Type of Alzheimer's With Intact Memory Offers New Research Paths

Patients with a rare type of Alzheimer’s disease do not show the memory loss characteristic of the condition even over the long term, new research suggests. They also show some differences in neuropathology to typical Alzheimer’s patients, raising hopes of discovering novel mechanisms that might protect against memory loss in typical forms of the disease.

“We are discovering that Alzheimer’s disease has more than one form. While the typical Alzheimer’s patient will have impaired memory, patients with primary progressive aphasia linked to Alzheimer’s disease are quite different. They have problems with language — they know what they want to say but can’t find the words — but their memory is intact,” lead author Marsel Mesulam, MD, told Medscape Medical News.   

“We have found that these patients still show the same levels of neurofibrillary tangles which destroy neurons in the memory part of the brain as typical Alzheimer’s patients, but in patients with primary progressive aphasia Alzheimer’s the nondominant side of this part of the brain showed less atrophy,” added Mesulam, who is director of the Mesulam Center for Cognitive Neurology and Alzheimer’s Disease at Northwestern University Feinberg School of Medicine, Chicago, Illinois. “It appears that these patients are more resilient to the effects of the neurofibrillary tangles.”  

The researchers also found that two biomarkers that are established risk factors in typical Alzheimer’s disease do not appear to be risk factors for the primary progressive aphasia (PPA) form of the condition.

“These observations suggest that there are mechanisms that may protect the brain from Alzheimer’s-type damage. Studying these patients with this primary progressive aphasia form of Alzheimer’s may give us clues as to where to look for these mechanisms that may lead to new treatments for the memory loss associated with typical Alzheimer’s disease,” Mesulam commented.

The study was published online in the January 13 issue of Neurology.

PPA is diagnosed when language impairment emerges on a background of preserved memory and behavior, with about 40% of cases representing atypical manifestations of Alzheimer’s disease, the researchers explain.

“While we knew that the memories of people with primary progressive aphasia were not affected at first, we did not know if they maintained their memory functioning over years,” Mesulam noted.

The current study aimed to investigate whether the memory preservation in PPA linked to Alzheimer’s is a consistent core feature or a transient finding confined to initial presentation, and to explore the underlying pathology of the condition.

The researchers searched their database to identify patients with PPA with autopsy or biomarker evidence of Alzheimer’s, who also had at least two consecutive visits during which language and memory assessment had been obtained with the same tests.

The study included 17 patients with the PPA-type Alzheimer’s disease. They were compared with 14 patients who had typical Alzheimer’s disease with memory loss.

The authors point out that characterization of memory in patients with PPA is challenging because most tests use word lists, and thus patients may fail the test because of their language impairments. To address this issue, they included patients with PPA who had had memory tests involving recalling pictures of common objects.

Patients with typical Alzheimer’s disease underwent similar tests but used a list of common words.

A second round of tests was conducted in the primary progressive aphasia group an average of 2.4 years later and in the typical Alzheimer’s group an average of 1.7 years later.

Brain scans were also available for the patients with PPA, as well as postmortem evaluations for eight of the PPA cases and all the typical Alzheimer’s cases.

Results showed that patients with PPA had no decline in their memory skills when they took the tests a second time. At that point, they had been showing symptoms of the disorder for an average of 6 years. In contrast, their language skills declined significantly during the same period. For typical Alzheimer’s patients, verbal memory and language skills declined with equal severity during the study.

Postmortem results showed that the two groups had comparable degrees of Alzheimer’s pathology in the medial temporal lobe — the main area of the brain affected in dementia.

However, MRI scans showed that patients with PPA had an asymmetrical atrophy of the dominant (left) hemisphere with sparing of the right sided medial temporal lobe, indicating a lack of neurodegeneration in the nondominant hemisphere, despite the presence of Alzheimer’s pathology.

It was also found that the patients with PPA had significantly lower prevalence of two factors strongly linked to Alzheimer’s — TDP-43 pathology and APOE ε4 positivity — than the typical Alzheimer’s patients.

The authors conclude that: “Primary progressive aphasia Alzheimer’s syndrome offers unique opportunities for exploring the biological foundations of these phenomena that interactively modulate the impact of Alzheimer’s neuropathology on cognitive function.”

“Preservation of Cognition Is the Holy Grail”

In an accompanying editorial, Seyed Ahmad Sajjadi, MD, University of California, Irvine; Sharon Ash, PhD, University of Pennsylvania, Philadelphia; and Stefano Cappa, MD, University School for Advanced Studies, Pavia, Italy, say these findings have important implications, “as ultimately, preservation of cognition is the holy grail of research in this area.”

They point out that the current observations imply “an uncoupling of neurodegeneration and pathology” in patients with PPA-type Alzheimer’s, adding that “it seems reasonable to conclude that neurodegeneration, and not mere presence of pathology, is what correlates with clinical presentation in these patients.”

The editorialists note that the study has some limitations: the sample size is relatively small; not all patients with PPA-type Alzheimer’s underwent autopsy; MRI was only available for the aphasia group; and the two groups had different memory tests for comparison of their recognition memory.

But they conclude that this study “provides important insights about the potential reasons for differential vulnerability of the neural substrate of memory in those with different clinical presentations of Alzheimer’s pathology.”

The study was supported by the National Institute on Deafness and Communication Disorders, the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, the Davee Foundation, and the Jeanine Jones Fund.

Neurol. Published online January 13, 2021. Abstract, Editorial  

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California Urges Stop to 300K COVID-19 Vaccines After Some Fall Ill

Editor’s note: Find the latest COVID-19 news and guidance in Medscape’s Coronavirus Resource Center.

LOS ANGELES (AP) — California’s state epidemiologist is urging a halt to more than 300,000 coronavirus vaccinations using a Moderna vaccine version because some people received medical treatment for possible severe allergic reactions.

Dr. Erica S. Pan on Sunday recommended providers stop using lot 41L20A of the Moderna vaccine pending completion of an investigation by state officials, Moderna, the U.S. Centers for Disease Control and the federal Food and Drug Administration.

“Out of an extreme abundance of caution and also recognizing the extremely limited supply of vaccine, we are recommending that providers use other available vaccine inventory,” Pan said in a statement.

She said more than 330,000 doses from the lot arrived in California between Jan. 5 and Jan. 12 and were distributed to 287 providers.

Fewer than 10 people, who all received the vaccine at the same community site, needed medical attention over a 24-hour period, Pan said. No other similar clusters were found.

Pan did not specify the number of cases involved or where they occurred.

However, six San Diego health care workers had allergic reactions to vaccines they received at a mass vaccination center on Jan. 14. The site was temporarily closed and is now using other vaccines, KTGV-TV reported.

The CDC has said the vaccine can cause side effects for a few days that include fever, chills, headache, swelling or tiredness, “which are normal signs that your body is building protection.”

However, severe reactions are extremely rare. Pan said in a vaccine similar to Moderna, the rate of anaphylaxis — in which an immune system reaction can block breathing and cause blood pressure to drop — was about 1 in 100,000.

The announcement came as California counties continue to plead for more COVID-19 vaccine as the state tries to reduce its rate of infection, which has led to record numbers of hospitalizations and deaths.

California, with a population of 40 million, has received about 3.5 million vaccine doses and has only administered about a third of them, according to the CDC.

So far the state has vaccinated just 2,468 people per 100,000 residents, a rate that falls well below the national average, according to the federal data.

Although Gov. Gavin Newsom announced last week said anyone age 65 and older would be eligible to start receiving the vaccine, Los Angeles County and some others have said they do not have enough doses to vaccinate so many people and are concentrating on inoculating health care workers and the most vulnerable elderly living in care homes first.

On Monday, the superintendent of the Los Angeles Unified School District sent a letter to state and county public health officials asking for authorization to provide COVID-19 vaccinations at schools for staff, local community members and for students once a vaccine for children has been approved.

“Doing so will help reopen schools as soon as possible, and in the safest way possible,” Superintendent Austin Beutner wrote.

California is nearing 3 million coronavirus cases and more than 33,600 people have died since the start of the pandemic last year, according to figures from Johns Hopkins University.

The death rate from COVID-19 in Los Angeles County — the nation’s most populous and an epicenter of the state pandemic — works out to about one person every six minutes.

On Sunday, the South Coast Air Quality Management District suspended some pollution-control limits on the number of cremations for at least 10 days in order to deal with a backlog of bodies at hospitals and funeral homes.

“The current rate of death is more than double that of pre-pandemic years,” the agency said.

California has had about 500 deaths and 40,000 new cases daily for the past two weeks. Although hospitalizations and intensive care unit admissions remained on a slight downward trend, officials have warned that could reverse when the full impact from transmissions during Christmas and New Year’s Eve gatherings is felt.

“As case numbers continue to rise in California, the total number of individuals who will have serious outcomes will also increase,” the state Department of Public Health said in a statement Sunday.

Adding to concerns, California is experiencing new, possibly more transmissible forms of COVID-19.

The state health department announced Sunday that an L452R variant of the virus is increasingly showing up in genetic sequencing of COVID-19 test samples from several counties.

The variant was first identified last year in California and in other states and countries but has been identified more frequently since November and in several large outbreaks in Northern California’s Santa Clara County, the department said.

Overall, the variant has been found in at least a dozen counties. In some places. testing has found the variant in a quarter of the samples sequenced, said Dr. Charles Chiu, a virologist and professor of laboratory medicine at the University of California San Francisco.

However, not all test samples receive genetic sequencing to identify variants so its frequency wasn’t immediately clear.

However, health officials said it was linked to a Christmas-time outbreak at Kaiser Permanente San Jose that infected at least 89 staff members and patients, killing a receptionist. The outbreak has been blamed on an employee who visited the hospital emergency room wearing an air-powered inflatable Christmas tree costume.

The variant is different from another mutation, B117, that was first reported in the United Kingdom and appears to spread much more easily, although it doesn’t appear to make people sicker.

That variant has already shown up in San Diego County and Los Angeles County announced over the weekend that it had detected its first case.

Repeated Ketamine Infusions Linked to Rapid Relief of PTSD

Repeated intravenous infusions of ketamine provide rapid relief for patients with posttraumatic stress disorder (PTSD), new research suggests.

In what investigators are calling the first randomized controlled trial of repeated ketamine administration for chronic PTSD, 30 patients received six infusions of ketamine or midazolam (used as a psychoactive placebo) over 2 consecutive weeks. 

Between baseline and week 2, those receiving ketamine showed significantly greater improvement than those receiving midazolam. Total scores on the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) for the first group were almost 12 points lower than the latter group at week 2, meeting the study’s primary outcome measure.

In addition, 67% vs 20% of the patients, respectively, were considered to be treatment responders; time to loss of response for those in the ketamine group was 28 days.

Although the overall findings were as expected, “what was surprising was how robust the results were,” lead author Adriana Feder, MD, associate professor of psychiatry, Icahn School of Medicine, Mount Sinai, New York City, told Medscape Medical News.

Dr Adriana Feder/Source:  Mount Sinai Health System

It was also a bit surprising that in a study of just 30 participants, “we were able to show such a clear difference” between the two treatment groups, said Feder, who is also a co-inventor on issued patents for the use of ketamine as therapy for PTSD, and codirector of the Ehrenkranz Lab for the Study of Human Resilience at Mount Sinai.

The findings were published online January 5 in the American Journal of Psychiatry.

Unmet Need

Ketamine is a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist that was first approved by the US Food and Drug Administration for anesthetic use in 1970. It has also been shown to be effective for treatment-resistant depression.

PTSD has a lifetime prevalence of about 6% in the United States. “While trauma-focused psychotherapies have the most empirical support, they are limited by significant rates of nonresponse, partial response, and treatment dropout,” the investigators write. Also, there are “few available pharmacotherapies for PTSD, and their efficacy is insufficient,” they add.  

“There’s a real need for new treatment interventions that are effective for PTSD and also work rapidly, because it can take weeks to months for currently available treatments to work for PTSD,” Feder said.

The researchers previously conducted a “proof-of-concept” randomized controlled trial of single infusions of ketamine for chronic PTSD. Results published in 2014 in JAMA Psychiatry showed significant reduction in PTSD symptoms 24 hours after infusion.

For the current study, the investigative team wanted to assess whether ketamine was viable as a longer-term treatment.

“We were encouraged by our initial promising findings” of the earlier trial, Feder said. “We wanted to do the second study to see if ketamine really works for PTSD, to see if we could replicate the rapid improvement and also examine whether a course of six infusions over 2 weeks could maintain the improvement.”

Thirty patients (ages 18-70; mean age, 39 years) with chronic PTSD from civilian or military trauma were enrolled (mean PTSD duration, 15 years).

The most cited primary trauma was sexual assault or molestation (n = 13), followed by physical assault or abuse (n = 8), witnessing a violent assault or death (n = 4), witnessing the 9/11 attacks (n = 3), and combat exposure (n = 2).

During the 2-week treatment phase, half of the patients were randomly assigned to receive six infusions of ketamine hydrochloride at a dose of 0.5 mg/kg (86.7% women; mean CAPS-5 score, 42), while the other half received six infusions of midazolam at a dose of 0.045 mg/kg (66.7% women; mean CAPS-5 score, 40).

In addition to the primary outcome measure of 2-week changes on the CAPS-5, secondary outcomes included score changes on the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Impact of Event Scale-Revised (IES-R).

Treatment response was defined as a 30% or more improvement in symptoms on the CAPS-5. A number of measures were also used to assess potential treatment-related adverse events (AEs).

Safe, Effective

Results showed significantly lower total CAPS-5 scores for the ketamine group vs the midazolam group at week 1 (score difference, 8.8 points; P = .03) and at week 2 (score difference, 11.88 points; P = .004).

Those receiving ketamine also showed improvements in three of the four PTSD symptom clusters on the CAPS-5: avoidance (P < .0001), negative mood and cognitions (P = .02), and intrusions (P = .03). The fourth symptom cluster — arousal and reactivity — did not show a signficant improvement.

In addition, the ketamine group showed significantly greater improvement scores on the MADRS at both week 1 and week 2.

Treatment response at 2 weeks was achieved by 10 members of the ketamine group and by three members of the midazolam group (P = .03).

Secondary analyses showed rapid improvement in the treatment responders within the ketamine group, with a mean change of 26 points on the total IES-R score between baseline and 24 hours after their first infusion, and a mean change of 13.4 points on the MADRS total past-24-hour score, a 53% improvement on average.

“A response at 2 weeks is very rapid but they got better sometimes within the first day,” Feder noted.

There were no serious AEs reported. Although some dissociative symptoms occurred during ketamine infusions, with the highest levels reported at the end of the infusion, these symptoms had resolved by the next assessment, conducted 2 hours after infusion.

The most frequently reported AE in the ketamine group compared with midazolam after the start of infusions was blurred vision (53% vs 0%), followed by dizziness (33% vs 13%), fatigue (33% vs 87%), headache (27% vs 13%), and nausea or vomiting (20% vs 7%).

“Large-Magnitude Improvement”

The overall findings show that, in this patient population, “repeated intravenous ketamine infusions administered over 2 weeks were associated with a large-magnitude, clinically significant improvement in PTSD symptoms,” the investigators write.

The results “were very satisfying,” added Feder. “It was heartening also to hear what some of the participants would say. Some told us about how their symptoms and feelings had changed during the course of treatment with ketamine, where they felt stronger and better able to cope with their trauma and memories.”

She noted, however, that this was not a study designed to specifically assess ketamine in treatment-resistant PTSD. “Some patients had had multiple treatments before that hadn’t worked, while others had not received treatment before. Efficacy for treatment-resistant PTSD is an important question for future research,” Feder said.

Other areas worth future exploration include treatment efficacy in patients with different types of trauma and whether outcomes can last longer in patients receiving ketamine plus psychotherapy treatment, she noted.

“I don’t want to ignore the fact that currently available treatments work for a number of people with chronic PTSD. But because there are many more for whom [the treatments] don’t work, or they’re insufficiently helped by those treatments, this is certainly one potentially very promising approach that can be added” to a clinician’s toolbox, Feder said.

Speaks to Clinical Utility

Commenting for Medscape Medical News, Gerard Sanacora, MD, PhD, professor of psychiatry at Yale University School of Medicine, New Haven, Connecticut, called this a “very solid and well-designed” study.

Dr Gerard Sanacora

“It definitely builds on what’s been found in the past, but it’s a critical piece of information speaking to the clinical utility of this treatment for PTSD,” said Sanacora, who is also director of the Yale Depression Research Program and was not involved with the current research.

He agreed with the investigators that PTSD has long been a condition that is difficult to treat.

“It’s an area that has a great unmet need for treatment options. Beyond that, as ketamine is becoming more widely used, there’s increasing demand for off-label uses. This [study] actually provides some evidence that there may be efficacy there,” Sanacora said.

Although he cautioned that this was a small study, and thus further research with a larger patient population will be needed, it provides a compelling foundation to build upon.

“This study provides clear evidence to support a larger study to really give a definitive statement on the efficacy and safety of its use for PTSD. I don’t think this is the study that provides that definitive evidence, but it is a very strong indication and it very strongly supports the initiation of a large study to address that,” said Sanacora.

He noted that although he’s used the term “cautious optimism” for studies in the past, he has “real optimism” that ketamine will be effective for PTSD based on the results of this current study.

“We still need some more data to really convince us of that before we can say with any clear statement that it is effective and safe, but I’m very optimistic,” Sanacora concluded. “I think the data are very strong.”

The study was funded by the Brain and Behavior Research Foundation; Mount Sinai Innovation Partners and the Mount Sinai i3 Accelerator; Gerald and Glenda Greenwald; and the Ehrenkranz Laboratory for Human Resilience. Feder is a co-inventor on issued patents for the use of ketamine as therapy for PTSD. A list of all disclosures for the other study authors are listed in the original article.

Am J Psychiatry. Published online January 5, 2021. Abstract

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TRILUMINATE in Print: TriClip's Promise Awaits Further Validation

One-year outcomes of the TRILUMINATE trial show improved symptoms, function, and quality of life after clip-based transcatheter repair of the often overlooked tricuspid valve.

The 1-year findings from the 85-patient, single-arm study, reported today in the Journal of the American College of Cardiology and presented at virtual conferences last summer, confirm positive 6-month data that led to an April CE mark approval for the TriClip (Abbott) device in the European Union.

Follow-up among the older (mean age, 77.8 years), symptomatic cohort at high surgical risk showed that 87% (54 of 62 evaluable patients) had tricuspid regurgitation (TR) severity reduced by at least one grade at 1 year, with 70% (44/63 patients) having moderate or less TR.

A full 83% of patients were New York Heart Association functional class I/II, up from 31% at baseline (P < .0001).

The repair was also associated with robust quality-of-life improvements, reduced hospitalizations, and consistent signs of reverse right ventricular (RV) remodeling, the investigators report.

RV end diastolic diameter decreased from 5.28 cm at baseline to 4.79 cm at 1-year follow-up (P < .0001), and RV function, measured by tricuspid annular plane systolic excursion, increased from 1.44 cm to 1.59 cm (P = .0002).

“I’d also like to highlight that mortality was only 7.1% after 1 year and this is certainly much lower than expected and as compared to a natural history cohort of patients with tricuspid regurgitation,” for whom mortality was about 15% to 25%, lead author Philipp Lurz, MD, PhD, University of Leipzig Heart Center, Germany, told theheart.org | Medscape Cardiology.

Although the TriClip device remains investigational in the United States, tricuspid valve repair with the TriClip is currently reimbursed in Germany, he noted.

“All the signals from the field point toward the right direction, attesting that patients benefit from a clinical point of view. Having said that, obviously, we have to wait until we have results from a randomized trial but this TRILUMINATE trial — the first of its kind — sort of sets the scene for the big pivotal trial,” Lurz said.

The ongoing 700-patient TRILUMINATE Pivotal Trial compares the TriClip device with standard medical therapy in symptomatic patients who are at intermediate or higher risk for surgery. It also includes a single arm for patients with more complex tricuspid disease and a roll-in for physicians requiring additional training prior to beginning randomization. The primary end point is a composite of all-cause mortality or tricuspid repair surgeries, heart failure hospitalizations, and quality-of-life at 12 months. The estimated primary completion date is August 2022.

The open-label TRI-FR trial is also scheduled to start this month in Europe and will compare best medical therapy alone or on top of TriClip repair in 300 patients with severe tricuspid disease. The primary end point is the Milton Packer clinical composite score at 12 months. Primary completion is set for January 2022.

In an accompanying editorial, TRI-FR principal investigator Erwan Donal, MD, PhD, Centre Hospitalier Universitaire (CHU) Rennes, France, and colleagues write that the 1-year TRIMULINATE results are “pretty exciting.” They not only show a sustained reduction in TR severity between 30 days and 1 year, but “also a decrease in right ventricular dimensions and, more importantly, a clinical benefit.”

That said, questions remain, like the relation between TR reduction and clinical benefit, Donal told theheart.org | Medscape Cardiology. “Sometimes we are a little bit surprised because we have a very good result in terms of correction of the tricuspid regurg thanks to the treatment, but when we discuss with the patient, they don’t feel better; and sometimes [it’s] the opposite.”

The editorial stresses the need to distinguish between different phenotypes of secondary TR and suggests the results challenge current pathophysiologic concepts, much like the discordant COAPT and MITRA-FR trials of the MitraClip did for mitral valve regurgitation.

“Thanks to MITRA-FR and COAPT, we realize that secondary mitral regurgitation is something that is quite complex and ’til now we don’t really understand who are the patients that should be absolutely treated and who shouldn’t be treated by the clip,” Donal said. “I think — and I’m not the only one — that we might have the same issue with the tricuspid regurg because, like in the case of mitral regurgitation, there are several phenotypes of tricuspid regurg and probably the response to treatment between phenotypes might be different.”

Transcatheter repair with the TriClip is not reimbursed in France and patients should not be treated outside clinical trials until the randomized results are known, Donal said. “We are really at the very beginning of a new story about the understanding of who these patients are with tricuspid regurg and probably there are different phenotypes of tricuspid regurg and different answers to treatment.”

Lurz agreed that it’s important to optimize patient selection and differentiate between ventricular functional TR and atrial functional TR, but noted that although patients with longstanding atrial fibrillation and preserved RV function do extremely well after TriClip repair, those “at the other end of the spectrum” with severe pulmonary hypertension can also benefit.

“The strongest signal so far — and that’s been shown by other groups — in terms of who will benefit and who will not is the question of how much you are able to reduce tricuspid regurg by the intervention. So, almost irrespective of what you have as a substrate, when you can bring down TR from grade 4 to 1,” clinical improvement is certain, he said. “There’s no doubt about that. These patients, they come back and tell you they have a different life.”

The study was funded by Abbott. Lurz has been a consultant to Abbott Structural Heart, Edwards Lifesciences, and Medtronic. Donal has received consultant fees from Abbott.

J Am Coll Cardiol. 2021;77:229-239, 240-242. Full text, Editorial

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Ultra-Early Tranexamic Acid of No Benefit for Subarachnoid Hemorrhage

NEW YORK (Reuters Health) – In patients with subarachnoid hemorrhage due to a ruptured aneurysm, ultra-early, short-term tranexamic acid (TXA) did not improve clinical outcomes in a multicenter, randomized controlled trial.

“The use of TXA in patients who have endured a subarachnoid hemorrhage has been a matter of debate for decades,” Dr. Rene Post of the University of Amsterdam told Reuters Health by email, “We could now convincingly demonstrate that TXA does not improve the clinical outcomes in these patients at six months’ follow-up.”

“What surprised us,” he said, “was that we did not find a significant reduction in the occurrence of rebleedings between the treatment groups, whereas this was always said to be the main reason for its use.”

“Our study showed that in half of the patients the aneurysm was secured within 14 hours,” he noted. “This early aneurysm treatment shortens the time window in which a rebleeding can occur, and thus the time window in which TXA can be effective. Secondly, we know that half of the rebleeds occur within three hours. Yet, despite ultra-early initiation of TXA treatment, the reduction of rebleeds was apparently not soon enough in our study to prevent a considerable amount of rebleedings.”

“A second conspicuous finding is that an excellent clinical outcome, defined as an mRS score of 0.2, as opposed to the primary outcome (mRS score 0.3), was significantly lower in the TXA group,” he added. “So, one may surmise that treatment with TXA could even be harmful. TXA treatment should therefore not be advised and removed from (inter)national guidelines.”

As reported in The Lancet, Dr. Post and colleagues randomly assigned 955 patients with subarachnoid hemorrhage (mean age, 58; about 68% women) to TXA or usual care.

TXA was started immediately after diagnosis: 1 g bolus, followed by continuous infusion of 1 g every 8 h, and stopped immediately before aneurysm treatment, or 24 h after the start of the medication, whichever came first.

The primary endpoint was clinical outcome at six months, assessed by the modified Rankin Scale: good (0-3) or poor (4-6).

In the intention-to-treat analysis, 60% of patients in the TXA group had a good outcome versus 64% of controls (treatment center-adjusted odds ratio 0.86).

Rebleeding occurred after randomization and before aneurysm treatment in 10% of TXA patients and 14% of controls (OR, 0.71). Other serious adverse events – e.g., hydrocephalus, delayed cerebral ischemia, complications of aneurysm treatment – were comparable between groups.

The authors state, “Despite weak evidence for a reduction in rebleeds in the tranexamic acid treatment group compared with the control group in our study, this did not result in improved clinical outcome.”

Dr. Alejandro Rabinstein of Mayo Clinic in Rochester, Minnesota, author of a related editorial, commented by email to Reuters Health, “Many clinicians with experience in subarachnoid hemorrhage, including myself, had been using very brief courses of TXA for prevention of rebleeding – just 1-3 doses in most cases, given the impetus for early aneurysm treatment, which now should even be more emphasized.”

“The results of this trial are therefore practice-changing for many of us,” he said. “I do think future guidelines will change based on this trial.”

“As to idea of a single dose in patients presenting very early to hospitals without capabilities for aneurysm treatment and whose treatment will consequently be delayed until after patient transfer, I think that such approach is not unreasonable,” he added. “Yet, it is not supported by the results of this trial (and) I would be very surprised if a trial on a single dose of TXA were funded in the future.”

SOURCE: https://bit.ly/3qoX40p The Lancet, online December 21, 2020.

Gut Microbiome Predicts Nivolumab Efficacy in Gastric Cancer?

Preliminary data suggest that a certain pattern of gut microbes may be useful in predicting which patients with advanced gastric cancer are likely to benefit from treatment with the immunotherapy nivolumab (Opdivo).

Researchers have demonstrated bacterial invasion of the epithelial cell pathway in the gut microbiome and suggest that this could potentially become a novel biomarker.

“In addition, we found gastric cancer–specific gut microbiome predictive of responses to immune checkpoint inhibitors,” said study author Yu Sunakawa, MD, PhD, an associate professor in the Department of Clinical Oncology at the St. Marianna University School of Medicine, Kawasaki, Japan.

Sunakawa presented the study’s results during the Gastrointestinal Cancers Symposium (GICS) 2021, which was held online this year.

The gut microbiome holds great interest as a potential biomarker for response. Previous studies suggested that it may hold the key to immunotherapy responses. The concept has been demonstrated in several studies involving patients with melanoma, but this is the first study in patients with gastric cancer.

Nivolumab monotherapy has been shown to provide a survival benefit with a manageable safety profile in previously treated patients with gastric cancer or gastroesophageal junction (GEJ) cancer, Sunakawa noted. However, fewer than half of patients responded to therapy.

“The disease control rate was about 40%, and many patients did not experience any tumor degradation,” he said. “About 60% of the patients did not respond to nivolumab as a late-line therapy.”

In the observational/translational DELIVER trial, investigators enrolled 501 patients with recurrent or metastatic adenocarcinoma of the stomach or GEJ. The patients were recruited from 50 sites in Japan.

The primary endpoint was the relationship between the genomic pathway in the gut microbiome and efficacy of nivolumab and whether there was progressive disease or not at the first evaluation, as determined in accordance with RECIST criteria.

Genomic data were measured by genome shotgun sequence at a central laboratory. Biomarkers were analyzed by Wilcoxon rank sum test in the first 200 patients, who constituted the training cohort. The top 30 candidates were validated in the last 300 patients (the validation cohort) using the Bonferroni method.

Clinical and genomic data were available for 437 patients (87%). Of this group, 180 constituted the training cohort, and 257, the validation cohort.

The phylogenetic composition of common bacterial taxa was similar for both cohorts.

In the training cohort, 62.2% of patients had progressive disease, as did 53.2% in the validation cohort. The microbiome was more diverse among the patients who did not have progressive disease than among those who did have progressive disease.

The authors note that although there was no statistically significant pathway to be validated for a primary endpoint using the Bonferroni method, bacterial invasion of epithelial cells in the KEGG pathway was associated with clinical outcomes in both the training cohort (P = .057) and the validation cohort (P = .014). However, these pathways were not significantly associated with progressive disease after Bonferroni correction, a conservative test that adjusts for multiple comparisons.

An exploratory analysis of genus showed that Odoribacter and Veillonella species were associated with tumor response to nivolumab in both cohorts.

Sunakawa noted that biomarker analyses are ongoing. The researchers are investigating the relationships between microbiome and survival times, as well as other endpoints.

Still Some Gaps

In a discussion of the study, Jonathan Yeung, MD, PhD, of the Princess Margaret Cancer Center, Toronto, Canada, congratulated the investigators on their study, noting that “the logistical hurdles must have been tremendous to attain these data.”

However, Yeung pointed out some limitations and gaps in the data that were presented. For example, he found that the ratio of the training set to the validation set was unusual. “The training set is usually larger and usually an 80/20 ratio,” he said. “In their design, the validation set is larger, and I’m quite curious about their rationale.

“The conclusion of the study is that a more diverse microbiome was observed in patients with a tumor response than in those without a response,” he continued, “but they don’t actually show the statistical test used to make this conclusion. There is considerable overlap between the groups, and more compelling data are needed to make that conclusion.”

Another limitation was the marked imbalance in the number of patients whose condition responded to nivolumab in comparison with those whose condition did not (20 vs 417 patients). This could have affected the statistical power of the study.

But overall, Yeung congratulated the authors for presenting a very impressive dataset. “The preliminary data are very interesting, and I look forward to the final results,” he said.

The study was funded by Ono Pharmaceutical and Bristol-Myers Squibb, which markets nivolumab. Sunakawa has received honoraria from Bayer Yakuhin, Bristol-Myers Squibb Japan, Chugai, Kyowa Hakko Kirin, Lilly Japan, Nippon Kayaku, Sanofi, Taiho, Takeda, Yakult Honsha. He has held a consulting or advisory role for Bristol-Myers Squibb Japan, Daiichi Sankyo, and Takeda and has received research funding from Chugai Pharma, Daiichi Sankyo (inst), Lilly Japan (inst), Sanofi, Taiho Pharmaceutical, and Takeda (inst).

Gastrointestinal Cancers Symposium (GICS) 2021: Abstract 161, presented January 15, 2021

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Milk Thistle Promotes Liver Function

Milk thistle (Silybum marianum) is a member of the Asteraceae family and an herbaceous perennial native to Southern Europe and Asia. The plant enjoys full sun and grows to a height of nearly 5 feet. It blooms between July and August with deep purple to pink flowers.1

Throughout history, people have used the fruit and seeds of the milk thistle plant as a treatment for liver disorders. The plant goes by several other names, including Holy thistle, Mary thistle, Our Lady’s thistle, wild artichoke and St. Mary thistle.2

Traditionally, the leaves have been harvested to use in salads and the flower may be roasted and used as a coffee substitute. However, it is the seeds of the milk thistle that were prized for their medicinal activity.

According to the NIH, the oldest recorded use of the plant was by Dioscorides, who believed it could be used as a treatment for snake bites.3 During the Middle Ages it was used as an antidote for liver toxins and by 1898 physicians were using it to treat liver, kidney and spleen disorders. Currently, the German Commission E lists milk thistle for the treatment of hepatic cirrhosis and toxin-induced liver damage and to support chronic inflammatory liver conditions.

Milk Thistle Protects Your Liver Health

The main bioactive compound in milk thistle is a group of flavonolignans called silymarin.4 Flavonolignans are a group of flavonoids with known hepatoprotective properties.5 Silymarin consists of seven different flavonolignans among which silybin has the highest concentration and biological effect. Nearly 70% of silymarin is in the form of silybin A and silybin B.6

Silymarin can be isolated from milk thistle seeds, and while the term milk thistle and silymarin have been used interchangeably, it is technically inaccurate. Multiple studies have demonstrated the ability of silymarin to help protect your liver, and it is regularly used in individuals whose liver has been damaged by nonalcoholic fatty liver disease, hepatitis and liver cancer.7,8

Silymarin also has a protective effect against amatoxin, a deadly toxin produced by the death cap mushroom. Nearly 90% of fatalities from mushrooms worldwide are due to the death cap mushroom.9 Symptoms manifest six to eight hours after ingestion and are followed by kidney and liver failure.

In one review, researchers found nearly 1,500 documented cases where the mortality was less than 10% in patients treated with Legalon® SIL, a pharmaceutical silibinin compound. In another case report,10 doctors successfully treated two patients who accidentally ingested the death cap mushroom with a combination of n-acetylcysteine, cimetidine, silibinin and high-dose penicillin.

Benefits to liver health from silymarin likely result from the antioxidant, anti-inflammatory and antifibrotic properties of the compound. Silymarin also has demonstrated the ability to reduce virus-related liver damage and has a direct antiviral effect when administered intravenously in patients with hepatitis C.11

Silymarin has a positive effect on nonalcoholic steatohepatitis (NASH), which is a more advanced form of nonalcoholic fatty liver disease.12 The compound can also help reduce the fibrotic changes that lead to liver cirrhosis.13 In combination with vitamin E, researchers found silymarin helps improve liver function tests and can be:14

“… an alternative valid therapeutic option particularly when other drugs are not indicated or have failed or as a complementary treatment associated with other therapeutic programs.”

Your Liver: The Great Detoxifier

One of the largest organs in your body is your liver, and for good reason. It performs many metabolic and detoxifying functions, helping to convert toxic substances into harmless substances that are then released from your body.15

Your liver is in your upper abdominal cavity just under your right diaphragm, where it sits on top of your stomach. A normal healthy adult liver weighs about 3 pounds and is made of two lobes connected by a band of connective tissue.16

Just inside the hollow under the liver is the gallbladder, where your body stores bile. At any given time, your liver holds about 13% of your body’s blood supply, which it filters and then excretes toxins in 800 milliliters to 1,000 milliliters of bile each day.17 This is emptied into your gallbladder.

In addition to detoxifying your blood, your liver also produces some of the proteins for blood plasma, converts excess sugar into glycogen and helps balance the production of glucose.18 Your liver is also responsible for regulating blood clotting mechanisms, resisting infections and clearing bilirubin that is formed when hemoglobin breaks down.

Silymarin offers significant benefits to your liver, including the ability to increase glutathione, which is a powerful antioxidant crucial for liver detoxification.19 Researchers have also found it may help your liver cells to regenerate, supporting the only organ in your body capable of regeneration.20

Incidence of Liver Disease on the Rise

As you can imagine, liver damage affects these functions and more. Although many tend to equate liver disease with alcohol use, as many as 100 million people suffer from nonalcoholic fatty liver disease (NAFLD),21 which is associated with obesity.22 As the incidence of obesity in the U.S. has risen, so has NAFLD. In 2017-2018, the age adjusted prevalence of obesity in the U.S. was 42.4% of adults.23 

Risk factors for nonalcoholic fatty liver disease include obesity, diabetes, high triglyceride levels and poor eating habits. The condition is sometimes called a silent disease because you may not experience any symptoms and many people may live with the condition without developing further liver damage.24 If NAFLD progresses with signs of inflammation and cell damage, it is called nonalcoholic steatohepatitis (NASH).

NAFLD is also the most common type of liver disease found in children.25 Data released in January 202026 from a large cohort in the U.K. found 20% of young adults had NAFLD.

When the researchers widened the data set, they found over 20% had evidence of NAFLD and 2.5% had developed fibrosis. Breaking out the data further, they found at 17 years, 2.5% had moderate to severe levels, yet by age 24 this had risen to 13%.

Silymarin Reduces Cellular Inflammation

Many of the health benefits attributed to silymarin are the result of the compound’s capacity to help reduce cellular inflammation. Research has suggested silymarin does this using a two-phase process similar to that used by other natural compounds such as curcumin and epigallocatechin gallate, found in green tea.27

During the first phase there was a rapid increase in genetic expression that is linked with cellular stress. After this follows a longer sustained depression of genetic expression that is found with inflammation. As described by the National Center for Complementary and Integrative Health, in this study, silymarin:28

  • Induced endoplasmic reticulum stress
  • Triggered activating transcription factor 4 (ATF-4) and AMP-activated protein kinase (AMPK), and inhibited mammalian target of rapamycin (mTOR)
  • Modulated the actions of many types of metabolites
  • Inhibited inflammatory signaling pathways, when given on a prolonged basis (at 24 hours, in this study)

An important factor in those steps is the activation of AMP-activated protein kinase (AMPK). This is an enzyme that sometimes is called the “metabolic master switch” since it plays an important role in regulating metabolism.29 According to the Natural Medicine Journal, AMPK regulates biological activities to normalize energy imbalances. In addition:30

“AMPK helps coordinate the response to these stressors, shifting energy toward cellular repair, maintenance, or a return to homeostasis and improved likelihood of survival. The hormones leptin and adiponectin activate AMPK. In other words, activating AMPK can produce the same benefits as exercise, dieting, and weight loss — the lifestyle modifications considered beneficial for a range of maladies.”

More Health Benefits With Milk Thistle

These factors mean milk thistle offers a wide range of health benefits. Milk thistle extracts have been tested for anticancer actions in prostate cancer both in the lab and in clinical trials. According to one study, “extracts enriched for isosilybin B, or isosilybin B alone, might possess improved potency in prostate cancer prevention and treatment.”31

The plant also has neuroprotective effects and has been used in the treatment of Alzheimer’s and Parkinson’s disease in modern society and neurological diseases such as cerebral ischemia for well over 2,000 years.32 The antioxidant and anti-inflammatory properties may contribute to the neuroprotective effects that help prevent a decline in brain function as you age.33

In one study, researchers used silymarin to reduce oxidative stress and inflammation in an animal model that helped reduce the potential for dementia in obese animal subjects.34 Other studies have also demonstrated the ability of milk thistle to reduce amyloid plaques in animal models associated with Alzheimer’s disease.35,36

Silymarin has also demonstrated antiosteoclastic activity in animal studies, causing one research team to conclude it significantly prevents bone loss, potentially “either due to direct interaction with Erbeta [an estrogen receptor beta-isoform] or increasing bone formation parameters including calcium, phosphorus, osteocalcin and PTH.”37

The American Pregnancy Association writes that blessed thistle has been used for hundreds of years to raise a woman’s milk supply, and it is especially effective when taken with fenugreek.38

One published study of 50 healthy lactating women demonstrated oral supplementation with 420 milligrams per day of silymarin boosted their milk supply by 85.94% as compared to the women taking a placebo whose milk supply went up 32.09%.39 None of the women dropped out and no one reported unwanted side effects.

Considerations Before Planting Milk Thistle at Home

Before planting milk thistle in your garden or picking up a milk thistle supplement, there are a few things to consider. Research has found silibinin is poorly absorbed as it has low water solubility. Using a novel formulation, combining silibinin with phosphatidylcholine, researchers were able to improve the solubility and bioavailability, which markedly improved the therapeutic efficiency.40

If you’re hoping to grow your own plants in your backyard and harvest for tea and salads, be forewarned the plant is highly invasive and spreads quickly. While you may not mind having it all over your yard, it doesn’t respect your neighbor’s boundaries and will likely end up in their yard as well.

Milk thistle is also highly toxic to livestock, so if you have grazing animals it’s important you don’t plant it outside.41 Milk thistle has adapted to growing even in poor quality soil. The plants enjoy full sun and once the flowers have begun to dry, they’ll be ready for harvest.42

Cut the flowers and place them in a paper bag, storing the bag in a dry place so the flower heads dry. Once all the moisture is gone, shake the bag to separate the seeds, which can then be kept in a dry airtight container.

The seeds can be powdered in a coffee grinder and sprinkled on your salads, added to smoothies or even raw juice. You can use the seeds to make your own tea, which you’ll find a recipe for in “Magnificent Milk Thistle.”

Weekly Health Quiz: Linoleic Acid, Hacks and Pathogens

1 According to recent research, the reason why some COVID-19 patients develop life-threatening organ failure is because they:

  • Are deficient in calcium
  • Consume excessive amounts of unsaturated fats such as omega-6 linoleic acid

    A compelling report in the journal Gastroenterology offers a novel explanation as to why some COVID-19 patients develop life-threatening organ failure, namely their high unsaturated fat intake. Unsaturated fat intake is associated with increased mortality from COVID-19, while saturated fat intake lowers your risk of death. Learn more.

  • Eat too many eggs
  • Have not exercised enough

2 Which of the following vaccine ingredients is suspected of being the culprit causing allergic, including life-threatening anaphylactic responses in some recipients of Pfizer’s COVID-19 vaccine?

  • mRNA
  • Thimerosal
  • Polyethylene glycol (PEG)

    Pfizer’s mRNA vaccine contains polyethylene glycol (PEG), and studies have shown 70% of people develop antibodies against this substance. This suggests PEG may trigger fatal allergic reactions in many who receive the vaccine. Learn more.

  • Egg albumen

3 The SARS-CoV-2 PCR test was developed based on:

  • Viral isolate of SARS-CoV-2 collected from patient zero in Wuhan, China
  • Viral isolate from a single American with cold symptoms
  • The full genetic sequence obtained from viral isolate
  • An incomplete genetic sequence published by Chinese scientists

    The SARS-CoV-2 PCR test was developed based on a genetic sequence published by Chinese scientists, not the viral isolate. Missing genetic code was simply made up. Learn more.

4 Which of the following is a technique that allows scientists to make a pathogen more virulent?

  • Serial passaging

    One technique that allows scientists to make a pathogen more virulent is called “serial passaging.” By passing the virus through a series of cells from different animals, the virus progressively adapts to the new host cell. Learn more.

  • Sequential massaging
  • Fromage processing
  • Prime addition

5 Which of the following countries detained or arrested the greatest number of journalists in 2020?

  • The Philippines
  • China

    China tops the list of countries where suppression of journalism is taking place. As of December 1, 2020, 117 Chinese journalists had been arrested, many because of their reporting on the COVID-19 pandemic. December 28, 2020, the Shanghai Pudong People’s Court sentenced citizen journalist Zhang Zhan to four years in prison for “picking quarrels and provoking trouble.” Learn more.

  • Norway
  • Serbia

6 According to financial guru and former assistant secretary of housing, Catherine Austin Fitts, the riots that occurred in the U.S. during 2020 were:

  • An emotional response to racial inequality
  • The result of poor upbringing
  • Part of a real estate acquisition scheme

    The riots in the U.S. were not random. According to Catherine Austin Fitts, the pattern suggests they were part of a real estate acquisition plan. Learn more.

  • An outgrowth of pandemic restrictions

7 Which of the following “hacks” will make fasting easier by preventing hunger pangs?

  • Eating a high-carb breakfast
  • Never fasting for longer than 12 hours
  • Avoiding exercise while fasting
  • Having coffee, with or without MCT oil, butter and/or prebiotics, first thing in the morning

    A simple hack that will make fasting easier is to raise your ketone level with black mycotoxin-free coffee, with or without added MCT oil and grass fed butter. Adding prebiotics to your morning coffee will also prevent hunger. Learn more.