Research suggests dose-sparing approach reduces virus immunity
The monkeypox vaccine that’s become the main method doctors are using to try to stop the global scourge may be less potent than hoped, new research shows.
The recommended series of shots with Bavarian Nordic A/S’s Jynneos vaccine yielded relatively low levels of monkeypox antibodies with poor neutralizing capacity, researchers at the Erasmus University Medical Center in Rotterdam, Netherlands, said. Those immunized hadn’t been previously infected or vaccinated against smallpox, which is believed to provide some protection against monkeypox.
Food poisoning incidents thought to be caused by bad lettuce served at Wendy’s has spread to New York and Kentucky, raising the number of states where diners have fallen ill to six, the CDC reported on Thursday.
The e. Coli cases have jumped to 97 — up from 84 last week – and an additional five have been hospitalized from the 38 initially reported, the CDC said.
The agency has not confirmed the cause but said “many sick people reported eating sandwiches with romaine lettuce at Wendy’s restaurants … before getting sick,” according to the agency’s website.
The federal agency did not specify where in New York or Kentucky the incidents were reported. It had previously reported cases in Indiana, Michigan, Ohio and Pennsylvania.
“The true number of sick people in this outbreak is likely higher than the number reported, and the outbreak may not be limited to the states with known illnesses,” according to Food Poison Journal.
Wendy’s has removed the sandwich lettuce at some of its affected restaurants, the company said in astatementon Aug. 19, the last time it has addressed the outbreak, which began in July.
Some victims who were hospitalized have had severe symptoms, including diarrhea that can lead to kidney failure, according to lawsuits filed against Wendy’s.
The Biden administration worked in tandem with social media giants like Facebook and Twitter tocensor statements they deemed “misinformation”about topics including the COVID-19 pandemic, two Republican stateattorneys general said Thursdayas they pushed for the release of emails between top executive branch officials and Big Tech titans.
In a petition filed Wednesday in Louisiana federal court, state Attorney General Jeff Landry and his Missouri counterpart Eric Schmitt charged that “dozens of federal officials across at least eleven federal agencies” engaged in a “massive, sprawling federal ‘Censorship Enterprise,'” with the “intent and effect of pressuring social-media platforms to censor and suppress private speech that federal officials disfavor.”
The Biden administration has not been shy about leaning on social media companies to police their content. On July 15, 2021, then-White House press secretary Jen Psaki admitted her colleagues were “flagging problematic posts for Facebook that spread disinformation.”
“It’s important to take faster action against harmful posts … and Facebook needs to move more quickly to remove harmful violative posts,” Psaki added at the time.
Shortly after Biden’s comments, an email from an unidentified Facebook official to Surgeon General Vivek Murthy read in part: “I know our teams met today to better understand the scope of what the White House expects from us on misinformation going forward.”
Seven days later, on July 23, the same Facebook official proudly informed officials at the Department of Health and Human Services that the company was taking action against a group dubbed the “disinformation dozen” for their posts about COVID-19 vaccines.
“[W]e removed 17 additional Pages, Groups and Instagram accounts tied to the disinfo dozen (so a total of 39 Profiles, Pages, Groups and IG accounts deleted thus far, resulting in every member of the disinfo dozen having had at least one such entity removed),” the email read, later adding: “We also expanded the group of false claims that we remove to keep up with recent trends of misinformation that we are seeing.”
The relationship was so cozy that on July 20, 2021, White House COVID-19 Response Team Digital Director Clarke Humphrey received a response from Facebook in seconds when he asked about getting a fake Dr. Anthony Fauci Instagram account taken down.
“Hi there — any way we can get this pulled down?” Humphrey wrote, along with a link to the account. “It is not actually one of ours.”
“Yep, on it!” the answer came back.
Another email, from April 2021, shows a scheduled meeting for White House staffers to be “briefed by Twitter on vaccine misinfo.” Still another record, from July 28 of that year, shows a Facebook official proposing to a CDC counterpart that “in addition to our weekly meetings, doing a monthly misinfo/debunking meeting, with maybe claim topics communicated a few days prior so that you can bring in the matching experts and chat casually for 30 minutes or so.”
“Yes, we would love to do that,” the CDC official answered.
“We have already received a number of documents that clearly prove that the federal government has an incestuous relationship with social media companies and clearly coordinate to censor freedom of speech, but we’re not done,” Schmitt said in a statement Thursday.
“The Department of Justice is cowering behind executive privilege and has refused to turn over communications between the highest-ranking Biden Administration officials and social media companies. That’s why, yesterday, we asked the Court to compel the Department of Justice to produce those records. We’re just getting started – stay tuned.”
The AGs say they have identified at least 45 people within HHS and the Department of Homeland Security alone who communicated with social media companies about “misinformation”. They also claim that officials at other agencies, including the Census Bureau, the Food and Drug Administration, the FBI, the State Department, and the Treasury Department were at least aware of the “Censorship Enterprise.”
In addition to the document dump, Meta has disclosed that at least 32 officials, including workers at the FDA, US Election Assistance Commission and the White House have communicated with the company about content moderation — but those contacts weren’t disclosed in the government’s disclosures, Landry and Schmitt said. YouTube disclosed contacts with 11 officials, some of which weren’t shared by the government in response to the lawsuit, the AGs alleged.
Columbia researchers have found a link between a common back ailment and a type of heart failure, suggesting that screening patients with lumbar spinal stenosis could identify those at risk of the heart disease and prevent premature deaths.
Once considered rare, theheart disease, called transthyretin amyloid cardiomyopathy, is now thought to be a more common but underdiagnosed cause of heart failure. The disease is caused by proteins called transthyretin that can clump together and createamyloid depositsin the heart, the spine, ligaments, and other tissues. In the heart, the deposits stiffen the walls and reduce the amount of blood the heart can pump.
Until recently, no treatment was available for this type of heart failure. But in 2019, after a clinical trial led by Columbia cardiologist Mathew S. Maurer, MD, the FDA approved a drug that prevents transthyretin amyloid deposition. (Amyloid deposits also appear in Alzheimer's disease, but those develop from a different protein and cannot be treated with the drug).
"We have a good treatment that reduces the risk of dying from this condition, and now we clearly need a better way to screen people and find those at risk," says Maurer, professor of medicine at Columbia University Vagelos College of Physicians and Surgeons. "Because the drug does not reduce existing amyloid, it's most effective when taken early in the disease."
Screening back patients
Recent studies suggest that many patients diagnosed with lumbar spinal stenosis develop transthyretin amyloid cardiomyopathy five to 15 years after their stenosis diagnosis. That led Maurer to consider whether screening stenosis patients who undergo surgery could identify those at risk of transthyretin cardiomyopathy or who are already in the early stages.
"Many spinal stenosis patients undergo spinal surgery, and it is easy to take a sample of tissue removed during the procedure and test it for transthyretin amyloid," Maurer says. If amyloid is present in the spine, doctors could use advanced imaging or a heart muscle biopsy to determine if the heart is also affected.
To see if such screening would be worthwhile, Maurer's team at Columbia analyzed spinal tissue from 47 patients (ages 62 to 76) undergoing spinal decompression surgery. The researchers detected amyloid in the spine of 34% of patients; two-thirds had transthyretin amyloid, while the amyloid content of the other third could not be identified. Among those with confirmed transthyretin amyloid (10 patients), one had already developed cardiac amyloidosis and subsequently began treatment with tafamidis. The other nine patients are being closely monitored by their physicians for future heart problems.
"Based on these findings, we would suggest that all patients who undergo surgery for spinal stenosis should be screened for transthyretin amyloid," says Maurer. "I'd certainly recommend screening if a patient has additional orthopedic issues, such as carpal tunnel syndrome, joint deterioration, or bicep tendon injury, each of which can be caused by transthyretin amyloid. Such patients are especially likely to have transthyretin amyloid and be at risk for heart failure in the future."
The research was published in the Journal of the American Geriatrics Society.
More information: Mathew S. Maurer et al, Analysis of lumbar spine stenosis specimens for identification of amyloid, Journal of the American Geriatrics Society (2022). DOI: 10.1111/jgs.17976
Vaccinated people who were infected by the first omicron subvariants have four times greater protection than vaccinated people who were not infected. These results are part of a study that will be published today in theNew England Journal of Medicine.
The study was led by Luís Graça, group leader at the Instituto de Medicina Molecular João Lobo Antunes (iMM) and Full Professor at the Faculty of Medicine of the University of Lisbon, and by Manuel Carmo Gomes, Associate Professor with Aggregation at the Faculty of Sciences of the University of Lisbon (Ciências ULisboa). Both researchers are members of the Technical Commission on Vaccination against COVID-19 (CTVC) of the Direção Geral de Saúde (DGS).
This is one of the first studies worldwide to analyze the probability of becoming infected with the subvariant currently in circulation in vaccinated people, by estimating the degree of protection conferred by infections with previous variants and using real-world data.
"Vaccinated people who were infected by omicron subvariants BA.1 and BA.2 have a protection against infection with subvariant BA.5, in circulation since June, about four times greater than vaccinated people who were not infected at any time," says Luís Graça, co-leader of the study.
"Infections in 2020 and 2021 that occurred through infection with earlier variants of the SARS-CoV-2 virus (ancestral lineage, alpha and delta variants) also confer protection against infection for the more recent omicron variant, although this protection is not as high as that of individuals infected with the BA.1 and BA.2 variants, at the beginning of 2022."
"These results are very important because the adapted vaccines that are in clinical development and evaluation are based on the BA.1 subvariant of the virus, which was a dominant variant in infections in January and February 2022. Until now, it was not known what degree of protection this subvariant provides against the subvariant that is currently in circulation. These results show that this protection is very significant and allows us to anticipate the benefit of the adapted," says Graça.
To carry out this study, the researchers had access to the registry of COVID-19 cases at Portugal's national level. "We used the Portuguese national registry of COVID-19 cases to obtain information on all cases of SARS-CoV-2 infections in the population over 12 years of age residing in Portugal. The virus variant of each infection was determined considering the date of infection and the dominant variant at that time. We considered the infections caused by the first variants of omicron BA.1 and BA.2 together," says Manuel Carmo Gomes.
"With these data, we analyzed the probability of a person that was previously infected to be reinfected with the current variant, which allowed us to calculate the percentage of protection provided by previous infections," says João Malato, Ph.D. student in Luís Graça's group and first author of the study.
"This study demonstrates, in the period of time analyzed, that previous infection in vaccinated people (the so-called hybrid immunity) continues to confer for the variants that are known for their ability to evade the immune response, such as the subvariant currently dominant," says Válter Fonseca, co-author of this study and coordinator of the CTVC of the DGS.
More information: João Malato et al, Risk of BA.5 infection in individuals exposed to prior SARS-CoV-2 variants, (2022). DOI: 10.1101/2022.07.27.22277602
João Malato et al, Risk of BA.5 Infection among Persons Exposed to Previous SARS-CoV-2 Variants, New England Journal of Medicine (2022). DOI: 10.1056/NEJMc2209479 (Correspondence)
A groundbreaking study at Tel Aviv University effectively eradicated glioblastoma, a highly lethal type of brain cancer. The researchers achieved the outcome using a method they developed based on their discovery of two critical mechanisms in the brain that support tumor growth and survival: one protects cancer cells from the immune system, while the other supplies the energy required for rapid tumor growth. The work found that both mechanisms are controlled by brain cells called astrocytes, and in their absence, the tumor cells die and are eliminated.
The study was led by Ph.D. student Rita Perelroizen, under the supervision of Dr. Lior Mayo of the Shmunis School of Biomedicine and Cancer Research and the Sagol School of Neuroscience, in collaboration with Prof. Eytan Ruppin of the National Institutes of Health (NIH) in the U.S.. The paper was published in the journalBrainand was highlighted with special commentary.
The researchers explain, "Glioblastoma is an extremely aggressive and invasive brain cancer, for which there exists no known effective treatment. The tumor cells are highly resistant to all known therapies, and, sadly, patient life expectancy has not increased significantly in the last 50 years. Our findings provide a promising basis for the development of effective medications for treating glioblastoma and other types of brain tumors."
Dr. Mayo says, "Here, we tackled the challenge of glioblastoma from a new angle. Instead of focusing on the tumor, we focused on its supportive microenvironment, that is, the tissue that surrounds the tumor cells. Specifically, we studied astrocytes—a major class of brain cells that support normal brain function, discovered about 200 years ago and named for their starlike shape. Over the past decade, research from us and others revealed additional astrocyte functions that either alleviate or aggravate various brain diseases. Under the microscope we found that activated astrocytes surrounded glioblastoma tumors. Based on this observation, we set out to investigate the role of astrocytes in glioblastoma tumor growth."
Using an animal model, in which they could eliminate active astrocytes around the tumor, the researchers found that in the presence of astrocytes, the cancer killed all animals with glioblastoma tumors within 4-5 weeks. Applying a unique method to specifically eradicate the astrocytes near the tumor, they observed a dramatic outcome: the cancer disappeared within days, and all treated animals survived. Moreover, even after discontinuing treatment, most animals survived.
Dr. Mayo says, "In the absence of astrocytes, the tumor quickly disappeared, and in most cases, there was no relapse—indicating that the astrocytes are essential to tumor progression and survival. Therefore, we investigated the underlying mechanisms: How do astrocytes transform from cells that support normal brain activity into cells that support malignant tumor growth?"
To answer these questions, the researchers compared the gene expression of astrocytes isolated from healthy brains and from glioblastoma tumors.
They found two main differences—thereby identifying the changes that astrocytes undergo when exposed to glioblastoma. The first change was in the immune response to glioblastoma.
"The tumor mass includes up to 40% immune cells—mostly macrophages recruited from the blood or from the brain itself. Furthermore, astrocytes can send signals that summon immune cells to places in the brain that need protection. In this study, we found that astrocytes continue to fulfill this role in the presence of glioblastoma tumors. However, once the summoned immune cells reach the tumor, the astrocytes 'persuade' them to 'change sides' and support the tumor instead of attacking it. Specifically, we found that the astrocytes change the ability of recruited immune cells to attack the tumor both directly and indirectly—thereby protecting the tumor and facilitating its growth," says Dr. Mayo.
The second change through which astrocytes support glioblastoma is by modulating their access to energy—via the production and transfer of cholesterol to the tumor cells. Dr. Mayo: "The malignant glioblastoma cells divide rapidly, a process that demands a great deal of energy. With access to energy sources in the blood barred by the blood-brain barrier, they must obtain this energy from the cholesterol produced in the brain itself—namely in the astrocytes' 'cholesterol factory,' which usually supplies energy to neurons and other brain cells. We discovered that the astrocytes surrounding the tumor increase the production of cholesterol and supply it to the cancer cells. Therefore, we hypothesized that, because the tumor depends on this cholesterol as its main source of energy, eliminating this supply will starve the tumor."
Next, the researchers engineered the astrocytes near the tumor to stop expressing a specific protein that transports cholesterol (ABCA1), thereby preventing them from releasing cholesterol into the tumor. Once again, the results were dramatic: with no access to the cholesterol produced by astrocytes, the tumor essentially "starved" to death in just a few days. These remarkable results were obtained in both animal models and glioblastoma samples taken from human patients and are consistent with the researchers' starvation hypothesis.
Dr. Mayo notes, "This work sheds new light on the role of the blood-brain barrier in treating brain diseases. The normal purpose of this barrier is to protect the brain by preventing the passage of substances from the blood to the brain. But in the event of a brain disease, this barrier makes it challenging to deliver medications to the brain and is considered an obstacle to treatment. Our findings suggest that, at least in the specific case of glioblastoma, the blood-brain barrier may be beneficial to future treatments, as it generates a unique vulnerability—the tumor's dependence on brain-produced cholesterol. We think this weakness can translate into a unique therapeutic opportunity."
The project also examined databases from hundreds of human glioblastoma patients and correlated them with the results described above. The researchers explain, "For each patient, we examined the expression levels of genes that either neutralize the immune response or provide the tumor with a cholesterol-based energy supply. We found that patients with low expression of these identified genes lived longer, thus supporting the concept that the genes and processes identified are important to the survival of glioblastoma patients."
Dr. Mayo concludes, "Currently, tools to eliminate the astrocytes surrounding the tumor are available in animal models, but not in humans. The challenge now is to develop drugs that target the specific processes in the astrocytes that promote tumor growth. Alternately, existing drugs may be repurposed to inhibit mechanisms identified in this study. We think that the conceptual breakthroughs provided by this study will accelerate success in the fight against glioblastoma. We hope that our findings will serve as a basis for the development of effective treatments for this deadly brain cancer and other types of brain tumors."
More information: Rita Perelroizen et al, Astrocyte immunometabolic regulation of the tumour microenvironment drives glioblastoma pathogenicity, Brain (2022). DOI: 10.1093/brain/awac222 , academic.oup.com/brain/advance … rain/awac222/6650959
Kai Murk et al, Forced but effective partners in crime: how astrocytes drive the progression of glioblastoma, Brain (2022). DOI: 10.1093/brain/awac302
An Inserm team at the Lille Neuroscience & Cognition laboratory (Inserm/Université de Lille, Lille University Hospital) has joined forces with its counterparts at Lausanne University Hospital (CHUV) to test the efficacy of GnRH injection therapy in order to improve the cognitive functions of a small group of patients with Down syndrome.
First the scientists revealed a dysfunction of the GnRH neurons in an animal model of Down syndrome and its impacts on the cognitive function impairment associated with the condition. Then apilot studytesting GnRH pulsatile injection therapy was conducted in seven patients. The results were promising: The therapy led to improved cognitive function and brain connectivity. This study has been published inScience.
Down syndrome, also known as trisomy 21, affects around one in 800 births and results in a variety of clinical manifestations, including decline in cognitive capacity. With age, 77% of people with the condition experience symptoms similar to those of Alzheimer's disease. Gradual loss of the ability to smell, typical of neurodegenerative diseases, is also commonly encountered from the prepubertal period, with potential sexual maturation deficits occurring in men.
GnRH-secreting neuron dysfunction identified in Down syndrome
Recent discoveries have suggested that the neurons expressing gonadotropin-releasing hormone (GnRH)—which is known for regulating reproduction via the hypothalamus—could also act on other brain regions with a potential role in other functions, such as cognition.
With this idea in mind, the Lille Neuroscience & Cognition laboratory team led by Inserm Research Director Vincent Prévot studied the mechanism which regulates GnRH in mouse models of Down syndrome.
The laboratory demonstrated that five strands of microRNA regulating the production of this hormone—which are found on chromosome 21—are dysfunctional. This supernumerary chromosome then leads to abnormalities in the neurons that secrete GnRH. These findings were confirmed at both genetic and cellular levels. The Inserm scientists were able to demonstrate that the progressive cognitive and olfactory deficiencies seen in the mice were closely linked to dysfunctional GnRH secretion.
Restoring GnRH production to restore cognitive function
The Inserm scientists were then able to demonstrate that restoring physiological GnRH system function restores cognitive and olfactory functions in trisomic mice.
These findings in mice were discussed with Nelly Pitteloud, professor at the Faculty of Biology and Medicine of the University of Lausanne and head of the Endocrinology, Diabetology, and Metabolism Department at CHUV. Her research focuses on congenital GnRH deficiency, a rare disease which manifests by the absence of spontaneous puberty. These patients are given pulsatile GnRH therapy in order to reproduce the natural pulsatile rhythm of this hormone's secretion, in order to induce puberty.
The researchers therefore decided to test the efficacy of pulsatile GnRH therapy on cognitive and olfactory deficits in trisomic mice, following a protocol identical to that used in humans. After 15 days, the team was able to demonstrate the restoration of olfactory and cognitive functions in mice.
Pulsatile GnRH therapy improves cognitive function and neural connectivity in a small patient group
The next stage for the scientists and doctors involved a pilot clinical trial in patients to evaluate the effects of this treatment. Seven men with Down syndrome, between 20 and 50 years of age, received one subcutaneous dose of GnRH every two hours for 6 months via a pump placed on the arm. Cognition and olfactory tests as well as MRI exams were performed before and after the treatment.
From the clinical viewpoint, cognitive performance increased in 6 of the 7 patients with better three-dimensional representation, better understanding of instructions, improved reasoning, attention, and episodic memory. However, the treatment had no impact on the ability to smell. These measures to improve cognitive functions were confirmed by brain imaging conducted by the CHUV Department of Clinical Neurosciences, which revealed a significant increase in functional connectivity.
These data suggest that the treatment acts on the brain by strengthening the communication between certain regions of the cortex. "Maintaining the GnRH system appears to play a key role in brain maturation and cognitive functions," explains Prévot. "In Down syndrome, pulsatile GnRH therapy is looking promising, especially as it is an existing treatment with no significant side effects," adds Pitteloud.
These promising findings now justify the launch of a larger study—with the inclusion of women—to confirm the efficacy of this treatment in people with Down syndrome, but also for other neurodegenerative conditions such as Alzheimer's disease.
