In one of the studies, about 10% of children and 35% of adults who got an antibiotic prescription during an office visit had no specific reason for the antibiotic in their record.

The rate of this type of prescribing is especially high in adults treated seen in emergency departments and in adults seen in clinics who have Medicaid coverage or no insurance, the studies show. But the issue also occurs in children.

Without information about what drove these inappropriate prescriptions, it will be even harder for clinics, hospitals and health insurers to take steps to ensure that antibiotics are prescribed only when they’re really needed, the researchers say.

Overuse and misuse of antibiotics raise the risk that bacteria will evolve to resist the drugs and make them less useful for everyone. Inappropriately prescribed antibiotics may also end up doing more harm than good to patients.

“When clinicians don’t record why they are prescribing antibiotics, it makes it difficult to estimate how many of those prescriptions are truly inappropriate, and to focus on reducing inappropriate prescribing,” said Joseph Ladines-Lim, M.D., Ph.D., first author of both of the new studies and a combined internal medicine/pediatrics resident at Michigan Medicine, U-M’s academic medical center.

“Our studies help contextualize the estimates of inappropriate prescribing that have been published previously,” he added. “Those estimates don’t distinguish between antibiotic prescriptions that are considered inappropriate due to inadequate coding and antibiotic prescriptions truly prescribed for a condition that they can’t treat.”

Ladines-Lim worked with U-M pediatrician and health care researcher Kao-Ping Chua, M.D., Ph.D., on the new studies. The one on outpatient prescribing by insurance status is in the Journal of General Internal Medicine and the one on trends in emergency department prescribing is in Antimicrobial Stewardship and Healthcare Epidemiology.

Building on previous research

Chua and colleagues recently published findings about trends in inappropriate antibiotic prescribing in outpatients under age 65, suggesting about 25% were inappropriate. But that number includes antibiotic prescriptions written for infectious conditions that antibiotics don’t help, such as colds, and antibiotic prescriptions that aren’t associated with any diagnoses that could be a plausible antibiotic indication.

The new studies add more nuance to that finding, by looking more closely at these two different types of inappropriate prescriptions.

Most antibiotic stewardship efforts to date have focused on reducing the use of the first type of inappropriate prescription — those written for infectious but antibiotic-inappropriate conditions like colds. The new studies show such patients still account for 9% to 22% of all antibiotic prescriptions, depending on the setting and age group.

But since doctors and other prescribers aren’t required to run a test for a bacterial infection or list a specific diagnosis in order to prescribe antibiotics, symptoms provide potential clues to why they might have written a prescription anyway.

So some of those 9% to 22% of all people receiving antibiotics may have also had a secondary bacterial infection that the clinician suspected based on symptoms.

However, it’s impossible to know.

As for those with no infection-related diagnoses or symptoms in their records who got antibiotics, the researchers suggest that clinicians may not have bothered to add these diagnoses or symptoms to the patient record inadvertently — or even deliberately, to try to avoid the scrutiny of antibiotic watchdogs.

But the researchers also speculate that the lower rate of diagnosis documentation in patients in the healthcare safety net may also have to do with the way healthcare organizations are reimbursed.

Often, clinics and hospitals receive a fixed amount from Medicaid to care for all their patients with that type of coverage. So they aren’t incentivized to create records that are as detailed as for privately insured patients, whose care traditionally is reimbursed under a fee-for-service model.

“This could actually be a matter of health equity if people with low incomes or no insurance are being treated differently when it comes to antibiotics,” says Ladines-Lim, who has also studied antibiotic use related to immigrant and asylum-seeker health and will soon begin a fellowship in infectious diseases.

He said that private and public insurers, and health systems, may need to incentivize accurate diagnosis coding for antibiotic prescriptions — or at least make it easier for providers to document why they’re giving them.

That might even include steps such as requiring providers to record the reason for antibiotic prescribing before prescriptions can be sent to pharmacies through electronic health record systems.

After all, Ladines-Lim said, physicians often have to list a diagnosis that justifies tests they order, such as CT scans or x-rays. With antibiotic resistance posing an international threat to patients who have antibiotic-susceptible conditions, similar steps to justify prescriptions of antibiotics might be advisable.

In addition to Ladines-Lim and Chua, the other authors of the two articles are Michael A. Fischer, M.D., M.S. of Boston Medical Center and Boston University, and Jeffrey A. Linder, M.D., M.P.H. of Northwestern University Feinberg School of Medicine.

The research was funded by a Resident Research Grant from the American Academy of Pediatrics, a Physician Investigator Award from Blue Cross Blue Shield Foundation of Michigan, and a Research Grant from the National Med-Peds Residents’ Association.

Increases are expected to be largest in countries where life expectancy is lower, contributing to a convergence of increased life expectancy across geographies. The trend is largely driven by public health measures that have prevented and improved survival rates from cardiovascular diseases, COVID-19, and a range of communicable, maternal, neonatal, and nutritional diseases (CMNNs).

This study indicates that the ongoing shift in disease burden to non-communicable diseases (NCDs) — like cardiovascular diseases, cancer, chronic obstructive pulmonary disease, and diabetes — and exposure to NCD-associated risk factors — such as obesity, high blood pressure, non-optimal diet, and smoking — will have the greatest impact on disease burden of the next generation.

As the disease burden continues to shift from CMNNs to NCDs and from years of life lost (YLLs) to years lived with disability (YLDs), more people are expected to live longer, but with more years spent in poor health. Global life expectancy is forecasted to increase from 73.6 years of age in 2022 to 78.1 years of age in 2050 (a 4.5-year increase). Global healthy life expectancy (HALE) — the average number of years a person can expect to live in good health — will increase from 64.8 years in 2022 to 67.4 years in 2050 (a 2.6-year increase).

To come to these conclusions, the study forecasts cause-specific mortality; YLLs; YLDs; disability-adjusted life years (DALYs, or lost years of healthy life due to poor health and early death); life expectancy; and HALE from 2022 through 2050 for 204 countries and territories.

“In addition to an increase in life expectancy overall, we have found that the disparity in life expectancy across geographies will lessen,” said Dr. Chris Murray, Chair of Health Metrics Sciences at the University of Washington and Director of the Institute for Health Metrics and Evaluation (IHME). “This is an indicator that while health inequalities between the highest- and lowest-income regions will remain, the gaps are shrinking, with the biggest increases anticipated in sub-Saharan Africa.”

Dr. Murray added that the biggest opportunity to speed up reductions in the global disease burden is through policy interventions aimed to prevent and mitigate behavioral and metabolic risk factors.

These findings build upon the results of the GBD 2021 risk factors study, also released today in The Lancet. This accompanying study found that the total number of years lost due to poor health and early death (measured in DALYs) attributable to metabolic risk factors has increased by 50% since 2000. Read more on the risk factors report at https://bit.ly/GBDRisks2021.

The study also puts forth various alternative scenarios to compare the potential health outcomes if different public health interventions could eliminate exposure to several key risk factor groups by 2050.

“We forecast large differences in global DALY burden between different alternative scenarios to see what is the most impactful on our overall life expectancy data and DALY forecasts,” said Dr. Stein Emil Vollset, first author of the study who leads the GBD Collaborating Unit at the Norwegian Institute of Public Health. “Globally, the forecasted effects are strongest for the ‘Improved Behavioral and Metabolic Risks’ scenario, with a 13.3% reduction in disease burden (number of DALYs) in 2050 compared with the ‘Reference’ (most likely) scenario.”

The authors also ran two more scenarios: one focused on safer environments and another on improved childhood nutrition and vaccination.

“Though the largest effects in global DALY burden were seen from the ‘Improved Behavioral and Metabolic Risk’ scenario, we also forecasted reductions in disease burden from the ‘Safer Environment’ and ‘Improved Childhood Nutrition and Vaccination’ scenarios beyond our reference forecast, said Amanda E. Smith, Assistant Director of Forecasting at IHME. “This demonstrates the need for continued progress and resources in these areas and the potential to accelerate progress through 2050.”

“There is immense opportunity ahead for us to influence the future of global health by getting ahead of these rising metabolic and dietary risk factors, particularly those related to behavioral and lifestyle factors like high blood sugar, high body mass index, and high blood pressure,” continued Dr. Murray.

When the first land plants emerged from aquatic environments, they needed to adapt in order to survive.

Chang-Jun Liu, a senior scientist in Brookhaven’s Biology Department, said, “The emergence of lignin, which provides structural support for the plants, was a key evolutionary event that enabled plant survival in the new terrestrial environment.”

Understanding how plants developed protective mechanisms that enable survival in new environments is vital as they face challenges imposed by climate change today. But lignin is also of great interest to researchers searching for clean energy options. This tough plant material can be processed and converted into valuable bioproducts. And lignin is the only renewable source of aromatic compounds, which are chemically similar to molecules found in conventional jet fuel and can be used as “drop-in” fuel by airlines.

“Modern plants contain three types of lignin, but most early lignin-containing plants had only two types. The ‘newer’ lignin is called syringyl-lignin, or S-lignin,” explained Liu. S-lignin evolved relatively recently with flowering plants and is structurally less complex than the other lignin components. Its potential industrial applications, in particular, have captured the attention of scientists because S-lignin is relatively easy to break down to simple aromatics.

The new study, recently published in The Plant Cell, builds on years of research focused on lignin and the molecules responsible for its synthesis. In 2019, Liu and his colleagues discovered that a specific cytochrome b₅ protein, CB5D, is indispensable for the production of S-lignin but not the other, more ancient types of lignin.

“The uniqueness of CB5D’s role in S-lignin synthesis intrigued us,” Liu noted. “So, we were inspired to further explore its origin and evolution.”

Enzymatic teamwork

In a previous study, Liu’s team found that CB5D has a special partnership with an enzyme called ferulate 5-hydroxylase (F5H). Together, these molecules synthesized the valuable S-lignin.

The scientists knew that the evolution of F5H in flowering plants had led to the production of S-lignin. So, they expected to find that CB5D had co-evolved with F5H.

To explore their hypothesis, the scientists ran a genetic analysis to find other plant species whose DNA contained genes similar to the modern CB5D gene, which acts as instructions for assembling the CB5D protein. They identified 21 species, ranging from evolutionarily ancient to evolutionarily recent. The scientists then synthesized these genes and individually expressed them in a modern plant species that was genetically altered to lack the CB5D gene.

“Without the CB5D gene, the plant synthesizes only a small amount of S-lignin,” said Xianhai Zhao, a postdoctoral researcher at Brookhaven and lead author on the new paper. “But if this function was restored with the expression of one of the related genes, then we would know that gene functions similarly to the modern CB5D gene.”

The scientists discovered that a gene from a green algae species that evolved into an early land plant over 500 million years ago restored S-lignin synthesis in the modern plant. This indicated that the gene exhibited CB5D-type functionality. The scientists also found that the function was conserved in several early land plants, like liverworts and mosses.

“This means that the CB5D evolved millions of years earlier than we had expected,” explained Liu. “It was quite surprising to find that a modern electron acceptor like F5H had partnered with an ancient protein to develop new biochemical machinery that synthesizes the advanced lignin structure.”

Scientific teamwork and next steps

The CB5Dgene and its more ancient counterpart contained similar DNA sequences and functions. But the scientists wanted to make sure that the CB5D protein from an ancient species, like liverwort, was expressed in the same subcellular structures as modern CB5D.

So, they used confocal microscopy at the Center for Functional Nanomaterials, a DOE Office of Science user facility at Brookhaven Lab, to confirm that this was the case.

Having found ancient genes that encode proteins similar to the modern CB5D protein in terms of S-lignin synthesis in modern plants and cellular localization, the team wanted to learn more about this protein’s ancient function and how it changed or expanded over time.

Their analysis showed the CB5D-like protein emerged in aquatic algae just before they transitioned to a terrestrial environment. And because it was conserved in early land plants, this protein likely serves one or more essential functions.

“Ancient plants like liverwort didn’t contain S-lignin,” said Zhao. “If the CB5D-type protein wasn’t responsible for synthesizing S-lignin, what did it do?”

Liu remarked, “That’s the beauty of research. Answering one question leads you to even more interesting questions waiting to be explored.”

“The drug is a genetically engineered version of the missing enzyme in iTTP, and we showed that it was able to reverse the disease process in a patient with an extremely severe form of this condition,” said lead author Pavan K. Bendapudi, MD, an investigator in the Division of Hematology and Blood Transfusion Service at Massachusetts General Hospital and an assistant professor of Medicine at Harvard Medical School.

iTTP results from an autoimmune attack against an enzyme called ADAMTS13 that is responsible for cleaving a large protein involved in blood clotting. The current mainstay of therapy for this life-threatening blood disorder is plasma exchange, which removes the harmful autoantibodies and provides extra ADAMTS13. Plasma exchange induces a clinical response in most patients but can restore at best only about half of normal ADAMTS13 activity. By contrast, a recombinant form of human ADAMTS13 (rADAMTS13) offers the possibility of greatly increased ADAMTS13 delivery.

rADAMTS13 was recently approved for patients with congenital thrombotic thrombocytopenic purpura, which occurs in patients born with complete loss of the ADAMTS13 gene. It’s questionable whether rADAMTS13 could be effective in iTTP given the presence of inhibitory anti-ADAMTS13 autoantibodies, but Bendapudi and his colleagues received permission from the US Food and Drug Administration to utilize rADAMTS13 donated from the manufacturer under a compassionate use protocol in a dying patient with treatment-resistant iTTP.

“We found that rADAMTS13 rapidly reversed this patient’s disease process despite the current dogma that inhibitory autoantibodies against ADAMTS13 would render the drug useless in this condition,” said Bendapudi. “We were the first physicians to use rADAMTS13 to treat iTTP in the United States, and in this case it helped to save the life of a young mother.”

Bendapudi noted that the infused rADAMTS13 overwhelmed the inhibitory autoantibodies in the patient and reversed the thrombotic effects of iTTP. This impact was observed almost immediately upon administration of rADAMTS13, after daily plasma exchange had failed to induce remission.

“I think rADAMTS13 has the potential to replace the current standard of care in acute iTTP. We will need larger, well-designed trials to evaluate this possibility,” said Bendapudi.

A phase 2b randomized clinical trial of rADAMTS13 in iTTP was recently initiated.

A collaboration involving researchers at the University of Illinois Urbana-Champaign and the University of Duisburg-Essen has shown that when graphene is irradiated with ions, or electrically charged atoms, the electrons that are ejected give information about the graphene’s electronic behavior. Moreover, the Illinois group performed the first calculations involving high-temperature graphene, and the Duisburg-Essen group experimentally verified the predictions by irradiation. This research was reported in the journal Nano Letters.

“Irradiating materials and observing the change in properties to deduce what’s going on inside the material is a well-established technique, but now we are taking first steps towards using ions instead of laser light for that purpose,” said André Schleife, the Illinois group lead and a professor of materials science & engineering. “The advantage is that ions allow highly localized, short-time excitations in the material compared to what laser light can do. This enables high-precision studies of how graphene and other 2D materials evolve over time.”

When an ion collides with a 2D material, energy is transferred to both the atomic nuclei and electrons. Some of the electrons are given enough energy to be ejected from the material. The features of these so-called “secondary electrons” are determined by the characteristics of the electrons in the material such as their temperature and distribution of energies.

“There’s a delay between the ion’s ‘impact’ and secondary electron emission, and that’s the key piece of information that we were after in our simulations,” said Yifan Yao, the study’s lead author and a graduate student in Schleife’s research group. “We did this for graphene at absolute zero with no thermal energy present as well as graphene that has thermal energy and a higher temperature. We’re actually the first to be simulating ‘hot’ graphene like this.”

The Illinois group performed calculations based on graphene irradiated with hydrogen ions — bare protons — and computed how secondary electrons were released over time and their resulting energy spectrum. These results agreed well with the Duisburg-Essen group’s results that used argon and xenon ions.

In addition, the computational study provides insight into the underlying mechanisms of secondary electron emission. High-temperature graphene released more secondary electrons, and a careful examination of the charge distributions indicated that the atomic nuclei in the material’s lattice rather than the material’s electrons are responsible.

According to Schleife, the promise of this technique goes beyond precision 2D material measurements. “Looking years into the future, there’s a possibility that ion irradiation can be used to deliberately introduce defects into materials and manipulate them,” he said. “But, in the near term, we have shown that irradiation can be used as a high-precision measurement technique.”

The paper, written by doctoral candidate Chinmay Katke, assistant professor C. Nadir Kaplan, and co-author Peter A. Korevaar from Radboud University in the Netherlands, proposes a new physical mechanism that could speed up the expansion and contraction of hydrogels. For one thing, this opens up the possibility for hydrogels to replace rubber-based materials used to make flexible robots — enabling these fabricated materials to perhaps move with a speed and dexterity close to that of human hands.

Soft robots are already being used in manufacturing, where a hand-like device is programmed to grab an item from a conveyer belt — picture a hot dog or piece of soap — and place it in a container to be packaged. But the ones in use now lean on hydraulics or pneumatics to change the shape of the “hand” to pick up the item.

Akin to our own body, hydrogels mostly contain water and are everywhere around us, e.g., food jelly and shaving gel. Katke, Korevaar, and Kaplan’s research appears to have found a method that allows hydrogels to swell and contract much more quickly, which would improve their flexibility and capability to function in different settings.

Living organisms use osmosis for such activities as bursting seed dispersing fruits in plants or absorbing water in the intestine. Normally, we think of osmosis as a flow of water moving through a membrane, with bigger molecules like polymers unable to move through. Such membranes are called semi-permeable membranes and were thought to be necessary to trigger osmosis.

Previously, Korevaar and Kaplan had done experiments by using a thin layer of hydrogel film comprised of polyacrylic acid. They had observed that even though the hydrogel film allows both water and ions to pass through and is not selective, the hydrogel rapidly swells due to osmosis when ions are released inside the hydrogel and shrinks back again.

Katke, Korevaar, and Kaplan developed a new theory to explain the above observation. This theory tells that microscopic interactions between ions and polyacrylic acid can make hydrogel swell when the released ions inside the hydrogel are unevenly spread out. They called this “diffusio-phoretic swelling of the hydrogels.” Furthermore, this newly discovered mechanism allows hydrogels to swell much faster than what has been previously possible.

Why is that change important?

Kaplan explained: Soft agile robots are currently made with rubber, which “does the job but their shapes are changed hydraulically or pneumatically. This is not desired because it is difficult to imprint a network of tubes into these robots to deliver air or fluid into them.”

Imagine, Kaplan said, how many different things you can do with your hand and how fast you can do them owing to your neural network and the motion of ions under your skin. Because the rubber and hydraulics are not as versatile as your biological tissues, which is a hydrogel, state-of-the-art soft robots can only do a limited number of movements.”

Katke explained that the process they have researched allows the hydrogels to change shape then change back to their original form “significantly faster this way” in soft robots that are larger than ever before.

At present, only microscopic-sized hydrogel robots can respond to a chemical signal quickly enough to be useful and larger ones require hours to change shape, Katke said. By using the new diffusio-phoresis method, soft robots as large as a centimeter may be able to transform in just a few seconds, which is subject to further studies.

Larger agile soft robots that could respond quickly could improve assistive devices in healthcare, “pick-and-place” functions in manufacturing, search and rescue operations, cosmetics used for skincare, and contact lenses.