Revenue increased 13% to $49.6 billion
GAAP1 operating earnings were $137 million, GAAP diluted EPS were $0.40
Non-GAAP operating earnings decreased 20% to $423 million due to a decline in Medical segment profit, partially offset by an increase in Pharmaceutical segment profit; non-GAAP diluted EPS decreased 7% to $1.20
Company reaffirmed fiscal year 2023 non-GAAP EPS guidance
Are voter ID laws an obstacle to transgender people exercising their rights at the ballot box? Some trans groups and the ACLU argue that this is the case as the midterm elections near.
The push against identification at the polls has been aggressive, with Democrats making up the bulk of people in opposition. A long list of excuses has been presented as to why very simple and straightforward laws requiring ID to vote are a violation of the civil liberties of various minorities. Notably, Democrats and the ACLU have suggested that such laws are “racist” because minorities often don't have or are “not capable” of getting a state ID.
The ACLU argues, for example, that over 25% of blacks and 16% of Hispanics of voting age in the US do not have ID. This data comes from the GOA and the nonpartisan Brennan Center for Justice at the New York University School of Law and was collected from 2012-2014, around a decade ago.
The problem with this argument is that there are no legal obstacles for minorities to get a state ID. If they don't have one then it is their fault they are not able to vote. The only people who would have trouble obtaining an ID are illegal immigrants who are not allowed to vote anyway. The minority access to ID argument just doesn't hold water.
However, not to be defeated, anti-ID groups are turning to a tiny portion of the population that might face legitimate confusion at polling stations because of their appearance – Transgenders.
Representatives from the ACLU in Tennessee where stricter enforcement of voter ID laws is underway suggest that the act of a trans person having to explain their trans status is humiliating:
“It’s not just embarrassing, but it’s terrifying to have to do that — to try to read the room and see, like, are they going to kick me out? It can be really dehumanizing to have your whole identity nitpicked just so that you can cast your ballot and have your voice be heard...” Says Henry Seaton, an ACLU advocate. Seaton is a woman who transitioned in appearance to a man who claims she once had her ID scrutinized in 2016.
Beyond the apparent embarrassment, trans rights groups also say that ID confusion could potentially lead to people being turned away from the polls, or it could put trans people “at risk” of harassment. Almost all stats involving trans harassment accounts are collected by trans rights groups with a clear political agenda, so it is difficult to say how serious this threat actually is and how much of it is fantasy.
“People who might be inclined to harass marginalized voters at the polls are more aware of trans people’s existence,” said Olivia Hunt, the policy director at the National Center for Transgender Equality. “So I expect that we’re going to hear more stories of trans people being harassed, whether by voters, poll workers, poll monitors or other folks who are present during the election.”
Legitimate harassment is illegal regardless of the individual, as are any acts of assault or violence. Trans people are protected under the same laws as everyone else, but groups like the ACLU claim that this is not enough and separate laws need to be established giving trans people special protections. This would include making them exempt from voter ID laws.
Frankly, this is yet another example of social justice proponents trying to make their problems into the country's problems. If a person's identification does not match their appearance then it is going to be scrutinized whether they are trans, a minority or they are white and straight. By attempting to change their appearance to look more like the opposite sex, trans people set themselves up for questions when going to vote. There are dozens of other scenarios where this would also be an issue. It is not for state governments to cater to every individual case; their job is only to ensure that ballots are secure and that non-citizens don't vote illegally.
Since the ACLU and trans rights organizations cannot come up with many examples of trans people being denied the right to vote and only present anecdotal stories of individuals being inconvenienced for five minutes, it's hard to find justification for an overhaul of state laws preventing voter fraud.
The more likely explanation for the growing interest in transgender voting is that social justice activists have hit a brick wall when it comes to stopping the spread of ID laws and they are looking for a legal toe hold or weakness in the armor. Their exploitation of minorities failed, but if voter ID can be challenged using trans people as a foil, then these groups might be able to bring down all ID laws for everyone, including illegal immigrants; the real golden goose for progressive politicians. https://www.zerohedge.com/political/transgender-groups-claim-their-voting-rights-will-be-restricted-state-id-laws
by Zachary Stieber via The Epoch Times,
Miss United States of America is legally able to reject men who claim that they’re women, an appeals court has ruled.
The beauty pageant’s “natural born female” requirement conveys a message and the U.S. Constitution’s First Amendment gives the pageant the ability to voice that message and enforce the rule, Circuit Judge Lawrence VanDyke, a Trump appointee, wrote in a Nov. 2 ruling.
“Forcing the Pageant to accept Green as a participant would fundamentally alter the Pageant’s expressive message in direct violation of the First Amendment,” VanDyke wrote for the majority of a panel of the U.S. Court of Appeals for the Ninth Circuit.
The ruling was against Anita Noelle Green, a biological male who identifies as transgender and sued Miss United States of America in 2019, alleging the pageant violated an Oregon law called the Oregon Public Accommodations Act (OPAA) by rejecting Green’s application to participate in the pageant.
The appeals court upheld a 2021 ruling from U.S. District Judge Michael Mosman, a George W. Bush appointee.
VanDyke was joined by Circuit Judge Carlos Bea, a George W. Bush appointee.
Circuit Judge Susan Graber, a Clinton appointee, dissented.
Graber said it wasn’t clear whether the Oregon law applies to the pageant because the law only applies to businesses that have membership policies “so unselective that the organization can fairly be said to offer its services to the public.” The lack of clarity means the district court should have allowed discovery or briefing on the matter, she said.
“In sum, by assuming that the statute applies to Defendant—an assumption that is not definitively supported by the extant record—the majority risks issuing an unconstitutional advisory opinion and flouts a longstanding tradition of judicial restraint in the federal courts,” Graber argued.
“Applying our ordinary rule of constitutional avoidance, I would vacate the judgment and remand this case to the district court to determine whether the OPAA applies to Defendant before we address any constitutional concerns regarding the application of the statute.”
Graber also said the Oregon law “neither improperly compels speech nor violates the owner’s freedom of association.”
VanDyke authored a concurring opinion to address the dissent, finding that the pageant is protected by the First Amendment from both compelled speech and forced association.
He referenced a previous Supreme Court ruling that enabled the Boy Scouts to exclude a gay leader because including him would “interfere with the Boy Scouts’ choice not to propound a point of view contrary to its beliefs.”
“The case before us is not meaningfully distinguishable,” he said. Green identifies as a transgender woman and an activist who has talked about using pageant platforms to deliver a message that runs against Miss United States of America’s beliefs.
“The Pageant expresses its message through its contestants—both by those who compete and those who ultimately succeed,” VanDyke said. “And the Pageant has actively and consistently enforced its eligibility requirements precisely over a concern about protecting its message. The forced inclusion of a male would therefore directly impact the Pageant’s message in a way fundamentally at odds with the Pageant’s views on womanhood.”
Genentech (Roche)’s Ocrevus (ocrelizumab) stole the show at last month’s European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) meeting, particularly in relapsing-remitting MS (RRMS).
The South San Francisco-based biotech made approximately 35 presentations involving Ocrevus, which is a key driver of Roche’s pharmaceutical division. The drug gained 16% in third-quarter sales, bringing in a total of $1.52 billion Swiss francs.
In an interview with BioSpace, Ashish Pradhan, M.D., executive director and disease area lead, neuroimmunology at Genentech noted that with MS there are two broad treatment strategies.
The first is escalation, which is the use of relatively older but now less effective therapies. This has been shown in head-to-head clinical trials, Pradhan said.
In some cases, physicians may start treatment with those drugs, and then “escalate” to a “highly effective therapy”, such as Ocrevus, if they do not get the response they’re looking for, he noted.
But increasingly, the treatment strategy is to start with the highly effective therapies, “so you hit the disease with the best therapy that you have and try to contain [it] as quickly and as effectively as possible without putting the patient through the process of starting on a less-effective therapy.”
What is important, within the context of some of these clinical studies, is that many patients may have been on less-effective treatments before shifting to newer therapies such as Ocrevus, “which also means that a number of years have passed since their diagnosis,” Pradhan said. This forms part of the basis for Genentech’s Phase IIIb ENSEMBLE trial.
The company presented two-year interim analysis from the open-label study at ECTRIMS. The trial evaluates the effectiveness and safety of the drug in patients with early-stage RRMS over 192 weeks with a follow-up period of at least 48 weeks.
After 96 weeks of treatment with Ocrevus, 77% of patients saw no evidence of disease activity (NEDA), the most standard accepted measure of disability. “They will, of course, be followed for another couple of years,” to determine the final results, Pradhan said.
“What particularly needs to be pointed out is that the EDSS [expanded disability status scale] score, which is a measure of disability, remained stable, or in some instances even showed some improvements in these patients,” he added.
Another study looked at long-term safety across all Ocrevus clinical trials over the last nine years. This safety research has been presented at almost every major MS-related conference since the drug was approved, Pradhan noted.
Genentech collects data from all of the studies as well as from various regulatory databases, and the company’s own Ocrevus website database, “which is the first in the industry,” he said. This particular presentation included approximately 250,000 people from all clinical trials that are ongoing. It looks at two predominant safety outcomes, serious infections and malignancies with a particular focus on female breast cancer.
Genentech has not seen any particular signal for a particular adverse event, Pradhan said, noting that this has been the case in previous instances.
The company plans to continue its vigilance program, as well as long-term studies such as ENSEMBLE, studies in pregnant women and the CHIMES trial in Black and Hispanic Americans.
Interim analysis from CHIMES was also presented at ECTRIMS. One-year data is expected to read out at some point in 2023.
“We demonstrated again that Ocrevus is effective in these populations, which are under-represented in clinical trials,” Pradhan said.
“We’re very proud to say that our commitment to this molecule continues unabated,” Pradhan said of Ocrevus. “It’s a very rich investigation program that is still ongoing and will continue for many years.”
Scientists at Scripps Research have uncovered a critical feature that a promising new class of cancer drugs, known as CELMoDs, needs to be effective.
CELMoDs are designed to attack cancer in a novel way, by binding to a regulatory protein called cereblon, which then triggers the degradation of key cancer-driving proteins. In the study, reported on November 3 in Science, researchers discovered that these drugs, in order to work, need to cause a critical shape-change in cereblon when they bind to it. The finding enables researchers to reliably design effective CELMoDs.
“There are a lot of research groups that have spent considerable time making drugs that bind very tightly to cereblon, but have then scratched their heads in puzzlement that these drugs fail to work,” says study senior author Gabriel Lander, PhD, professor in the Department of Integrative Structural and Computational Biology at Scripps Research.
The study’s first author was Randy Watson, PhD, a postdoctoral researcher in the Lander lab.
Cereblon works as part of a major protein-disposal system in cells. This system tags targeted proteins with molecules called ubiquitin, which mark the proteins for destruction by roving protein-breaking complexes known as proteasomes. The ubiquitin-proteasome system is used not only to destroy abnormal or damaged proteins, but also to help regulate the levels of some normal proteins. Cereblon is one of hundreds of “adaptors” used by the ubiquitin-proteasome system to guide the ubiquitin-tagging process towards specific sets of target proteins.
Scientists now recognize that some cancer drugs, including the best-selling myeloma drug lenalidomide (Revlimid), happen to work by binding to cereblon. They do so in a way that forces the ubiquitin-tagging, and consequent destruction, of key proteins that promote cell division—proteins that couldn’t be targeted easily with traditional drugs. Inspired in part by that recognition, drug companies have begun developing cereblon-binding drugs—CELMoDs, also called protein-degradation drugs—that will work even better against myeloma and other cancers.
One enduring problem for the field has been the fact that some of these drugs bind tightly to cereblon, yet fail to cause sufficient degradation of their protein targets. Understanding why this happens has been difficult. Scientists have wanted to use high-resolution imaging methods to map cereblon’s atomic structure and study its dynamics when bound by CELMoDs. But cereblon is a relatively fragile protein that has been hard to capture with such imaging methods.
In the study, Watson spent more than a year devising a recipe for stabilizing cereblon in association with a ubiquitin-system partner protein, in order to image it with low-temperature electron microscopy (cryo-EM). In this way, he was able ultimately to resolve the cereblon structure at near-atomic scale. Watson also imaged the cereblon-partner complex with CELMoD compounds and target proteins.
The structural data revealed that CELMoDs must bind to cereblon in a way that changes its shape, or conformation. Cereblon, the researchers determined, has a default “open” conformation, but must be switched to a particular “closed” conformation for the ubiquitin-tagging of target proteins.
The main significance of the finding is that drug companies developing CELMoDs now have a much better idea of what their candidate drugs must do to be effective.
“Companies have been developing cereblon-binding protein-degradation drugs that they can see are better degraders, but they didn’t know this was because the drugs are better at driving this closed conformation,” Watson says. “So now they know, and they can test their drugs for this key property.”
Watson’s breakthrough recipe for stabilizing cereblon in preparation for cryo-EM imaging also is now being adopted widely by researchers in this field.
Lander says his lab hopes now to facilitate the development of protein-degradation drugs that work by binding to other ubiquitin-proteasome adaptor proteins besides cereblon. As he notes, the big attraction of the protein-degradation drug strategy is that it can be used to hit virtually any disease-relevant protein, including the very large class of proteins that can’t be targeted with traditional drugs.
“Molecular glue CELMoD compounds are allosteric regulators of cereblon conformation” was co-authored by Edmond “Randy” Watson, Scott Novick, Patrick Griffin, and Gabriel Lander of Scripps Research; and Mary Matyskiela, Philip Chamberlain, Andres Hernandez de la Peña, Jin-Yi Zhu, Eileen Tran, and Ingrid Wertz of Bristol Myers Squibb.
The research was supported by Bristol Myers Squibb.
Science
Molecular glue CELMoD compounds are regulators of cereblon conformation
A longstanding question in neuroscience is how mammalian brains (including ours) adapt to external environments, information, and experiences. In a paradigm-shifting study published in Nature, researchers at the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital and Baylor College of Medicine have discovered the mechanistic steps underlying a new type of synaptic plasticity called behavioral timescale synaptic plasticity (BTSP). The study, led by Dr. Jeffrey Magee, professor at Baylor, who is also a Howard Hughes Medical Institute, and Duncan NRI investigator, reveals how the entorhinal cortex (EC) sends instructive signals to the hippocampus — the brain region critical for spatial navigation, memory encoding, and consolidation — and directs it to specifically re-organize the location and activity of a specific subset of its neurons to achieve altered behavior in response to its changing environment and spatial cues.
Neurons communicate with one another by transmitting electrical signals or chemicals through junctions called synapses. Synaptic plasticity refers to the adaptive ability of these neuronal connections to become stronger or weaker over time, as a direct response to changes in their external environment. This adaptive ability of our neurons to respond quickly and accurately to external cues is critical for our survival and growth and forms the neurochemical foundation for learning and memory.
An animal’s brain activity and behavior adapt quickly in response to spatial changes
To identify the mechanism that underlies the mammalian brain’s capacity for adaptive learning, a postdoctoral fellow in the Magee lab and lead author of the study, Dr. Christine Grienberger, measured the activity of a specific group of place cells, which are specialized hippocampal neurons that build and update ‘maps’ of external environments. She attached a powerful microscope to the brains of these mice and measured the activity of these cells as the mice were running on a linear track treadmill.
In the initial phase, the mice were acclimated to this experimental setup and the position of the reward (sugar water) was altered at each lap. “In this phase, the mice ran continuously at the same speed while licking the track continuously. This meant the place cells in these mice formed a uniform tiling pattern,” said Dr. Grienberger who is currently an assistant professor at Brandeis University.
In the next phase, she fixed the reward at a specific location on the track along with a few visual cues to orient the mice and measured the activity of the same group of neurons. “I saw that changing the reward location altered the behavior of these animals. The mice now slowed down briefly before the reward site to taste the sugar water. And more interestingly, this change in behavior was accompanied by increased density and activity of place cells around the reward site. This indicated that changes in spatial cues can lead to adaptive reorganization and activity of hippocampal neurons,” Dr. Grienberger added.
This experimental paradigm allowed the researchers to explore how changes in spatial cues shape mammalian brains to elicit adaptive new behaviors.
For more than 70 years, Hebbian theory which is colloquially summarized as, “neurons that fire together, wire together”, singularly dominated the neuroscientists’ view of how synapses become stronger or weaker over time. While this well-studied theory is the basis of several advancements in the field of neuroscience, it has some limitations. In 2017, researchers in the Magee lab discovered a new and powerful type of synaptic plasticity - behavioral timescale synaptic plasticity (BTSP) - which overcomes these limitations and offers a model that best mimics the timescale of how we learn or remember related events in real life.
Using the new experimental paradigm, Dr. Grienberger observed that in the second phase, place cell neurons that were previously silent acquired large place fields abruptly in a single lap after the reward location was fixed. This finding is consistent with a non-Hebbian form of synaptic plasticity and learning. Additional experiments confirmed that the observed adaptive changes in the hippocampal place cells and in the behavior of these mice were indeed due to BTSP.
The entorhinal cortex instructs the hippocampal place cells on how to respond to spatial changes
Based on their previous studies, the Magee team knew BTSP involves an instructive/supervisory signal that does not necessarily lie within or adjacent to the target neurons (in this case, the hippocampal place cells) that are being activated. To identify the origin of this instructive signal, they studied the axonal projections from a nearby brain region called the entorhinal cortex (EC), which innervates the hippocampus and acts as a gateway between the hippocampus and neocortical regions that control higher executive/decision-making processes.
“We found that when we specifically inhibited a subset of EC axons that innervate the CA1 hippocampal neurons we were recording from, it prevented the development of CA1 reward over-representations in the brain,” Dr. Magee said.
Based on several lines of investigations, they concluded that the entorhinal cortex provides a relatively invariant target instructive signal which directs the hippocampus to reorganize the location and activity of place cells which in turn, affects the animal’s behavior.
“The discovery that one part of the brain (entorhinal complex) can direct another brain region (hippocampus) to alter the location and activity of its neurons (place cells) is an extraordinary finding in neuroscience,” Dr. Magee added. “It completely changes our view of how learning-dependent changes in the brain occur and reveals new realms of possibilities that will transform and guide how we approach neurological and neurodegenerative disorders in the future.”
This study was funded by the Howard Hughes Medical Institute, the Cullen Foundation, and the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital.
Experimental study
Animals
Entorhinal cortex directs learning-related changes in CA1 representations
As personal and medical marijuana use increases nationwide, the American Dental Association (ADA) suggests patients refrain from using marijuana before dental visits after a new survey finds more than half of dentists (52%) reported patients arriving for appointments high on marijuana or another drug.
Currently, recreational marijuana use is legal in 19 states and the District of Columbia, with five more states voting on ballot measures Nov. 8. Medicinal use is legal in 37 states and the District of Columbia.
“When talking through health histories, more patients tell me they use marijuana regularly because it is now legal,” says ADA spokesperson Dr. Tricia Quartey, a dentist in New York. “Unfortunately, sometimes having marijuana in your system results in needing an additional visit.”
That’s because being high at the dentist can limit the care that can be delivered. The survey of dentists found 56% reported limiting treatment to patients who were high. Because of how marijuana and anesthesia impact the central nervous system, 46% of surveyed dentists reported sometimes needing to increase anesthesia to treat patients who needed care.
Findings were uncovered in two online surveys earlier this year – one of 557 dentists and a second nationally representative survey of 1,006 consumers – conducted as part of trend research by the ADA.
“Marijuana can lead to increased anxiety, paranoia and hyperactivity, which could make the visit more stressful. It can also increase heart rate and has unwanted respiratory side effects, which increases the risk of using local anesthetics for pain control,” Dr. Quartey said. “Plus, the best treatment options are always ones a dentist and patient decide on together. A clear head is essential for that.”
Studies have also shown regular marijuana users are more likely to have significantly more cavities than non-users.
“The active ingredient in marijuana, THC, makes you hungry, and people don’t always make healthy food choices under its influence,” Dr. Quartey said. “Medically speaking, munchies are real.”
The science behind oral health and marijuana is beginning to emerge, particularly when it comes to edible or topical forms. Still, there are strong indications that smoking marijuana is harmful to oral and overall health. The ADA surveyed 1,006 consumers in a second poll around marijuana and vaping use. The results of the representative sample found nearly 4 in 10 (39%) patients reported using marijuana, with smoking the most common form of use. Separately, 25% of respondents said they vaped, and of those respondents, 51% vaped marijuana.
“Smoking marijuana is associated with gum disease and dry mouth, which can lead to many oral health issues,” Dr. Quartey said. “It also puts smokers at an increased risk of mouth and neck cancers.”
The ADA has called for additional research around marijuana and oral health and will continue to monitor the science to provide clinical recommendations for dentists and patients.
In the meantime, survey results show 67% of patients say they are comfortable talking to their dentist about marijuana. The ADA recommends dentists discuss marijuana use while reviewing health history during dental visits.
“If we ask, it’s because we’re here to keep you in the best health we can,” Dr. Quartey says. “If you use it medicinally, we can work with your prescribing physician as part of your personal healthcare team.”
In the meantime, patients who use marijuana can stay on top of their oral health with a strong daily hygiene routine of brushing twice a day with fluoride toothpaste, cleaning between teeth daily and visiting the dentist regularly and making healthy snack choices.
For more information on the oral health effects of marijuana, visit ADA.org.
