Spinal cord injury: Can brain and nerve stimulation restore movement?

 In 1999, when Jason Carmel, MD, Ph.D., was a second-year medical student at Columbia, his identical twin brother suffered a spinal cord injury, paralyzing him from the chest down and limiting use of his hands.

Jason Carmel's life changed that day, too. His brother's injury ultimately led Carmel to become a neurologist and a neuroscientist, with the goal of developing new treatments to restore movement to people living with paralysis.

Now, a nerve stimulation therapy that Carmel is developing at Columbia is showing promise in animal studies and may eventually allow people with spinal cord injuries to regain function of their arms.

"The stimulation technique targets the nervous system connections spared by injury," says Carmel, a neurologist at Columbia University and NewYork-Presbyterian, "enabling them to take over some of the lost function."

In recent years, some high-profile studies of spinal cord electrical stimulation have allowed a few people with incomplete paralysis to begin to stand and take steps again.

Carmel's approach is different because it targets the arm and hand and because it pairs brain and spinal cord stimulation, with electrical stimulation of the brain followed by stimulation of the spinal cord. "When the two signals converge at the level of the spinal cord, within about 10 milliseconds of each other, we get the strongest effect," he says, "and the combination appears to enable the remaining connections in the spinal cord to take control."

In his latest study, Carmel tested his technique—called spinal cord associative plasticity (SCAP)—on rats with moderate spinal cord injuries. Ten days after injury, the rats were randomized to receive 30 minutes of SCAP for 10 days or sham stimulation. At the end of the study period, rats that received SCAP targeted to their arms were significantly better at handling food, compared to those in the control group, and had near-normal reflexes.

"The improvements in both function and physiology persisted for as long as they were measured, up to 50 days," Carmel says.

The findings, published recently in the journal Brain, suggest that SCAP causes the synapses (connections between neurons) or the neurons themselves to undergo lasting change. "The paired signals essentially mimic the normal sensory-motor integration that needs to come together to perform skilled movement," says Carmel.

From mice to people

If the same technique works in people with spinal cord injuries, patients could regain something else they lost in the injury: independence. Many spinal cord stimulation studies focus on walking, but "if you ask people with cervical spinal cord injury, which is the majority, what movement they want to get back, they say hand and arm function," Carmel says. "Hand and arm function allows people to be more independent, like moving from a bed to a wheelchair or dressing and feeding themselves."

Carmel is now testing SCAP on spinal cord injury patients at Columbia, Cornell, and the VA Bronx Healthcare System in a clinical trial sponsored by the National Institute of Neurological Disorders and Stroke. The stimulation will be done either during a clinically indicated surgery or noninvasively, using magnetic stimulation of brain and stimulation of the skin on the front and back of the neck. Both techniques are routinely performed in clinical settings and are known to be safe.

In the trial, the researchers hope to learn more about how SCAP works and how the timing and strength of the signals affect motor responses in the fingers and hands. This would lay the groundwork for future trials to test the technique's ability to meaningfully improve hand and arm function.

Looking farther ahead, the researchers think that the approach could be used to improve movement and sensation in patients with lower-body paralysis.

In the meantime, Jason Carmel's twin is working, married, and raising twins of his own. "He has a full life, but I'm hoping we can get more function back for him and other people with similar injuries," says Carmel.

More information: Ajay Pal et al, Spinal cord associative plasticity improves forelimb sensorimotor function after cervical injury, Brain (2022). DOI: 10.1093/brain/awac235

https://medicalxpress.com/news/2023-01-spinal-cord-injury-brain-nerve.html

Hybrid immunity is the best protection against COVID-19

 A University of Calgary research group joined forces with members of the World Health Organization (WHO) to tackle a global health question. What is the best protection against COVID-19? Analyzing data from controlled studies throughout the world, researchers discovered people with hybrid immunity are the most protected against severe illness and reinfection.

Hybrid immunity occurs when someone has had at least the full series of vaccines and has a prior infection, in any order. The study published in The Lancet Infectious Diseases helps public policy makers understand the optimal timing of vaccinations.

"The results reinforce the global imperative for vaccination," says Dr. Niklas Bobrovitz, first author on the study. "A common question throughout the pandemic was whether previously infected people should also get vaccinated. Our results clearly indicate the need for vaccination, even among people that have had COVID-19."

The global emergence and rapid spread of the omicron variant of concern required scientists and policymakers to reassess population protection against omicron infection and severe disease. In the study, investigators were able to look at immune protection against omicron after a prior SARS-CoV-2 infection (the virus that causes COVID-19), vaccination, or hybrid immunity.

"Protection against hospitalization and severe disease remained above 95 percent for 12 months for individuals with hybrid immunity," says Dr. Lorenzo Subissi, MSc, Ph.D., WHO-Scientist and senior author on the study. "We know more variants are going to emerge. The study shows to reduce infection waves, vaccinations could be timed for roll-out just prior to expected periods of higher infection spread, such as the winter season."

The systematic review and meta-analysis find that protection against omicron infection declines substantially by 12 months, regardless of whether you've had an infection, vaccinations, or both, which means that vaccination is the best way to periodically boost your protection and to keep down levels of infection in the population. In total, 4,268 articles were screened and 895 underwent full-text review. A difficult task before the assistance of experts in health informatics.

"This study demonstrates the power of machine translation. We were able to break through language barriers, most of the time systematic reviews aren't done in every language they are limited to one or two," says Dr. Tyler Williamson, Ph.D., director of the Centre for Health Informatics at the Cumming School of Medicine.

"These former BHSc classmates along with the large diverse team they brought together have emerged as global leaders in SARS-CoV-2 research and delivered decision-grade evidence to the world." And while the findings demonstrate that vaccination along with a prior infection carries the most protection, the scientists warn against intentional exposure to the virus.

"You should never try to get COVID-19," says Bobrovitz. "The virus is unpredictable in how it will affect your system. For some, it can be fatal or send you to hospital. Even if you have a mild infection, you risk developing long COVID."

The group says the next phase of this research would be to investigate how the bivalent vaccine performs against severe disease.

The study is supported by WHO COVID-19 Solidarity Response Fund and the Coalition for Epidemic Preparedness Innovation (CEPI). The views reported do not necessarily reflect the official position of WHO or CEPI.

Findings from the study complement data on the serotracker dashboard which monitors studies and news reports to track seroprevalence data—the percentage of people in a population who have antibodies against the novel coronavirus. The website aggregates serology data from studies and news reports in different populations, and built-in filters allow users to compare seroprevalence levels between countries, occupations, and demographic groups.

More information: Niklas Bobrovitz et al, Protective effectiveness of previous SARS-CoV-2 infection and hybrid immunity against the omicron variant and severe disease: a systematic review and meta-regression, The Lancet Infectious Diseases (2023). DOI: 10.1016/S1473-3099(22)00801-5

Serotracker dashboard:serotracker.com/en/Explore

https://medicalxpress.com/news/2023-01-hybrid-immunity-covid-.html

Role of lymphatic system in bone healing

 It was previously assumed that bones lacked lymphatic vessels, but new research from the MRC Human Immunology Unit at Oxford's MRC Weatherall Institute for Molecular Medicine not only locates them within bone tissue, but demonstrates their role in bone and blood cell regeneration and reveals changes associated with aging.

The lymphatic system is a network of vessels that branch out throughout the body, and play an important role in draining excess fluid from tissues, clearing waste products and supporting immune responses.

The fine network of lymph vessels extends throughout the body, but a small number of sites such as the brain, eye and bone were previously assumed to lack lymph tissue. The hard tissue of bone in particular has traditionally made studying the distribution and role of blood and lymph more difficult.

New research published in Cell uses light-sheet imaging to overcome these barriers, identifying and visualizing the lymphatic vessels of bone in high-resolution 3D. Researchers discovered an active network of lymph vessels within bone and further identified some of the key signals happening between lymph vessels, blood stem cells and bone stem cells.

Dr. Lincoln Biswas, a Post-Doctoral Research Associate in the MRC Human Immunology Unit and co-first author of this study, said, "Interestingly after injury, lymphatic vessels in bone show dynamic crosstalk with blood stem cells and with specialized perivascular cells in order to accelerate bone healing. Such interactions between lymphatics and bone stem cells can harnessed to promote bone healing such as in fracture repair."

The researchers found that lymphatic vessels in bone increase during injury via a signaling molecule called IL6, and trigger expansion of bone progenitor cells by secreting a different signal, called CXCL12. Dr. Junyu Chen, a co-first author of the study now based at Sichuan University said, "Aging is associated with diminished capacity for bone repair, and our findings show that lymphatic signaling is impaired in aged bones. Remarkably, the administration of young lymphatic endothelial cells restores healing of aged bones, thus providing a future direction to promote bone healing in elderly."

Dr. Anjali Kusumbe, Group Leader of the Tissue and Tumor Microenvironments Group at the MRC Human Immunology Unit, who led the research said, "I am very excited as these findings not only demonstrate that lymphatic vessels do exist in bone but also reveal their critical interactions with blood stem cells and perivascular bone stem cells after injury to promote healing, thereby presenting lymphatics as a therapeutic avenue to stimulate bone and blood regeneration. Further, these findings are very fundamental, opening doors for understanding the impact of bone lymphatics on the immune system and their role in bone and blood diseases."

Lymph vessels were shown not only to be present in bone, but to play a role in bone and blood cell regeneration. Exploring the role of aging on bone lymphatic vessels, they found that aging bones showed reduced expansion of lymphatic vessels in response to injury. The researchers aim to expand on this research to explore the role of lymphatic vessels in bone-based diseases such as rheumatoid arthritis, and to explore the potential for new therapeutic approaches to treat bone and blood diseases.

"The lab used innovative imaging techniques to identify the presence of lymphatics within bones for the first time. Kusumbe then defined roles for these bone lymphatics in blood and immune cell production and bone regeneration which were impaired during aging. These disruptive findings have important ramifications for age related disorders of the bone and immune system," says Professor Alison Simmons, Director of the MRC Human Immunology Unit at the University of Oxford. "As such the work will act as a foundation for a variety of future endeavors focused on this new anatomy, from discovery to translation."

More information: Lincoln Biswas et al, Lymphatic vessels in bone support regeneration after injury, Cell (2023). DOI: 10.1016/j.cell.2022.12.031

https://medicalxpress.com/news/2023-01-role-lymphatic-bone-revealed.html

Orienteering can train the brain, may help fight cognitive decline

 The sport of orienteering, which draws on athleticism, navigational skills and memory, could be useful as an intervention or preventive measure to fight cognitive decline related to dementia, according to new research from McMaster University.

Researchers hypothesized that the physical and cognitive demands of orienteering, which integrates exercise with navigation, may stimulate parts of the brain that our ancient ancestors used for hunting and gathering. The brain evolved thousands of years ago to adapt to the harsh environment by creating new neural pathways.

Those same brain functions are not as necessary for survival today due to modern conveniences such as GPS apps and readily available food. Researchers suggest it is a case of "use it or lose it."

"Modern life may lack the specific cognitive and physical challenges the brain needs to thrive," says Jennifer Heisz, Canada Research Chair in Brain Health and Aging at McMaster University, who supervised the research. "In the absence of active navigation, we risk losing that neural architecture."

Heisz points to Alzheimer's disease, in which losing the ability to find one's way is among the earliest symptoms, affecting half of all afflicted individuals, even in the mildest stage of the disease.

In the study, published today in the journal PLoS ONE, researchers surveyed healthy adults, ranging in age from 18 to 87 with varying degrees of orienteering expertise (none, intermediate, advanced and elite).

People who participate in orienteering reported better spatial navigation and memory, suggesting that adding elements of wayfinding into regular workouts could be beneficial over the span of a lifetime.

"When it comes to brain training, the physical and cognitive demands of orienteering have the potential to give you more bang for your buck compared to exercising only," says lead author Emma Waddington, a grad student in the Department of Kinesiology who designed the study and is a coach and member of the national orienteering team.

The goal of orienteering is to navigate by running as quickly as possible over unfamiliar territory, finding a series of checkpoints using only a map and compass. The most skillful athletes must efficiently switch between several mental tasks, making quick decisions while moving across the terrain at a rapid pace.

The sport is unique because it requires active navigation while making quick transitions between parts of the brain that process spatial information in different ways. For example, reading a map depends on a third-person perspective relative to the environment. Orienteers must quickly translate that information relative to their own positions within the environment, in real-time, as they run the course.

It is a skill which GPS systems have engineered out of modern life, say researchers. That may affect not only our ability to navigate but also affect our spatial processing and memory more generally because these cognitive functions rely on overlapping neural structures.

Researchers suggest there are two simple ways to incorporate more orienteering into daily life: turn off the GPS and use a map to find your way when traveling and challenge yourself—spatially—by using a new route for your run, walk or bike ride.

"Orienteering is very much a sport for life. You can often see participants spanning the ages of 6 to 86 years old engaged in orienteering," says Waddington. "My long-term involvement in this sport has allowed me to understand the process behind learning navigational skills and I have been inspired to research the uniqueness of orienteering and the scientific significance this sport may have on the aging population," says Waddington.

More information: Emma Waddington et al, Orienteering experts report more proficient spatial processing and memory across adulthood, PLoS ONE (2023).

https://medicalxpress.com/news/2023-01-brain-cognitive-decline.html

Shorter Post-Op Antibiotic Course Non-Inferior for Complex Appendicitis

 Two days of postoperative intravenous antibiotics for complex appendicitis was non-inferior to 5 days in terms of complications and mortality, according to results of an open-label randomized trial.

In 1,005 patients, the vast majority of whom underwent laparoscopic appendectomy, that composite endpoint occurred in 10% of the 2-day group and 8% of the 5-day group, for an adjusted absolute risk difference of 2% (95% CI -1.6 to 5.6), reported Ann van den Boom, MD, of Erasmus MC-University Medical Centre in Rotterdam, The Netherlands, and colleagues.

As shown in their study in The Lancet

opens in a new tab or window, patients in the 5-day group had fewer Clavien-Dindo class 2 complications, visits to the emergency department, and hospital readmissions. Patients in the 2-day group had fewer adverse effects from antibiotics, and their overall hospital stay was shorter, even when including readmissions.

The majority of patients in the trial (95%) underwent laparoscopic appendectomy. In the small number of patients whose laparoscopy was converted to open appendectomy, those in the 5-day group had fewer infectious complications than the 2-day group did (4% vs 27%).

"To our knowledge, this is the first adequately powered level I randomized controlled trial that evaluates the safety and efficacy of postoperative antibiotics restricted to 2 days," the researchers wrote. "The optimum duration of treatment has been a topic of debate, while the increasing global threat of antimicrobial resistance calls for antibiotic stewardship."

"This study indicates that more than 2 days of postoperative antibiotics for complex appendicitis is not needed after adequate source control," the team continued, adding that adopting this strategy for patients with complex appendicitis could reduce the adverse effects of antibiotics and relieve pressure on hospital bed capacity.

The researchers cautioned, however, that the recommendations are valid for laparoscopic appendectomy in a "well-resourced" healthcare setting. "After open appendectomy, patients might benefit from an extended regimen of antibiotics. Whether 2 days of antibiotics is safe for patients who are immunocompromised or pregnant is unknown," van den Boom and co-authors wrote.

The trial included patients ages 8 and older from 15 hospitals in the Netherlands. These patients had acute appendicitis, an American Society of Anesthesiologists classification of I–III, and a diagnosis of complex appendicitis, defined as the presence of necrosis, perforation, or abscess. Pregnant and immunocompromised patients were excluded. The majority of patients were ages 18 to 64 years, and 57% were male.

Patients were randomized 1:1 to either course of antibiotics. However, there was no placebo, and neither physicians nor patients were blinded to treatment. The primary endpoint was a composite of infectious complications and mortality within 90 days. The main outcome was the absolute risk difference in the primary endpoint, adjusted for age and severity of appendicitis, with a non-inferiority margin of 7.5%. Outcomes were assessed with electronic records and a telephone consultation 90 days after appendectomy.

There were no treatment-related deaths, the authors noted. One patient in the 2-day group died of metastatic esophageal cancer on postoperative day 84.

In an accompanying editorialopens in a new tab or window, Aneel Bhangu, MD, PhD, of the University of Birmingham in England, and colleagues agreed with the study authors' conclusions. "Taken together, the findings suggest that giving shorter courses of antibiotics is safe and should be adopted in patients who have laparoscopic appendectomy," the editorialists wrote.

"Subgroup analysis suggested that the small number of patients who had open surgery, including laparoscopic surgery that was converted to an open operation, had more infections if they received shorter antibiotic courses. For such patients, more caution might be needed as longer courses could be protective," Bhangu and co-authors suggested.

The researchers speculated that the higher rate of hospital readmissions in the 2-day group (12% vs 6%, HR 2.1, 95% CI 1.3-3.34) might have been due to caution on the part of physicians. "Physicians could have had a low threshold for readmitting patients and restarting antibiotics for patients in the 2-day group, as this was experimental when the study started," van den Boom and co-authors noted.

"It can be concluded that the benefit of reduced antibiotic use and shorter hospital stay outweighs an increased risk of readmission or complications that do not need surgical or radiological interventions," the researchers added.

A key limitation of the study, they said, was that just 28% of eligible patients agreed to participate. While the reasons for non-participation were not known, this could have introduced some form of selection bias. The lack of a placebo and masking were other obvious limitations. Such methods, however, would not have been practical or feasible, the researchers explained, as it would have required placebo patients to stay additional days in the hospital receiving intravenous saline.

Disclosures

The study was funded by The Netherlands Organization for Health Research and Development.

van den Boom and co-authors reported having no conflicts of interest.

Bhangu and co-authors reported having no conflicts of interest.

Primary Source

The Lancet

Source Reference: opens in a new tab or windowde Wijkerslooth EML, et al "2 days versus 5 days of postoperative antibiotics for complex appendicitis: a pragmatic, open-label, multicentre, noninferiority randomised trial" Lancet 2023; DOI: 10.1016/S0140-6736(22)02588-0.

Secondary Source

The Lancet

Source Reference: opens in a new tab or windowBhangu A, et al "Postoperative antibiotics can be de-escalated after laparoscopic surgery for complex appendicitis" Lancet 2023; DOI: 10.1016/S0140-6736(22)02544-2.

https://www.medpagetoday.com/gastroenterology/generalgastroenterology/102729

FDA, NIH Must Penalize Researchers Who Don't Report Trial Results, House Member Says

 Researchers may be legally required to report clinical trial results to the federal government, but many of them aren't doing it, and they're not being penalized for it -- something which needs to be remedied, according to one high-ranking House member.

"According to a recent studyopens in a new tab or window, sponsors of 31% of registered trials required to report results have failed to report any results, and another 30% of sponsors of registered trials required to report results failed to do so on time, totaling 5,364 trials in violation of applicable reporting requirements," Rep. Frank Pallone (D-N.J.), ranking member of the House Energy & Commerce Committee, wrote Thursday in a letteropens in a new tab or window to NIH Acting Director Lawrence Tabak, DDS, PhD, and FDA Commissioner Robert Califf, MD.

Pallone also cited a 2022 study

opens in a new tab or window from the HHS Office of Inspector General, which found that of 72 reviewed clinical trials funded by the NIH, 37 failed to comply with applicable reporting requirements and either submitted results late or not at all. "Despite these troubling results, the FDA and NIH have only carried out limited enforcement activities for failure to comply with ClinicalTrials.govopens in a new tab or window requirements," Pallone noted, referring to the government-funded publicly available database of clinical trials and their results.

Pallone explained that "Congress originally required NIH to establish a public database of clinical trials in 1997 to help patients find trials for serious illnesses. In 2007, the FDA Amendments Act expanded the types of trials required to register as well as the types of information required to be submitted, including clinical trial results."

"While compliance with ClinicalTrials.gov reporting requirements has slowly but steadily improved since 2007, significant gaps remain," he continued, noting that in the first study he referenced, "sponsors of only 40% of trials required to report results did so within 1 year of completion, as required by law, and under 69% did so at any time. The study also found academic medical centers lagged behind other sponsors in the timeliness and completeness of trial reporting."

Pallone expressed particular disappointment that the FDA, who is responsible for compliance with reporting rules in most cases, has taken so little enforcement action, "considering that it is apparent when FDA takes action, it has great effect." For example, all of the 15 preliminary noncompliance letters the agency sent during a pilot-testing program between 2013 and 2016 resulted in compliance. "Over the next 5 years, FDA issued more than 40 additional [letters], and over 90% of recipients reported missing information shortly after receiving these letters," he added.

However, Pallone wrote, "these actions have only been taken with regard to a tiny fraction of the trials that have been or remain in violation of ClinicalTrials.gov requirements. Additionally, it appears FDA has not sent any compliance letters to NIH, despite the many trials NIH runs or oversees, and for which responsible parties have failed to comply with [reporting] requirements."

NIH, which can affect compliance on studies that it funds, also came in for its share of criticism. "With respect to NIH enforcement for publicly funded studies, [the 2022 OIG report] found that NIH notices of noncompliance 'were not always effective at gaining compliance,'" Pallone noted. "However, OIG concluded NIH 'did not take any additional enforcement actions against responsible parties that failed to submit clinical trial results' beyond notifications of noncompliance, and 'continued to fund new clinical trials' of noncompliant sponsors."

Pallone gave the FDA and NIH until February 17 to respond to the letter, which asks for details from both agencies on noncompliance letters sent and other enforcement actions taken. The Biotechnology Innovation Organization, which represents biotechnology companies, and Universities Allied for Essential Medicines, a group of more than 100 research universities, did not respond to MedPage Today's requests for comment on the letter.

Asked for his organization's comment, Andrew Powaleny, a spokesman for the Pharmaceutical Research and Manufacturers of America (PhRMA), said in an email that "PhRMA members are committed to enhancing public health and advancing the development of medicines by sponsoring and conducting clinical research that fully complies with all legal and regulatory requirements. Further, our Principles for Responsible Clinical Trial Data Sharing set forth PhRMA members' commitment to enhancing public health through responsible sharing of clinical trial data in a manner that safeguards the privacy of patients, respects the integrity of national regulatory systems, and maintains incentives for investment in biomedical research."

https://www.medpagetoday.com/publichealthpolicy/clinicaltrials/102734

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