A team of researchers including UTHealth Houston faculty members Aaron M. Gusdon, MD, assistant professor in the Vivian L. Smith Department of Neurosurgery with McGovern Medical School at UTHealth Houston; H. Alex Choi, MD, associate professor in the department as well as the Department of Neurology; and Louise D. McCullough, MD, PhD, professor and Roy M. and Phyllis Gough Huffington Distinguished Chair in the Department of Neurology, conducted a multi-site, randomized, double-blind, placebo-controlled, adaptive Phase 2 trial evaluating the safety and efficacy of an anti-inflammatory compound, called OP-101, in patients with severe COVID-19. The results of the trial were published today in Science Translational Medicine.

In the trial, 24 patients classified as having severe COVID-19 across five clinical sites in the U.S. were randomized to receive a single intravenous dose of placebo or OP-101 at 2, 4, or 8 mg/kg. All patients received standard of care, including corticosteroids.

“OP-101 is a novel nanotherapeutic compound that specifically targets activated macrophages and microglia, the primary immune cell in the brain,”said Gusdon, who was first author on the study. “Due to its excellent safety profile, we were excited to offer this therapy to these critically ill patients at Memorial Hermann Hospital.”

Hyperinflammation triggered by SARS-CoV-2 is a major cause of disease severity in COVID-19. OP-101 was found to be better than a placebo at decreasing inflammatory markers, as well as better at reducing markers of neurological injury, including neurofilament light chain and glial fibrillary acidic protein.

Additionally, risk for the composite outcome of mechanical ventilation or death at 30 or 60 days after treatment was 71% for patients receiving the placebo, but just 18% for patients in the pooled OP-101 treatment arms. At 60 days after treatment, 3 of 7 patients given placebo and 14 of 17 patients treated with OP-101 survived.

The data shows that OP-101 was well tolerated in the critically ill patient population and could serve as an effective treatment for patients hospitalized with COVID-19.

“Although this was a small-dose escalation trial, there was clearly a strong signal toward benefit at both acute and chronic timepoint,” Gusdon said. “The possibility that this therapy could also benefit patients with other diseases that lead to systemic inflammatory responses, including various forms of brain injury, is extremely exciting.”

OP-101 is a nanotherapeutic compound that has previously been evaluated in several animal models of inflammatory disease and has shown superior anti-inflammatory and anti-oxidant effects.

The COVID-19 pandemic has resulted in more than 300 million people infected globally, with more than 5 million deaths.

Sujatha Kannan, MD, professor in the Department of Anesthesiology and Critical Care Medicine at Johns Hopkins University School of Medicine in Baltimore, Maryland, was senior author on the study. Other co-authors from Johns Hopkins University included Nauder Faraday, MD, and Rangaramanujam M. Kannan, PhD, both also with the medical school; and Derek K. Ng, PhD, with the Bloomberg School of Public Health.

Also contributing to the study were John S. Aita, MD, with Avera McKennan Hospital in Sioux Falls, South Dakota; Sunil Kumar, MD, with Broward Health Medical Center in Fort Lauderdale, Florida; Ishan Mehta, MD, with Emory University School of Medicine in Atlanta, Georgia; Jeffery L. Cleland, PhD, with Ashvattha Therapeutics, Inc. in San Francisco, California; and Keith Robinson, MD, with Syneos Health in Morrisville, North Carolina.

McCullough is also a faculty member with The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences.

The resident’s enjoyment of the session and the benefit for their well-being is real. But the animal is not. It’s a robotic pet with synthetic fur and programmed movements and sounds. But researchers are finding that robotic pets can be useful in therapy, without some of the disadvantages and unpredictability of real animals.

In a paper published in the Canadian Journal of Recreation Therapy, University of Utah researcher Rhonda Nelson and graduate student Rebecca Westenskow developed a protocol for using robotic pets with older adults with dementia. The protocol uses a low-cost robotic pet, establishes ideal session lengths, and identifies common participant responses to the pets to aid in future research.

“Our protocol had questions like: Would you like to scratch the dog behind his ears? Would you like to pet him? Would you like to brush him?” says Nelson, an assistant professor in the Department of Occupational and Recreational Therapies. “And then we were evaluating how people responded to those different cues so that we could then provide some guidelines to people on how to have the most beneficial actions with these animals.”

An affordable robotic pet

Nelson has watched the development of robotic pets for the past decade, intrigued by the potential to use them therapeutically in long-term and geriatric care settings. But until recently the price was prohibitive. “Having been a therapist myself and training our students to work as therapists, I’m very aware that most facilities would never be able to purchase them.”

But with the introduction of Ageless Innovation’s Joy For All Companion pets in 2015, priced at under $150, widespread use of robotic pets as therapy “animals” seemed within reach. Robotic pets can get around many of the risks and drawbacks of live animals in long-term care settings. Many facilities don’t allow personal pets because of allergies, the potential for bites or scratches and other reasons.

Researchers have already begun to study how people with dementia interact with robotic pets, Nelson notes, but haven’t yet developed a unified protocol to give, say, assisted living staff a plan to gain the most benefit from the pets’ use through directed interaction.

“There was very little information on what people were doing with the pets,” Nelson says. “So without that guidance, it’s just a toy. And what do you do with it?”

Observing interactions

Prior to the COVID-19 pandemic, the researchers met with five people between 82 and 87 years old living in long-term care facilities who experienced severe cognitive impairment. In two sessions of 30 minutes each, the researchers brought out either a robotic dog or a cat (participants’ choice) in a pet carrier.

“Many participants leaned toward the [robotic pet] as it was taken out of the pet carrier,” the researchers noted, “then instinctively reached for it and began petting, rubbing or scratching the pet when first introduced.”

Throughout the session, the researchers asked questions, both about the participants’ experiences with past pets and about interacting with the current robotic pet. “Did they have dogs or cats?” Nelson says, giving examples of typical questions. “What were their names? Did they keep them indoors or outdoors? What types of food did they eat?”

The researchers carefully observed the responses of the participants to the pets. The robotic pets moved and made sounds, which Nelson says helped the participants engage with them.

“When the dog would bark they would say things like, ‘Oh, are you trying to tell me something?'” she says. “Or they would comment on the cat purring and would say things like, ‘Wow, you must really be happy! I feel you purring.’ One of the activities that people responded to the most was brushing the animals.”

In one case, though, the session proceeded in silence. The participant had difficulty communicating their thoughts but stayed focused on the robotic dog throughout. By the end of the session, the participant seemed to develop a connection with the robotic animal, saying “I like that dog. When he likes me.”

Nelson is often asked if the participants with cognitive decline understand that the robotic pets are not alive. In this study, she says, they all seemed aware that it was not a live animal.

“Interestingly enough one of our participants was a retired veterinarian,” she says. “So I was very intrigued to see how he would interact with it.” He chose to have both the robotic dog and cat on his lap at the same time. “We would never tell somebody that it was live if they asked. We would be honest with them. We usually introduce it as ‘Would you like to hold my dog’ and people react to it or respond to it in a way that’s meaningful for them.”

Initial recommendations

Unfortunately, data collection was cut short by the COVID-19 pandemic. But the researchers were able to draw some conclusions.

All of the participants enjoyed the activity, with several saying they liked it “very much.” One participant didn’t like the sounds the pet made, which was easily remedied by turning off the sound — not an option for a live animal.

The questions that spurred the most response related to personal reminiscences and directions for interacting with the pet.

A common, yet unprompted behavior, the researchers’ report, was communication with the pet. “Several participants used comments, sounds, specific inflections and facial expressions spontaneously with the pets,” the researchers wrote. “Some participants imitated the animal sounds made by the [pet] and repositioned the pet to look at its face or make eye contact.”

Although more research is needed to determine the optimal session length, the researchers noted that the 30-minute sessions in the study were sufficient. Nelson also hopes to explore how people with varying levels of cognitive decline respond to the pets, as well as how they can be used in a group setting.

The study found that the most meaningful interactions and the most enjoyable experiences came when the participant self-directed the session.

“In recreational therapy, we always talk about providing person-centered care,” Nelson says. So it’s not really about what I think about an activity. If somebody enjoys it and it brings happiness to them, then it’s really about what they think about it.”

Why does interacting with robotic pets provide such an enjoyable experience?

“People in long-term care facilities are in a position where everybody provides care to them,” Nelson says, “and to be in the role where you are nurturing something else, or you are the caregiver I think is also psychologically very comforting for people to feel like, even though they know that it’s not live, they’re the person who’s giving love and compassion to something, and it’s responding.”

“We found that giving the rats a multidrug antibiotic cocktail resulted in significant and sex-specific changes in both the stool, or large intestine, and the small bowel. For example, greater loss of the diversity of the microbes in both stool and small bowel was observed in the male rodents than in the females,” said Ruchi Mathur, MD, the study’s principal investigator.

“Changes in the diversity of the gut microbiome could have a negative impact. Previous studies of intestinal health have demonstrated that overall microbial diversity promotes vitality and resilience, often making for a healthier gut,” said Mathur, an endocrinologist.

In the controlled study, investigators from the Cedars-Sinai Medically Associated Science and Technology (MAST) Program compared the composition of the gut microbes of the male and female rats before, during and after treatment with broad-spectrum antibiotics, including vancomycin, ampicillin, metronidazole, and neomycin.

“We followed the rats for a period after the antibiotics were stopped and found that many of the sex-specific changes we observed during treatment remained. The constellation of microbes in the gut did not return to their original, pre-antibiotic compositions in either sex during the duration of the study,” said research associate Gonzalo Parodi, first author of the paper.

Some studies have identified sex-specific effects of antibiotics on the large bowel (stool) microbiome in mice. But Cedars-Sinai investigators emphasize that this is the first study to also examine changes in the small bowel microbiome induced by antibiotics and to also use male and female rats that had no significant differences in microbiome composition prior to treatment.

“It is difficult to tease out the impact of the drugs if the lab animals’ gut microbiomes are different to begin with. We used rats with similar gut profiles right out of the gate. This allowed us to pinpoint changes in the microbiomes of the male and female rats that could be attributed specifically to the impact of the antibiotics during and after exposure to the medicines,” said Mark Pimentel, MD, director of the MAST program and a co-author of the study.

More studies are needed using different combinations of antibiotics and exposure times. Investigators say if these findings hold true for humans, the research could have implications for the way antibiotics are prescribed.

“Sex is a biological variable, and like any variable, it needs to be taken into consideration in basic and medical research. Currently, we consider factors such as kidney function and weight when dosing medications for patients. Depending on the results of further research, specifically in humans, the sex of patients may one day be an important consideration when prescribing antibiotics,” said Mathur.

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Coincidence? Not likely, finds new research by anthropologist and professor Douglas Kennett of UC Santa Barbara.

Writing in the journal Nature Communications, lead author Kennett and collaborators in the fields of archaeology, history, geography and earth science suggest that drought may in fact have stoked the civil conflict that begat violence, which in turn led to the institutional instabilities that precipitated Mayapan’s collapse. This transdisciplinary work, the researchers said, “highlights the importance of understanding the complex relationships between natural and social systems, especially when evaluating the role of climate change in exacerbating internal political tensions and factionalism in areas where drought leads to food insecurity.”

“We found complex relationships between climate change and societal stability/instability on the regional level,” Kennett said in an interview. “Drought-induced civil conflict had a devastating local impact on the integrity of Mayapan’s state institutions that were designed to keep social order. However, the fragmentation of populations at Mayapan resulted in population and societal reorganization that was highly resilient for a hundred years until the Spanish arrived on the shores of the Yucatan.”

The researchers examined archaeological and historical data from Mayapan, including isotope records, radiocarbon data and DNA sequences from human remains, to document in particular an interval of unrest between 1400 and 1450 CE. They then used regional sources of climatic data and combined it with a newer, local record of drought from cave deposits beneath the city, Kennett explained.

“Existing factional tensions that developed between rival groups were a key societal vulnerability in the context of extended droughts during this interval,” Kennett said. “Pain, suffering and death resulted from institutional instabilities at Mayapan and the population fragmented and moved back to their homelands elsewhere in the region.”

The vulnerabilities revealed in the data, the researchers found, were rooted in Maya reliance on rain-fed maize agriculture, a lack of centralized, long-term grain storage, minimal investments in irrigation and a sociopolitical system led by elite families with competing political interests.

Indeed the authors argue that “long-term, climate-caused hardships provoked restive tensions that were fanned by political actors whose actions ultimately culminated in political violence more than once at Mayapan.”

Yet significantly, a network of small Maya states also proved to be resilient after the collapse at Mayapan, in part by migrating across the region to towns that were still thriving. Despite decentralization, trade impacts, political upheaval and other challenges, the paper notes, they adapted and persisted into the early 16^th century. It all points to the complexity of human responses drought on the Yucatan Peninsula at that time — an important consideration for the future as well as the past.

“Our study demonstrates that the convergence of information from multiple scientific disciplines helps us explore big and highly relevant questions,” Kennett said, “like the potential impact of climate change on society and other questions with enormous social implications.

“Climate change worries me, particularly here in the western U.S., but it is really the complexities of societal change in response to climatic perturbations that worry me the most,” he added. “The archaeological and historical records provide lessons from the past, and we also have so much more information about our Earth’s climate and the potential vulnerabilities in our own sociopolitical systems.”

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Materials provided by University of California – Santa Barbara. Original written by Shelly Leachman. Note: Content may be edited for style and length.

“Based upon over a decade of data, cannabis use was markedly more prevalent in states where recreational use is legal for adults, relative to states where it was not in 2017. Yet, the increases in cannabis use during this time period were as fast, or faster, in states where cannabis use is prohibited by law, relative to states that had legalized for recreational use by 2017,” said Renee Goodwin, PhD, adjunct associate professor of epidemiology at Columbia Mailman School and professor of epidemiology at CUNY, and lead author. “It remains to be seen how increased lawful accessi and growing use of cannabis among adults in all states — almost regardless of legal status — will impact the adolescent population. Recent trends, however, outline a potential explosion in both of-age and under-age use,” she noted.

The researchers used data from the 2004-2017 National Survey on Drug Use and Health, a representative survey of U.S. individuals aged 12 and older. State of residence was used to determine state-level medical and recreational cannabis laws. The total sample was 784,293 respondents and for 2017 was 56,276 respondents.

The study found that cannabis use and daily cannabis use increased in the U.S with little difference in the speed of increase by state-level legal status of cannabis use from 2004 through 2017. Cannabis use and daily cannabis were much more common in states with recreationally legal cannabis use, relative to those with legal medical cannabis and those with no legal cannabis use.

Cannabis use was even greater among Americans who also smoke cigarettes in states that had adopted recreational cannabis laws, relative to those where cannabis use was not legal. In 2017, one in three (33 percent) daily cigarette smokers reported cannabis use in the past month in recreationally legal states and almost one in five (18 percent) reported daily cannabis use. In contrast, among non-smokers, one in ten reported any cannabis use in recreationally legal states and 3 percent of non-cigarette smokers in these states reported daily use.

The study found that among adolescents ages 12-17 who used cigarettes daily, the majority (73 percent) had used cannabis in the past month and almost one in three (30 percent) used cannabis daily. Among adolescents who did not smoke cigarettes, 5 percent used cannabis in the past month and one percent used cannabis daily.

The study is published online in the journal Drug and Alcohol Dependence.

Goodwin observes, “U.S. states are rapidly passing legislation, yet what should be requisite public education on how cannabis can be used safely has not accompanied these changes. For instance, retail licenses are being issued and it is expected that recreational retail outlets will open within the year in New York State, yet New York has not provided evidence-based guidance outlining safe cannabis use practices or informing the public of potential health risks associated with various levels of cannabis use.”

Co-authors are Katarzyna Wyka, City University of New York and Andrea Weinberger, Yeshiva University.

The study was supported by National Institutes of Health/National Institute on Drug Abuse (grant number R01-DA20892).