larger, more complex systems, external facilitation along with prioritization of operational changes may be critical to successful quality improvement.

Improving Smoking and Blood Pressure Outcomes: The Interplay Between Operational Changes and Local Context Deborah J. Cohen, Ph.D., et al
Oregon Health & Science University, Department of Family Medicine, Portland, Oregon
https://www.annfammed.org/content/19/3/240

In a corresponding editorial titled "The Need for Coaches in a Clinical World", Robert L. Phillips, Jr, MD, MSPH, of the American Board of Family Medicine, identifies a common thread running throughout five studies in the May-June 2021 issue Annals of Family Medicine. Dr. Phillips notes that practice facilitation is key to improving primary care at a systems level. Each study he discusses investigates a different, though widely experienced, medical issue, including cardiovascular disease, antibiotic resistance, chronic pain and addiction and cesarean births. He writes that these studies offer meaningful insights about facilitating behavior change, the importance of culture, and respecting complexity.

The Need for Coaches in the Clinical World
Robert L. Phillips, Jr, M.D., MSPH
American Board of Family Medicine, Lexington, Kentucky
https://www.annfammed.org/content/19/3/194

COVID-19 Pandemic Presents Opportunities to Ensure Health Care is Fully Person-Centered

The COVID-19 pandemic has forced many physicians to approach patient care in completely different ways. Elena Rosenbaum, MD, an associate professor in the Department of Family and Community Medicine at Albany Medical College in New York, believes this is a critical time to refocus and ensure that health care is person-centered, encompasses all modifiable health determinants, and helps individuals achieve health rather than primarily manage disease. This is especially important now that COVID-19 has emphasized the flaws of the current health care system and the health inequities that exist in this country.

Changing the US health care system is daunting, but Rosenbaum is optimistic that the challenges we have faced during the pandemic will help bring about meaningful reform. She writes about the need for a multi-pronged approach that eliminates fee-for-service payment and advocates for universal health care or alternative payment models that allow physicians to address lifestyle, behavior and social determinants of health with their patients. Rosenbaum also recognizes the benefits of telemedicine, which has given doctors a window into patients' worlds and helped them stay connected to their most vulnerable patients. With the shift in how health care is administered, she believes now is the time for doctors to proactively reduce health disparities by examining and addressing systemic racism in medical care and collaborating with community members, public health experts and governments to break down health silos and bring about meaningful systemic change for our patients.

A Thoughtful Rebirth of Health Care: Lessons From the Pandemic
Elena Rosenbaum, MD
Department of Family and Community Medicine, Albany Medical College, Albany,York
https://www.annfammed.org/content/19/3/274

Personal, Environmental, Workplace and Population Factors Influence Family Physicians' Practice Scope

Although new family medicine graduates intend to provide a broader scope of practice than their senior counterparts, individual family physicians' scope of practice has been decreasing, with fewer family physicians providing basic primary care services, such pediatric and prenatal care. Russell et al conducted a study to explore family medicine graduates' attitudes and perspectives on modifiable and non-modifiable factors that influenced their scope of practice and career choices. The authors conducted five focus group discussions with 32 family physicians and explored their attitudes and perspectives on their desired and actual scope of practice. Using a conceptual framework to understand the influences on practice scope, the authors found that personal factors played a role on desired scope while workplace, environmental and population factors influenced actual practice scope. Stressors that occurred in these four categories often caused family physicians to narrow their scope of practice. Understanding personal, environmental, workplace and population factors that influence practice scope can inform specific interventions that create desirable jobs for family physicians and improve their ability to meet changing population needs. Supportive factors of a broader-scope practice include training and access to additional medical education after training; access to mentors; strong organizational leadership; and team-based care.

Drivers of Scope of Practice in Family Medicine: A Conceptual Model
Amy Russell, MD, et al
University of North Carolina Health Sciences at Mountain Area Health Education Center and HCA Healthcare, Asheville, North Carolina
https://www.annfammed.org/content/19/3/217

Health Care Industry Has Ways to Go Before Reaching Its Goal of Translating Care Into Clinical Quality Data

Family physicians provide nearly 20% of all clinical outpatient visits, translating to 200 million visits in the US annually, according to the Centers for Disease Control and Prevention. Frontline clinicians continue to report failures of certified electronic health records to meet federal certification requirements and electronic reporting needs.

Researchers created the Trial of Aggregate Data Exchange for Maintenance of certification and Raising Quality, a randomized controlled trial, to assess whether quality measure reporting could be made a byproduct of clinical care and quality improvement. They recruited family physicians from four health systems. A total of 256 family physicians participated. Of 19 measures negotiated for use, five were used by all systems. The researchers identified 15 types of errors, including breaks in data delivery; changes in measures; and nonsensical measure results. Only one system had no identified errors.

The study concluded that the secure transfer of standardized, physician-level quality measures from the four health systems, despite their having mature processes in place, proved difficult. There were many errors that required human intervention and manual repair, which precluded full automation. The study reconfirms that despite widespread health information technology adoption and federally meaningful use policies, health care remains far from reaching its goals of making clinical quality reporting a reliable byproduct of care.

Clinical Quality Measure Exchange Is Not Easy
Robert L. Phillips, MD, MSPH, et al
American Board of Family Medicine, Lexington, Kentucky
https://www.annfammed.org/content/19/3/207

Medical Student Learns Firsthand the Power of Long-Term Patient-Physician Relationships and Difficulties When They End

Melissa B. Hill, BS, a medical student at Icahn School of Medicine at Mount Sinai, writes a first-person narrative about her relationship with a pregnant patient with whom she connected while participating in a medical school program supporting expectant mothers with limited support systems during their pregnancies. Hill writes that, though she learned in her preclinical "doctoring" courses how to build quick connections with patients, her training didn't teach her how to manage meaningful, emotionally complex connections she might form with patients during longitudinal rotations. She notes how she invested an "enormous amount of time and invested a great deal emotionally" following and supporting the pregnant patient but lacked guidelines on how to end the partnership, causing her to feel like she was abandoning a good friend. As Hill reflects on the end of this particular relationship, she writes that she learned to appreciate the power of the longitudinal physician-patient relationship and that taking care of patients also requires that she take care of herself.

It's Not You, It's Me: Learning to Navigate the Patient-Physician Relationship
Melissa B. Hill, BS
Icahn School of Medicine at Mount Sinai, New York City, New York
https://www.annfammed.org/content/19/3/271

Innovations in Primary Care

Innovations in Primary Care are brief one-page articles that describe novel innovations from health care's front lines. In this issue:

Nonprofessional Health Workers on Primary Health Care Teams in Vulnerable Communities-- Nonprofessional health mediators were recruited from disadvantaged and rural Roma Hungarian communities to contribute to primary care teams. Cross-sectional health surveys found that the health of the community workers improved over time, with significant improvements in stress and smoking cessation.
https://www.annfammed.org/content/19/3/277

SALT LAKE CITY - Today in Nature Communications, researchers at Huntsman Cancer Institute at the University of Utah report critical new insights into how cells mount an attack against melanoma tumors.

Melanoma is an aggressive type of skin cancer that can arise from excess exposure to sun, frequent sunburns, genetics, and other environmental factors. Melanoma, like all cancers, begins within cells. Specially designed and refined over billions of years, cells are experts at working to root out and fix routine errors that arise. A tumor begins when a cell makes faulty copies of itself over and over again. If left unchecked, these faulty cell copies continue to grow into complex ecosystems that become tumors. Some tumors, like melanomas, can go on to develop mechanisms to sustain themselves with blood flow and oxygen. They can also send the cancerous cells through the body to proliferate in other organs, which ultimately causes death.

Immunotherapy, which trains the immune system to fight cancer cells, can sometimes be effective in treating melanomas. Some patients experience a long-lasting and durable response to immunotherapies. Yet many patients' tumors soon learn how to outsmart the drugs.

Understanding how cells mount a defense against an aggressive tumor like melanoma piqued the curiosity of Ryan O'Connell, PhD, a cancer researcher at HCI and professor of pathology at the University of Utah Health. His lab works to understand how immune cells and cancer cells interface. He wants to better understand the sophisticated metabolic processes within and around cells and to use those insights to develop more effective cancer therapies.

In this study, O'Connell and his team uncovered a key metabolic "switch" driven by an enzyme, nicotinamide phosphoribosyltransferase, or NAMPT. They learned how NAMPT plays an important role in how certain immune cells fight melanoma tumors.

"We were interested in better understanding NAMPT because it is increased in specific immune cells within tumors, called macrophages, in response to a substance secreted by other immune cells, called interferon, which is known to be important for effective antitumor responses," says O'Connell. O'Connell and his team used next-generation RNA sequencing to determine which metabolic genes increase within immune cells in response to different tumor processes.

"NAMPT was a top hit," says O'Connell. The research team found that a specific inflammatory signaling pathway triggers NAMPT. They discovered that when this inducible NAMPT pathway is disrupted, the antitumor function of cells was also impaired.

The study was co-led by Warren Voth, PhD, a research assistant professor and member of the O'Connell Lab. Voth helped design and conduct the experiments to study the role of Nampt and also mentored lab trainees who worked on the project. Using studies of cells in a laboratory setting, Voth helped to understand how NAMPT is induced in immune cells and what happens if the immune cells block NAMPT induction. The research team then created an experiment using a mouse model system and found the same NAMPT pathway was required for the mouse cells to initiate antitumor activity. Next, the team studied data from human tumors using The Cancer Genome Atlas, a federal cancer genomics program that molecularly characterized more than 20,000 primary cancer and matched normal samples across 33 cancer types. The critical role of the NAMPT pathway was also a factor in the genomic data they analyzed.

"Based on this work, we want to understand whether novel therapies that enhance the NAMPT pathway in immune cells in patient tumors could result in improved outcomes," says O'Connell. He hopes the next step will be to understand whether therapies that strengthen this pathway in certain immune cells could be the foundation for more effective treatments. He also wants to understand whether high levels of NAMPT in tumors may predict whether a patient will respond well to some immunotherapies that have inconsistent outcomes.

This work adds to the body of evidence that the metabolic state of tumors, immune cells, and the tumor microenvironment as a whole can have profound impacts on the course of disease by controlling the identity and functionality of immune cells that either fight to destroy the tumor or act to promote cancer growth. O'Connell's team also found strong evidence that this study has applications to other cancer types.

A new Dartmouth Engineering study shows that integrating renewable energy into the American Electric Power System (AEPS) would enhance the grid's resilience, meaning a highly resilient and decarbonized energy system is possible. The researchers' analysis is based upon the incremental incorporation of architectural changes that would be required to integrate renewable energy into AEPS.

The paper, "A Hetero-functional Graph Resilience Analysis of the Future American Electric Power System," was recently published by IEEE Access.

"We concluded that there are no structural trade-offs between grid sustainability and resilience enhancements, meaning these strategic goals can be pursued simultaneously," said Principal Investigator Amro Farid, a professor at Thayer School of Engineering at Dartmouth and research affiliate at the Massachusetts Institute of Technology (MIT).

"Whether you are of one political inclination or another, value resilience or sustainability, the efforts are entirely aligned and should serve as the basis for a bipartisan consensus on the transformation of the electric power grid," said Farid.

The results of the structural analysis are the first to take into account the hetero-functionality of the grid's resources, including renewable energy, using a new method that uniquely captures the true connectedness and capabilities of the grid. Using the novel hetero-functional graph theory, which Farid has been developing for over a decade, the researchers analyzed more than 175,000 energy resources throughout the United States such as power plants, substations, and transmission lines.

"Through the hetero-functional graph theory analysis of the American Electric Power Systems, we were better able to track the systems capabilities and structural resilience as the AEPS underwent both attacks and developments," said first author Dakota Thompson, a Dartmouth Engineering PhD candidate. Dartmouth Engineering alumnus Wester Schoonenberg also contributed to the study.

The authors received funding from the National Science Foundation (NSF) as part of the American Multi-Modal Energy System (AMES) project, which supported this work.

The researchers are already working on their next project: developing a synthetic model of the AMES, including electric power, oil, natural gas, and coal infrastructure, so that the research community can study how the model can evolve to meet current and future needs.

Researchers at UC Santa Cruz have developed a novel chip-based antigen test that can provide ultrasensitive detection of SARS-CoV-2 and influenza A, the viruses that cause COVID-19 and flu, respectively.

The test is sensitive enough to detect and identify individual viral antigens one by one in nasal swab samples. This ultrasensitive technique could eventually be developed as a molecular diagnostic tool for point-of-care use. The researchers reported their findings in a paper published May 4 in Proceedings of the National Academy of Sciences.

"This is a chip-based biosensor capable of detecting individual proteins one at a time, and we show how it can be used to detect and identify the antigens for multiple diseases at the same time," said senior author Holger Schmidt, professor of electrical and computer engineering at UC Santa Cruz.

"It's a whole new way of looking for molecular biomarkers, not only for infectious diseases, but for any protein biomarkers used in medical testing," added Schmidt, who holds the Kapany Chair in Optoelectronics and directs the W. M. Keck Center for Nanoscale Optofluidics at UCSC's Baskin School of Engineering.

The current gold standard for diagnosing SARS-CoV-2 infections uses PCR technology to amplify small amounts of the virus's genomic material, and samples are analyzed in centralized laboratories such as UCSC's Colligan Clinical Diagnostic Laboratory. Antigen tests, which detect viral proteins, are faster and easier to use and have been approved for testing at the point of care (e.g., doctor's offices) and even for at-home use, but these tests are not considered accurate enough for clinical decision-making, and their results may require confirmation with a more reliable technique.

The new chip-based antigen test is not only highly sensitive, but also enables simultaneous testing for multiple viruses from one sample. This is important for diseases such as COVID-19 and flu which have similar symptoms. Measures implemented to control the COVID-19 pandemic have reduced the incidence of flu dramatically, but in the future doctors may need a rapid test that can tell them which respiratory virus a patient is infected with.

Schmidt's lab, in collaboration with coauthor Aaron Hawkins' group at Brigham Young University, has pioneered "optofluidic chip" technology for biomedical diagnostics, combining microfluidics (tiny channels for handling liquid samples on a chip) with integrated optics for optical analysis of single molecules.

To develop the new antigen test, Schmidt's team designed a fluorescent probe bright enough that individual markers can be detected optically on the chip. "The ability to detect individual markers means there is no need for an amplification step, which removes some of the complexity of the processing," he explained.

Schmidt's lab had been developing tests for other infectious diseases when COVID-19 emerged as a global pandemic last year. At first, research ground to a halt as a statewide shutdown kept everyone at home. But it was clear to Schmidt that the diagnostic technology his lab was developing for Zika virus and other infectious diseases could be adapted for COVID-19.

"Once we were allowed to come back to the lab for essential research, my students started coming in to work in the lab by themselves on a coronavirus test," Schmidt said. "It was a heroic effort by my students to develop these tests from scratch. First we were shut down by the pandemic, and then the wildfires hit and we had to evacuate our samples to Stanford and shut down again. But they kept going."

Graduate student Alexandra Stambaugh led the effort and is first author of the paper. The team worked with the campus diagnostic lab to obtain nasal swab samples for testing. They only used samples that had tested negative for the coronavirus, adding viral antigens to the samples at clinically relevant concentrations to validate the tests.

The test uses an "antibody sandwich" approach commonly used for immunoassays. In this case, antibodies specific for the target antigen are attached to magnetic microbeads, so that any target antigen present in the sample sticks to the beads. After washing, a second antibody with the fluorescent marker attached is added, and it binds to any target antigen present on the beads. The fluorescent markers are attached to the antibodies by a spacer that can be cleaved by ultraviolet light, which releases the markers to flow through the detection chip where they are detected one by one. The researchers attached a green marker to the coronavirus antibody and a red marker to the influenza antibody to distinguish between the two viruses.

Gram-negative bacteria are the bane of health care workers' existence.

They're one of the most dangerous organisms to become infected with--and one of the hardest to treat. But new research from the University of Georgia suggests a component of bacteria's cell walls may hold the key to crushing the antibiotic-resistant microbes.

The reason Gram-negative bacteria are difficult to kill is their double cell membranes, which create an almost impenetrable shield of protection. This shield blocks antibiotics from entering, preventing medications from doing their job of destroying the bacteria. Meanwhile, toxic molecules, known as lipopolysaccharides, on the surface of the bacteria's outer membrane provoke a potentially deadly immune response.

In the study published by PNAS, researchers at the College of Veterinary Medicine identified the molecule cardiolipin's key role in getting those toxic molecules onto the membrane surface, something that could serve as a new target for future therapeutics.

"If you ask where we're having the most trouble in the world of antibiotic resistance, it is with Gram-negative bacteria," said Stephen Trent, corresponding author of the study and a UGA Foundation Distinguished Professor of Infectious Diseases. "The implication of this finding is that without cardiolipin, bacteria can't make the outer membrane. Without that membrane, they're sensitive to antibiotics and the bacteria is toast."

Blocking transport to the cell membrane could not only make bacteria vulnerable to antibiotics, but the accumulation of their own toxic molecules within the cell also cause the bacteria's death.

Prior to the study, no one really understood cardiolipin's role in bacteria. In animals, however, it plays an integral part in making up the membrane of mitochondria, the organelles from which cells generate energy.

To determine the molecule's role in bacteria, the researchers created mutant forms of E. coli, which has multiple ways of making cardiolipin, to try to determine what purpose the lipid served in the cell. The team manipulated the enzymes responsible for building cardiolipin to see whether their disruption had any effect on the bacterium.

Those experiments showed that altering the cardiolipin production in a bacteria's cell had deadly ramifications for the bacteria. Without cardiolipin, the cell will continue to produce its toxic lipopolysaccharides but is unable to transport them to the cell surface.

"Eventually the cell will pop open. They just bust," Trent said. And without the large molecules on the cell surface, the bacteria's armor that typically would make it invulnerable to most antibiotics becomes penetrable.

"This paper is one of the first to link cardiolipin to maintaining the outer membrane of E. coli," said Martin Douglass, lead author of the paper and a doctoral student in UGA's Department of Infectious Diseases. "Future therapeutics could target aspects of this process and make Gram-negative bacteria vulnerable to antibiotics."

ITHACA, N.Y. - A project based in Tanzania found significant improvements in the diversity of children's diets and food security for households after farmers learned about sustainable crop-growing methods, gender equity, nutrition and climate change from peer mentors.

The farmers experimented with practices introduced to them by Malawian farmers and Tanzanian and American scientists, decided which ones to incorporate within their own farms, and met monthly to share experiences and problem-solve.

The three-year study builds on longer-term research where these environmentally-friendly farming methods, called agroecology, combined with peer-mentoring and farmers collaborating in the process, had successfully improved adult nutrition in Malawi.

"There were a lot of questions about whether an approach that is effective in one context can work in other contexts," said Rachel Bezner Kerr, professor of global development in the College of Agriculture and Life Sciences at Cornell University and co-author of the study that published May 11 in the Journal of Nutrition.

Bezner Kerr is a co-principal investigator on the project, along with corresponding author Sera Young, associate professor of anthropology at Northwestern University, lead author Marianne V. Santoso and collaborators at Action Aid Tanzania, Nelson Mandela African Institute for Science and Technology and Singida Rural District Council.

Agroecology applies ecological principles to agriculture in a holistic manner. In trainings for this study, farmers learned about practices such as intercropping, in which several crops are planted together in the same beds, to provide diversified foods while also reducing pests that thrive in monocultures. Farmers decided which agroecological practices they wanted to test, such as environmentally safe botanical pesticides from local plants or adding compost and manure to improve soil health.

American and Tanzanian researchers invited food-insecure smallholder farmers with children under 1 year old from 20 villages in Singida, Tanzania, to participate. Ten of the villages began the program, while the other 10 served as a control group for two years before they too were taught the practices.

In total, 600 households participated, split evenly between the intervention and control groups. Before training began, the researchers conducted surveys about nutrition, farming practices, and gender equity and measured children's growth. Over the course of the program, these things continued to be assessed. Households in the intervention group were given about a pound of legume seeds of their choice, including cowpea, groundnut and pigeon pea, which enriched soil with nitrogen and added diversity to staple sorghum, millet and corn crops they grew. Farmers were able to save legume seeds from crops they grew for the following year.

At the start of the program, a group of 20 farmers that included one man and one woman from 10 villages were selected to be peer mentors in their communities. They were brought to Malawi to learn about different practices used by the Malawian farmers.

Then, Malawian peer-mentors traveled to Tanzania to teach a two-week agroecology course co-designed by farmers and researchers. The integrated curriculum had hand-on activities on agroecology, gender and social equity, child nutrition and climate change.

The researchers measured food security, children's dietary diversity and agricultural practices within households. They used a standard set of questions about diets and foods consumed in each category to arrive at a minimum dietary diversity score.

"We found that this intervention approach of combining agroecology with attention to nutrition and gender equity led to improvements in food security and children's dietary diversity for households that were food insecure at the start of the intervention," Bezner Kerr said.

They found no significant impact on child growth, which wasn't a surprise, as research shows that diversifying diets has significant impacts on child health and well-being, but less on growth, Bezner Kerr said.

Furthermore, data collected on division of labor within households, decision making and mental health outcomes led to a separate paper that showed the approach significantly improved women's mental health and well-being.

Researchers looking to help people suffering from addiction, depression, and pain are studying how certain brain neurons operate to see if they can be controlled.

In a paper published May 11 in Neuron, researchers at the University of Washington School of Medicine and Washington University in St. Louis, along with several other universities, successfully used a protein called parapinopsin to turn off brain circuits. This protein is found in lamprey - an ancient lineage of jawless fish similar to eel. Reserachers said the ability to inhibit neurons could eventually lead to turning off mood disorders and unwanted behaviors like depression and addiction.

"We found a particular protein that comes from lamprey that has been around for hundreds of millions of years. We took the gene from that protein and found we can control the way neurons talk to each other, which is how chemicals are transmitted into the brain," said lead corresponding author Michael Bruchas, professor of anesthesiology and pain medicine at the University of Washington School of Medicine and co-director of the Imaging and Neural Circuits core of the Center for Neurobiology of Addiction, Pain, and Emotion.

For decades, neuroscientists have been using different types of light-sensitive proteins that are expressed in plants and bacteria to experiment with brain circuitry, said Bruchas. But this is the first time a protein was taken from lamprey to control brain circuits.

Parapinopsin is a type of protein called a "g protein coupled receptor" or GPCR. These GPCRs emerged early on in evolution and can be found in organisms ranging from bacteria to humans. Bruchas said there at least 850 of these kinds of proteins in mammals. These proteins control everything from heart rate to fat storage, to reward and stress responses. GPCRs also respond well to chemicals, such as dopamine and serotonin, which make people feel good.

"Some of these GPCR pathways are highly conserved across millions of years of evolution, and that allowed us to hack into them using parapinopsin," said Bryan Copits, lead author and co-corresponding author, assistant professor of anesthesiology in the Pain Center at Washington University School of Medicine, where Dr. Bruchas was formerly located. Researchers from University of California (UC), Los Angeles, UC Davis, UC San Diego, and University of Zurich were also involved.

The Bruchas Lab focuses on GPCRs. But finding a way to inhibit neurons had been hard to come by until the parapinopsin discovery, Bruchas said.

The researchers found that the protein in lamprey respond to light not chemicals - another approach for targeted delivery. For example, if a part of the brain was having seizures from Parkinson's, it might be possible to isolate the effect with an electrode, dampen it with adjustments to neurotransmission, or to inhibit specific pathways to improve mood.

Bruchas said the original discovery of parapinopsin was made by researchers in Japan in the Terakita lab, who have been discovering different light-sensitive GPCRs across species.

"This is a perfect rationale for why basic science is so incredibly important," said Bruchas. "Because of someone's hard work of basic biological discovery, we have a new tool for medical research. "

Bruchas said his team is planning to use the discovery for research into expanding their knowledge of the inner workings of the brain and to identify treatments for stress, depression, addiction, and pain.

BOSTON - It's a real-life plot worthy of a classic spy novel: Researchers at Massachusetts General Hospital (MGH), the Dana-Farber Cancer Institute and other Boston-area research centers are turning the tables on glioblastomas, the most devastating and aggressive form of brain cancer, by transforming a type of cell that normally protects tumors and inhibits effective drug therapy into a stone-cold glioblastoma killer.

Glioblastoma, a type of brain tumor, is rapidly fatal: Most patients die within two years of diagnosis despite aggressive therapies such as brain surgery, whole-brain radiation and chemotherapy.

Despite hopes that a class of drugs known as immune checkpoint blockers (ICBs) - drugs that have revolutionized the treatment of patients with malignant melanoma, non-small-cell lung cancer, and other solid tumors - could also benefit patients with glioblastoma, ICBs have not been effective against the disease in clinical trials to date.

ICBs work by removing the brakes on the immune system, allowing previously inactive immune cells to recognize, attack and destroy mutated, cancerous cells while causing minimal damage to the normal tissues.

But as Rakesh K. Jain, PhD, director of the Edwin L. Steele Laboratories in the Department of Radiation Oncology at MGH, and colleagues show in a study published in Nature Communications, glioblastomas wreak havoc with the immune system by altering the landscape surrounding and within the tumor, known as the tumor microenvironment, reorganizing blood vessels, immune cells, and tissue structural proteins into an abnormal glioblastoma-promoting environment, effectively hampering the action of ICBs.

"These abnormalities promote a suppressive environment for the immune system, which blocks tumor-fighting immune cells at the tumor border while allowing infiltration of tumor-promoting immune cells known as regulatory T cells, or Tregs," explains Jain, who is also Andrew Werk Cook Professor of Radiation Oncology at Harvard Medical School (HMS). "Among elements of the tumor microenvironment, we exploited the preferential accumulation of Tregs in glioblastoma by therapeutically altering their function - a strategy known as reprogramming - to make them kill cancer cells instead of protecting them," he continues. "Because Tregs already present in these tumors can be reprogrammed, this strategy does not rely on additional recruitment of anti-tumor immune cells - another frequent barrier to successful immunotherapy in brain tumors."

The investigators accomplished Treg conversions by targeting a receptor (docking site) on glioblastoma Tregs called glucocorticoid-induced TNFR-related receptor (GITR), using an antibody (αGITR) that reprograms the tumor promoter into a tumor-fighting type of T cell. Combining this antibody with an ICB resulted in a strong survival benefit in mouse models of human glioblastoma.

"Importantly, some of these mice not only rejected tumors but developed a long-term immunity against glioblastoma," comments co-author Dai Fukumura, MD, PhD, deputy director of the Steele Labs.

Although their research thus far has been limited to mouse models of human glioblastoma, "our work offers a possible solution to overcome resistance to immunotherapy, and can be translated to patients," says lead author Zohreh Amoozgar, PharmD, PhD, a postdoctoral research fellow in the Steele Labs.

"In addition to showing that Tregs can be reprogrammed from tumor promoters to cancer killers, our study also demonstrated that a potent anti-tumor effect can be generated by both alleviating Treg-mediated resistance to immunotherapy and by reinvigorating CD8+ T cells, one of the major players in immune responses against cancer," explains co-corresponding author Hye-Jung Kim, PhD, an immunologist at the Dana-Farber Cancer Institute.

Their findings support the use of αGITR antibodies in combination with ICBs, with or without the current standard-of-care therapies, in patients with glioblastomas who have high levels of Tregs, Jain says.

DURHAM, N.C. -- With mosquito season upon us, people are stocking up on repellents to prevent itchy bites. Bug repellents are important because they don't just protect against the buzzing, blood-sucking little pests -- they also safeguard against the diseases they carry, which kill some 700,000 people worldwide each year.

Surprisingly, despite widespread use, no one understood exactly how most mosquito repellents keep the insects away. Now researchers are starting to uncover the first pieces of the puzzle.

A new study has identified a scent receptor in mosquitoes that helps them sniff out and avoid trace amounts of pyrethrum, a plant extract used for centuries to repel biting insects.

One of the oldest insecticides known, pyrethrum comes from the dried, crushed flowers of certain chrysanthemum species. Pyrethrum breaks down quickly in sunlight and isn't readily absorbed through the skin, so the insecticide has long been considered one of the safer options for use around children and pets.

What makes pyrethrum toxic to mosquitoes has been known for some time. It works by binding to tiny pores in the insects' nerve cells and paralyzing them on contact. But it has another property whose mode of action is more of a mystery. At lower concentrations it protects not by killing mosquitoes but by preventing them from getting close enough to land and bite in the first place.

Led by biology professor Ke Dong, who recently joined the faculty at Duke University, the team did a variety of tests to understand how mosquitoes detect and avoid pyrethrum, and which of the extract's chemical components help them do it.

First, they had people don a special rubber glove and put their hand in a cage holding 50 hungry mosquitoes. The glove had a window screen on the back made of two layers of loose-fitting mesh. The top layer acts as a barrier that mosquitoes are unable to bite through. Normally, mosquitoes find the heat and aroma of human skin wafting through the mesh irresistible, and are quick to land and check it out. But when the bottom layer of mesh closest to the skin was treated with pyrethrum, they lost interest.

These early experiments confirmed that mosquitoes don't have to get close enough to taste or touch pyrethrum-treated skin or clothing to stay away. To find out if smell was involved, the researchers attached tiny wire electrodes to the small hairs covering the mosquitoes' antennae and measured their electrical responses to puffs of air containing chemicals released by pyrethrum and other repellents.

A mosquito's ability to smell comes from special receptors embedded in nerve cells on the insect's antennae and mouth parts. Once odor molecules wafting through the air stimulate these receptors, the nerve cells send a message to the brain, which identifies the smell.

Dong and her colleagues were able to pinpoint a specific ingredient in pyrethrum flower extracts, called EBF, which activates a smell receptor in the mosquito's antenna called Or31.

They found that EBF works together with other components called pyrethrins to make an especially off-putting bouquet. Even tiny doses that mosquitoes barely seem to notice when the compounds occur alone -- fewer than five odor molecules per million molecules of air -- can send the insects flying or crawling away when they occur in combination.

While the researchers focused on the mosquito species Aedes aegypti -- which spreads viruses such as Zika, yellow fever and dengue -- they also found Or31 odor receptors with strikingly similar protein sequences in six other mosquito species.

More than 200 types of mosquitoes live in the United States alone; about a dozen of which spread germs that can make people sick.

With mosquitoes becoming increasingly resistant to our best chemical defenses, researchers are constantly on the lookout for new ways to fight them.

These findings, published May 5 in the journal Nature Communications, could help researchers develop new broad-spectrum repellents to keep a variety of mosquitoes at bay, and by extension stop them from biting people and spreading disease.

From the branching pattern of leaf veins to the variety of interconnected pathways that spread the coronavirus, nature thrives on networks -- grids that link the different components of complex systems. Networks underlie such real-life problems as determining the most efficient route for a trucking company to deliver life-saving drugs and calculating the smallest number of mutations required to transform one string of DNA into another.

Instead of relying on software to tackle these computationally intensive puzzles, researchers at the National Institute of Standards and Technology (NIST) took an unconventional approach. They created a design for an electronic hardware system that directly replicates the architecture of many types of networks.

The researchers demonstrated that their proposed hardware system, using a computational technique known as race logic, can solve a variety of complex puzzles both rapidly and with a minimum expenditure of energy. Race logic requires less power and solves network problems more rapidly than competing general- purposed computers.

The scientists, who include Advait Madhavan of NIST and the University of Maryland in College Park and Matthew Daniels and Mark Stiles of NIST, describe their work in Volume 17, Issue 3, May 2021 of the ACM Journal on Emerging Technologies in Computing Systems.

A key feature of race logic is that it encodes information differently from a standard computer. Digital information is typically encoded and processed using values of computer bits -- a "1" if a logic statement is true and a "0" if it's false. When a bit flips its value, say from 0 to 1, it means that a particular logic operation has been performed in order to solve a mathematical problem.

In contrast, race logic encodes and processes information by representing it as time signals -- the time at which a particular group of computer bits transitions, or flips, from 0 to 1. Large numbers of bit flips are the primary cause of the large power consumption in standard computers. In this respect, race logic offers an advantage because signals encoded in time involve only a few carefully orchestrated bit flips to process information, requiring much less power than signals encoded as 0s or 1s.

Computation is then performed by delaying some time signals relative to others, determined by the physics of the system under study. For example, consider a group of truck drivers who starts at point A and must deliver medicine to point E as fast as possible. Different possible routes go through three intersections -- call them B, C and D. To determine the most efficient route, the race logic circuit evaluates each possible segment of the trip, such as A-B and A-D. If A-B takes more time to travel than A-D, whether it's because the path is longer or has more traffic, A-B will be assigned a longer delay time. In the team's design, the longer time delay is implemented by adding additional resistance to the slower segment.

Race logic does indeed involve a race, but in this contest all the truck drivers initially drive in different directions. To determine which route to the final destination is fastest, they race over all possible routes through the different intermediate delivery points. In the new circuit, the NIST researchers inserted a group of time-encoded signals at the starting point, each acting as a different driver that speeds through the team's simulated hardware circuit.

Whenever a driver arrives at one of her intermediate destination points in the race, the model system sends out new drivers (new time signals) who fan out in different directions to the remaining destinations. If a driver arrives at a destination that another driver has already been to, that driver drops out, because her path is no longer competitive. The winner of the race -- the first driver to arrive at the end of the circuit -- indicates the solution to the particular puzzle that the hardware was programmed to solve.

Madhavan began pioneering work on race logic circuits while a graduate student at the University of California, Santa Barbara, in 2016. Those first systems used specialized circuits and silicon chips that were designed to simulate specific networks, such as DNA manipulation, and therefore could solve only a limited number of network-related problems.

At NIST, Madhavan and his colleagues have begun work on more advanced race logic circuits. Simulations conducted by Madhavan, Daniels and Stiles showed that their design, which has not yet been incorporated into a working device, can handle a much broader class of networks, enabling race logic to tackle a wider variety of computational puzzles. These puzzles include finding the best alignment between two proteins or two strings of nucleotides -- the molecules that form the building blocks of DNA -- and determining the shortest path between two destinations in a network.

"We showed how to use memory, which has not been used in previous implementations of race logic, to create a more general temporal computer," said Stiles. "Incorporating memory will allow us to treat a broad class of problems with the next race logic chip that we are planning to make," he added.

It's widely understood that people taking a common class of antibiotics, like ciprofloxacin and levofloxacin, run the risk of tendonitis and tendon ruptures. However, a new analysis sheds light on newer, third-generation fluoroquinolones and suggests they may have a lower risk of Achilles tendon rupture. Researchers from Jichi Medical University in Tochigi, Japan, used health care administrative data to identify 504 patient cases of Achilles tendon ruptures with co-occurrence of antibiotics. They found that third-generation fluoroquinolones were not associated with an increase in Achilles tendon rupture. First- and second-generation fluoroquinolones, like ciprofloxacin and ofloxacin, were at elevated risk of tendon rupture, which was consistent with previous evidence. Third-generation fluoroquinolones include moxifloxacin, garenoxacin, sitafloxacin, prulifloxacin and pazufloxacin, some of which are not yet approved by the Food and Drug Administration in the United States. The authors note that further studies are required to determine the risks of third-generation fluoroquinolones for other rare adverse events, such as heart damage.

Skoltech scientists have created a new monitoring system for agricultural applications that performs real-time image segmentation on board the drone to identify hogweed. The research was published in a high-profile journal, IEEE Transactions on Computers.

Sosnovsky's hogweed is equally hazardous for farming, local ecosystems, and human health. Direct contact with human skin, especially if aggravated by exposure to the Sun, causes severe burns that require continuous medical care and take weeks to heal. The rampant spread of Sosnovsky's hogweed has become a real environmental disaster that extends across the whole of Russia, from its central part to Siberia and from Karelia to the Caucasus. Every year, the government allocates huge budgets (last year, 350 million rubles for Moscow alone) for hogweed elimination. Eradicating the poisonous plant has become one of the biggest challenges for Russian farming, environment, and healthcare.

In the mid-20th century, there were plans to use hogweed as a fodder crop, given its quick growth, low maintenance requirements, and fast proliferation. However, it soon transpired that hogweed was no good as a livestock feed and its exceptional natural properties were a major problem rather than an advantage. One plant can produce up to 100,000 seeds per year, which are easily dispersed by the wind. This means that a single plant accidentally left behind makes the clearing operation utterly pointless.

Accurate real-time localization of hogweed was the first issue that researchers from the Skoltech Center for Computational and Data-Intensive Science and Engineering (CDISE) encountered when they started developing their monitoring platform two years ago. "Conventional monitoring methods are not effective enough, since ground observations are highly dependent on the human factor, while space remote sensing can spot large thickets only. Satellite images do not have sufficient resolution to discern individual plants. Besides, traditional monitoring strongly depends on weather and satellite revisit periods and, therefore, cannot provide up-to-date information," lead author and Skoltech PhD graduate Alexander Menshchikov explains.

The researchers decided to use drones that are able to capture up-to-date high-resolution hogweed images even in cloudy weather and opted for in-flight data acquisition and processing on board the drone instead of the classical "data capture - orthophotomap - data analysis" scheme. "Even though the traditional approach provides exhaustive information about the area, it is nearly as effective as processing data on board with segmentation for one type of object, i.e. Sosnovsky's hogweed. Besides, in the traditional method, after-flight image stitching and analysis takes several hours, whereas in-flight processing produces real-time data which are immediately downloaded to the base station, so that the clearing of the targeted area could start before the drone lands," Alexander adds.

The new monitoring solution uses a drone and a compact on-board computer which runs "heavy" segmentation algorithms based on Fully Convolutional Neural Networks (FCNN) that can identify an irregularly shaped object (in this case, Sosnovsky's hogweed) pixel-by-pixel. This will help to discern individual plants and raise the chances of killing all the weeds in the selected area.

Running FCNNs on low-power hardware, such as single-board computers (SBC), was the main hindrance for the project. Since there are only a limited number of computers that have sufficient resources and processors that support FCNN, the researchers had to find a suitable SBC architecture and optimize FCNN to make it run on the selected hardware version.

"We chose popular architectures, UNet, SegNet, and ResNet, for our neural networks and adapted them for the SBC. We installed and flight-tested our monitoring system on board the drone which covered an area of up to 28 hectares in 40 minutes, flying at an altitude of 10 meters. And it did not miss a single weed!" Skoltech assistant professor and project supervisor Andrey Somov comments.

"Our system displays a multifold increase in localization efficiency, even though it processes 4K images at a modest speed of 0.7 fps," Andrey adds.

The new approach holds great promise for farming: it could be used to monitor other crops, identify various vegetative indicators, assess plant health and detect plant diseases by applying multispectral imagery.