The findings publish in the September 30, 2021 issue of The New England Journal of Medicine.

The work involved researchers in Egypt, India, the United Arab Emirates, Brazil and the United States. “Although different doctors were caring for these children, all of the children showed the same symptoms and all had DNA mutations in the same gene,” said senior author Joseph G. Gleeson, MD, Rady Professor of Neuroscience at UC San Diego School of Medicine and director of neuroscience at the Rady Children’s Institute for Genomic Medicine.

The research team dubbed the condition “Zaki syndrome” after co-author Maha S. Zaki, MD, PhD, of the National Research Center in Cairo, Egypt, who first spotted the condition. Zaki syndrome affects prenatal development of several organs of the body, including eyes, brain, hands, kidneys and heart. Children suffer from lifelong disabilities. The condition appears to be rare, but future studies are required to determine prevalence.

“We have been perplexed by children with this condition for many years,” said Gleeson. “We had observed children around the world with DNA mutations in the Wnt-less (WLS) gene, but did not recognize that they all had the same disease until doctors compared clinical notes. We realized we were dealing with a new syndrome that can be recognized by clinicians, and potentially prevented.”

Co-author Bruno Reversade, PhD, a research director at the Agency for Science, Technology and Research (A*STAR) in Singapore, helped identify several families with members suffering from Zaki syndrome and investigate potential therapeutic intervention.

“While we have shown that it’s possible to mimic WNT-deficiency with dedicated drugs, the real challenge was to overcome, and possibly rescue, this congenital disease,” Reversade said.

Using whole genome sequencing, researchers documented mutations in the WLS gene, which controls signaling levels for a hormone-like protein known as Wnt (pronounced wint). Wnt signaling is a highly conserved group of protein pathways involved in embryonic development.

The scientists generated stem cells and mouse models for Zaki syndrome, and treated the condition with a drug called CHIR99021, which boosts Wnt signaling. In each mouse model, they found CHIR99021 boosted Wnt signals, and restored development. Mouse embryos grew body parts that had been missing and organs resumed normal growth.

“The results were very surprising because it was assumed that structural birth defects like Zaki syndrome could not be prevented with a drug,” said first author Guoliang Chai, PhD, a former postdoctoral fellow at UC San Diego School of Medicine now at Capital Medical University in Beijing, China. “We can see this drug, or drugs like it, eventually being used to prevent birth defects, if the babies can be diagnosed early enough.”

Co-authors include: Changuk Chung, Zhen Li, Lu Wang, Trevor Marshall, Nan Jiang, Xiaoxu Yang, Jennifer McEvoy-Venneri, Valentina Stanley, Paula Anzenberg and Nhi Lang, all at Rady Children’s and UC San Diego; Karl Willert, UC San Diego; Emmanuelle Szenker-Ravi, Muznah Khatoo and Vanessa Wazny, Genome Institute of Singapore; Jia Yu and David M. Virshup, National University of Sinapore; Rie Nygaard, Filippo Mancia, Rebecca Hernan and Wendy K. Chung, Columbia University; Rijad Merdzanic and Aida M. Bertoli-Avella, Centogene, Germany; Maria B.P. Toralles and Paula M.L. Pitanga, Laboratorio e Genetica Medica, Brazil; Ratna D. Puri, Sir Ganga Ram Hospital; and Nouriya Al-Sannaa, Dhahran Health Center, Saudi Arabia.

Where once about 60% of such patients survived at least 90 days in spring 2020, by the end of the year it was just under half.

The decreased survival over time might be due to a combination of factors, including which critically ill patients clinicians chose to place on ECMO as the pandemic went on, and the treatments the patients had received before they started on ECMO.

The new findings show how important it is for hospitals that offer ECMO to choose carefully which patients get access to this labor-intensive level of care, the authors say.

Hospitals should also make policies that can guide such choices when ECMO circuits are in high demand because of a pandemic surge, they advise.

The new findings are published in Lancet by an international team co-led by ECMO experts from the University of Michigan, Singapore and Columbia Universiity. The paper uses data from more than 4,800 patients over age 16 who were treated with ECMO for advanced COVID-19 in 41 countries during 2020.

The data for the study were contributed by ECMO centers to a registry run by ELSO, an international organization devoted to ECMO and other forms of advanced life support.

A last-chance options

ECMO, short for extracorporeal membrane oxygenation, has been used for decades in select hospitals to treat critically ill children and adults. It takes over for both the heart and lungs temporarily, circulating the blood outside the body under constant supervision of trained providers.

At the start of the pandemic, some experts had strong reservations about placing COVID-19 patients on ECMO, for fear of harming their lungs. As more centers began to try it, the survival rate mirrored that of ECMO’s use in other forms of acute lung failure, as the team behind the new paper reported a year ago.

But all the centers in that first study had begun offering ECMO before May of 2020, and most were highly experienced with providing ECMO in general, says Ryan Barbaro, M.D., M.S., co-first author of the new paper, associate professor at the U-M Medical School and intensive care physician at Michigan Medicine, U-M’s academic medical center.

The new study breaks the patients into three groups: those treated before May 1, 2020, those treated in these “early adopter” hospitals after May 1, and those treated with ECMO in other hospitals from May 1 through the end of 2020. May 1 was chosen because the evidence for how best to treat critically ill COVID-19 patients had evolved considerably by then.

“What we noticed right away is that the patients treated later in the pandemic were staying on ECMO longer, going from an average of 14 days to 20 days. They were dying more often, and these deaths were different,” said Barbaro. “This shows that we need to be thoughtful about who we’re putting on ECMO and when we’re making the decision to take patients off who aren’t getting better. Across the U.S. right now, we have places where ECMO is a scarce resource whereas in Michigan it’s not quite at that point, but we anticipate it might be.”

Within the “early adopter” centers, mortality rates increased from 37% in the months before May, to 52% after May. At the centers that didn’t start providing ECMO until at least May, 58% of the patients died within 90 days of being places on an ECMO circuit.

Patients treated with ECMO later in the pandemic were more likely to have received medications such as remdesivir and dexamethasone, and to have received non-invasive ventilation before being intubate for total breathing support.

Decisions and ethics during a surge

Having patients stay on ECMO for a longer time ties up many resources, including the machines and tubing that make up an ECMO circuit, and the specially trained nurses, respiratory therapists and other staff it takes to keep a circuit operating safely.

When a hospital has a large number of COVID-19 patients and others in intensive care, the team’s ability to provide the same level of care that they did before the surge can suffer, and mortality might increase.

If many hospitals in a region or collection of states are coping with a large number of critically ill COVID-19 patients, it can be hard to find an ECMO-capable hospital to transfer patients to. Sending more ECMO circuits — the pumps, tubes and controllers used in the treatment — to these hospitals is not sufficient; specially trained teams, adequate blood supply and other factors are all needed to support each ECMO patient.

So, the authors say, it’s important for ECMO centers to carefully consider which risk factors and personal characteristics might make a patient more or less likely to survive if placed on ECMO, especially if they might need to be on for a while. ELSO offers resources and guidelines can help.

The research team used methods developed by U-M School of Public Health statistician Philip Boonstra to adjust the data to make apples-to-apples comparisons. This allowed them to ensure, for instance, that the survival percentages were not affected by the fact that so many more patients were transferred out of their ECMO hospital later in the pandemic compared with at the start.

In addition to working on the ELSO COVID-19 registry, Barbaro is leading a clinical observational study called ASCEND that is tracking ECMO outcomes in children and adolescents at nearly 100 hospitals around the world. As the Delta variant of the novel coronavirus spreads rapidly, the research team has already noticed that the majority of pediatric patients being placed on ECMO at this time are needing it because of COVID-19.

“in these moments of crisis, our ability to meet demand presents ethical challenges, and COVID has drawn out the weaknesses in our system, as well as showing how those with resources and relatives who can advocate on their behalf are more able to find out about ECMO and seek the opportunity for their loved one to be treated,” Barbaro said. “Meanwhile, hospitals in non-surge areas need to reflect on what policies and procedures they’ll use if they experience another surge, to foster ethical allocation when resources are constrained.”

Physician-scientists from Beth Israel Deaconess Medical Center (BIDMC) developed a 12-week mind-body program that takes a new approach to chronic back pain. The novel intervention — which is not yet available at BIDMC to the general public — is based on an idea pioneered by the late John Sarno, MD, a professor of rehabilitation medicine at the New York University School of Medicine. In a new publication appearing in journal PAIN, the team demonstrated that the mind-body intervention was highly beneficial for treating back pain when compared to standard care, with 64 percent of research volunteers reporting being 100 percent pain free six months later.

“The current paradigm of pain management focuses mostly on treatment of a physical origin of pain, however, in many cases of chronic back pain a physical source of pain cannot be identified,” said corresponding author Michael W. Donnino, MD, a physician in the Departments of Critical Care and Emergency Medicine at BIDMC. “Our group focused on the hypothesis that non-specific back pain is the symptomatic manifestation of a psychological process, substantively driven by stress, repressed emotions and other psychological processes. The exact mechanism remains unclear, but an analogy could be made to other known effects of acute emotional states on acute physiological changes, such as how the emotion of embarrassment may result in the capillary vasodilation we know as blushing.”

Donnino and colleagues’ experimental program, termed Psychophysiologic Symptom Relief Therapy (PSRT), is designed to address underlying stressors and psychological contributors to persistent pain as well as conditioned pain responses and fear avoidant behaviors. Treatment strategies include educating patients about the links between stressors and pain, as well as the relationship with emotions. Armed with this knowledge, participants learn healthier ways to process stress and express emotions. The program also focuses on desensitization or reverse conditioning to help patients break the associations that often are formed with triggers of pain such as bending or sitting.

“Often these triggers are assumed to be cause of pain, but they are perhaps better described as associations that can be unknowingly conditioned in a way that is similar to how Pavlov conditioned dogs to salivate to a bell by pairing the bell with food,” Donnino noted. “Our program works to reverse these conditioned responses and thus improve pain and pain disability.”

The program’s final eight weeks focus on mindfulness-based stress reduction, or MBSR, the goal of which is to provide the tools to better process current and future stressors, while allowing time to practice the techniques from the first portion of the program.

To assess whether PSRT can reduce symptoms and pain-related anxiety in patients with non-specific chronic back pain, Donnino and colleagues enrolled 35 participants, 18 to 67 years old with chronic back pain that lacked a clear physical origin. Participants were randomly assigned to receive either the novel 12-week PSRT intervention, eight weeks of MBSR only, or usual care under the guidance of their physicians without influence from the study team. All participants filled out pain-related questionnaires prior to the interventions and periodically up to six months after the interventions to assess changes in functional limitations or disability, back pain bothersomeness and pain-related anxiety.

After just four weeks, researchers saw an astonishing 83 percent decrease in reported pain disability in the PSRT group compared to 22 percent and 11 percent in the MBSR and usual care groups, respectively. With regard to pain bothersomeness over the same time period, the PSRT group had a 60 percent drop compared to 8 percent and 18 percent decreases in pain bothersomeness for the mindfulness and usual care groups, respectively.

The PSRT group was superior to both usual care and MBSR for the primary endpoint of pain disability at every interval and at the end of the six-month monitoring period. Moreover, at the end of the six-month period, 64 percent of patients with chronic back pain in the PSRT group were completely pain free (reporting 0 out 10 on a pain scale) whereas only 25 percent and 17 percent reported being pain free in the mindfulness and usual care arms, respectively.

“Within four weeks, differences between PSRT, MBSR, and usual care were apparent across multiple domains including the primary outcome measure of functional disability as well as pain bothersomeness,” Donnino said. “When patients recognize the relationship between the mind and their physical pain, this orientation sheds new light and provides them a basis to engage with the multifaceted program that works interchangeably to improve pain and disability. This study shows that our program has the potential to be highly beneficial when compared to both usual care as well as usual care plus additional treatments such as MBSR.”

Co-authors included Garrett S. Thompson, Shivani Mehta, Patricia Howard, Lakshman Balaji, Long H. Ngo, and Anne V. Grossestreuser of BIDMC; and Myrella Paschali, Robert Edwards, Sofie B. Antonsen and Suzanne M. Bertisch of Brigham & Women’s Hospital. This work was supported by a philanthropic donation from Adam D’Angelo. The authors have declared no conflicts.

As part of a project titled, “Food Resilience in the Face of Catastrophic Global Events,” an international team of researchers has found that these vegetables can be grown in a variety of soilless production systems in small spaces indoors, with or without artificial lighting. The findings are especially relevant amid a pandemic that has disrupted food supply chains.

With microgreens, people can produce fresh and nutritious vegetables even in areas that are considered food deserts, according to team leader Francesco Di Gioia, assistant professor of vegetable crop science, College of Agricultural Sciences, Penn State.

“The current COVID-19 pandemic revealed the vulnerability of our food system and the need to address malnutrition issues and nutrition-security inequality, which could be exacerbated by potential future emergencies or catastrophes,” he said. “Nutrient-dense microgreens have great potential as an efficient food-resilience resource.”

Microgreens’ nutritional profile is associated with the rich variety of colors, shapes, textural properties and flavors obtained from sprouting a multitude of edible vegetable species, including herbs, herbaceous crops and wild edible species.

With a short growth cycle requiring only minimal inputs of fertilizer, microgreens have great potential to provide essential nutrients and antioxidants, Di Gioia noted. Using simple agronomic techniques, it is possible to produce microvegetables that could address specific dietary needs or micronutrient deficiencies, as well as nutrition-security issues in emergency situations or in challenging environmental conditions.

Consumers could produce microgreens at home using simple tools available in a kitchen, Di Gioia pointed out. A grower also would need seeds, growing trays and a growth medium — which could consist of a common peat or peat and perlite growth mix.

Given all the characteristics of microgreens, scientists at NASA and the European Space Agency also have proposed them as a source of fresh food and essential nutrients for astronauts engaged in long-term space missions. And because microgreens may be used as functional food to enhance nutrition security under current conditions and during future emergencies or catastrophes, Di Gioia suggested that microgreen production kits including seeds could be prepared and stored, then made available when needed.

“Under such circumstances, a variety of fresh and nutrient-rich microgreens could be grown providing a source of minerals, vitamins and antioxidants in a relatively short time,” he said. “Or alternatively, kits could be distributed to vulnerable segments of the population as a short-term nutrition-security resource.”

Di Gioia presented the study virtually during the International Symposium on Soilless Culture and Hydroponics sponsored by the International Society for Horticultural Science last spring. Originally scheduled to be held in Lemesos, Cyprus, the symposium took place online because of COVID concerns. The research paper was published recently in Acta Horticulturae, the journal of the International Society for Horticultural Science.

Also on the research team were Spyridon Petropoulos, Department of Agriculture, University of Thessaly, Magnissia, Greece; Isabel C.F.R. Ferreira, Instituto Politécnico de Bragança, Centro de Investigaçã o de Montanha, Campus de Santa Apolónia, Bragança, Portugal; and Erin Rosskopf, Horticultural Research Laboratory, U.S. Department of Agriculture’s Agriculture Research Service, Fort Pierce, Florida.

Open Philanthropy and the U.S. Department of Agriculture’s National Institute of Food and Agriculture supported this research.

Story Source:

Materials provided by Penn State. Note: Content may be edited for style and length.