Ultragenyx, Mereo drug reduces fractures in bone disorder study

 

• Ultragenyx Pharmaceutical and Mereo BioPharma on Tuesday said their experimental treatment for a rare bone disorder showed prolonged effects in the early part of a Phase 2/3 study.

• The trial included people with a condition called osteogenesis imperfecta, which impacts bone metabolism and increases the risk of fractures, deformities and other issues. Ultragenyx and Mereo’s drug, setrusumab, is designed to block a protein known as sclerostin that can negatively affect bone formation

• In October 2023, the companies said setrusumab significantly reduced fractures and built lumbar spine bone mineral density in a group of patients followed for at least six months. The results revealed Tuesday, showed that effect was sustained through at least 14 months of follow-up with ongoing improvement in bone density.

The longer-term results offer reassurance to investors who are eagerly awaiting the first readout of the Phase 3 portion of the companies’ “Orbit” trial, analysts said. That interim analysis is expected either at the end of this year or early next year.

Safety results are also encouraging, the companies said. In the time period analyzed, there were no serious treatment-related side effects. The most common adverse events were headaches and infusion-related events, they said.

The initial Phase 2 part of the study included 24 patients between the ages of 5 and 25 who received one of two doses of setrusumab. In the two years before entering the trial, every one of the participants had experienced at least one fracture. Treatment produced a 67% reduction in the annualized fracture rate, the companies said.

Following the initial success of the trial, researchers transitioned to Phase 3, which includes an additional 158 patients who are randomized at a 2:1 ratio to either receive the drug or a placebo. The companies are also conducting a separate Phase 3 trial known as Cosmic in patients under the age of seven.

Ultragenyx and Mereo began working together on the drug in December 2020. The latest results follow another research success for Ultragenyx announced in May. In that case, the company released positive top-line results for a Phase 3 study of a gene therapy for patients with glycogen storage disease.

https://finance.yahoo.com/m/54284f72-e223-38c4-a755-1cd8082f6ecb/ultragenyx%2C-mereo-drug.html

HHS Sued Over Rule Requiring Health Care Providers To Perform 'Gender Transition' Procedures

 by Tom Ozimek via The Epoch Times (emphasis ours),

The attorneys general of Montana and Texas on Tuesday filed a lawsuit against Xavier Becerra, Secretary of the Department of Health and Human Services (HHS), over a rule that says states must pay for “gender transition” procedures through their Medicaid programs and requires health care providers who receive federal funding to perform such procedures even in violation of state law.

The complaint, filed on June 11 with the U.S. District Court for the Eastern District of Texas, Tyler Division, asks the court to block a new rule recently published by HHS in the Federal Register that modifies non-discrimination protections of the Affordable Care Act (ACA) in a way that expands the definition of “sex” discrimination to include discrimination based on “gender identity.”

The final rule, called “Nondiscrimination in Health Programs and Activities,” implements Section 1557 of the ACA in a way that reinstates and expands on many of the 2016 regulations from the administration of then President Barack Obama while reversing much of the 2020 version of the rule adopted under then President Donald Trump.

The rule, which applies to health programs and activities that receive federal financing, has staggered effective dates starting on July 5, 2024. It provides nondiscrimination health care protections to individuals in protected groups, including prohibiting denial of benefits, coverage, and program participation based on factors like race, age, disability, and sex—which has been expanded to include the concept of “gender identity.”

The rule explicitly provides nondiscrimination protections based on “gender identity” and sexual orientation, and categorically prohibits the denial of “gender-affirming” care.

More Details

The attorneys general of Montana and Texas object to what they call in their complaint a “devastatingly drastic social change” under Section 1557. They argue that the change effectively forces taxpayers in those states to pay for controversial drugs and experimental surgeries for people seeking “gender transition,” which they label as procedures that “inflict permanent harm.”

“We are suing to stop the Biden Administration from withholding federal healthcare funds to force medical professionals to perform these experimental and dangerous procedures,” Texas Attorney General Ken Paxton said in a statement.

The two attorneys general argue in the complaint that the final rule is unlawful and an unconstitutional attempt to override state law. They’re seeking injunctive relief to prevent the rule from being enforced.

“States should not be compelled to foot the bill for treatments that are leaving people, even children, with irreversible damage,” Montana Attorney General Austin Knudsen said in a statement.

Mr. Knudsen said that in some states, Montana included, health care providers may be forced to choose between violating state law or losing federal funding. He cited Montana’s Senate Bill 99, which bans the provision of surgical procedures to address a minor’s perception that their “gender” differs from their biological sex.

HHS did not respond to a request for comment on the lawsuit.

However, in announcing the new final rule on April 26, 2024, HHS said in a statement that it amounted to “bold action” to bolster protections against discrimination.

“Today’s rule is a giant step forward for this country toward a more equitable and inclusive health care system, and means that Americans across the country now have a clear way to act on their rights against discrimination when they go to the doctor, talk with their health plan, or engage with health programs run by HHS,” Mr. Becerra said in a statement.

HHS also stated that the new final rule adds protections against discrimination by codifying that Section 1557’s prohibition against discrimination based on sex “includes LGBTQI+ patients.”

Transgender Agenda in Focus

Transgenderism has become a prominent issue in America’s social and political landscape in recent years.

Nearly half of America’s states have passed legislation banning medical sex-change procedures for minors, according to data compiled by Movement Advance Project.

Conservatives have backed laws that give parents more authority to prevent their children from undergoing transgender procedures or impose penalties on doctors who perform them without parental consent.

Progressives, by contrast, have tended to support “gender-affirming care” and laws that protect access to transgender procedures, which in some cases limit the ability of parents to have a say in their children’s decisions to seek sex-reassignment procedures and medications.

President Joe Biden has advanced various policies that promote gender ideology and special protections for individuals who identify as something different from their birth sex.

For instance, on his first day in office, President Biden signed an executive order calling for the heads of government agencies to consult with the U.S. Attorney General to eliminate discriminatory rules or regulations in any “existing orders, regulations, guidance documents, policies, programs, or other agency actions” that were based on “gender identity or sexual orientation.”

“Transgender Black Americans face unconscionably high levels of workplace discrimination, homelessness, and violence, including fatal violence,” says the order.

Also, in a move that sparked controversy and triggered multiple lawsuits, the Department of Education (DOE) expanded the decades-old Title IX law that prohibits sex discrimination in schools to now include sexual orientation and “gender identity.”

The changes, which stop short of prohibiting schools from banning female-identifying male athletes from competing against females, are slated to go into effect on Aug. 1, 2024.

By contrast, former President Trump has opposed the pro-transgender agenda and related policy moves. For instance, he has vowed to reverse the Biden administration’s expansion of Title IX protections for transgender students.

A recent declaration by a coalition of doctors and medical groups, including the American College of Pediatricians, sounded the alarm on the long-term risks of subjecting children to so-called “gender-affirming” procedures. Rather than backing gender transition in children experiencing confusion or distress about their sex, medical professionals should instead focus on psychotherapy for underlying mental health issues such as depression, autism, or anxiety, per the declaration.

Bonnie Gasper, vice chair of the Child Protection League Action, told The Epoch Times in an interview that the declaration gives “a lot more weight,” to their arguement. “They’re calling for a halt to all this stuff, because obviously, the data is out there” on interventions like puberty blockers and cross-sex hormones, Ms. Gasper said.

https://www.zerohedge.com/political/hhs-sued-over-rule-requiring-health-care-providers-perform-gender-transition-procedures

Hezbollah Rains Down 160 Rockets On Northern Israel As War Expands

 The Israel-Hezbollah war continues spreading and expanding along the border region, as on Wednesday the Shia paramilitary group backed by Iran fired some 160 missiles into Israel after the IDF killed a top Hezbollah commander, Taleb Sami Abdullah, in south Lebanon the day prior.

According to details from a regional war correspondent, Hezbollah "fired missiles and rockets at two Israeli military bases in retaliation for the Israeli strike on a house about six miles from Israel's northern border, inside Lebanon, that killed Abdullah, 55, and three other Hezbollah officials who were meeting there."

The commander oversaw all of the group's military operations in the central area of the Lebanon-Israel border, Hezbollah later confirmed. He was so senior in the organization that he been active in fighting Israel even going back to the 1990s.

An Israeli military statement had confirmed his identity: "Israeli Airforce aircraft eliminated Sami Taleb Abdullah, the commander of the Nasr Unit in the Hezbollah terrorist organization, last night," the IDF announced Wednesday.

"This was part of a strike on a Hezbollah command and control center in the area of Jouaiyya in southern Lebanon, which was used to direct terrorist attacks against Israel from southeastern Lebanon in recent months."

The IDF and Israeli media pointed out, "Abdullah was one of Hezbollah's most senior commanders in southern Lebanon who planned, advanced, and carried out a large number of terrorist attacks against Israeli civilians."

Last week, Israeli Prime Minister Benjamin Netanyahu warned the military is preparing an "extremely powerful" response to the continuing onslaught of Hezbollah attacks, which days ago resulted in dozens of fires across northern Israel.

The past week has also witnessed Israel's war cabinet take part in active discussion over whether to mobilize reserve forces, and whether the northern front should be expanded and an official war declaration made.

Some 80,000 Israeli residents of the north have remained forcibly evacuated from their homes since Oct.7, given the constant threat of missiles and drones from Lebanon. This is putting further political pressure on the war cabinet to act.

https://www.zerohedge.com/geopolitical/hezbollah-rains-down-160-rockets-northern-israel-war-expanding

House Moves To Defund Ukrainian NGO That Issued 'Enemies List' After Rep. Jim Banks Takes Action

 Rep. Jim Banks (R-IN) has taken swift and decisive action against the Data Journalism Agency (texty.org.ua), a Ukrainian NGO with US State Department links that recently published an 'enemies list' of individuals and organizations opposed to the war in Ukraine.

Following a letter sent by Banks to his Republican colleagues, the House Appropriations Committee has passed a provision that would prohibit US funding and sever ties with the NGO, which deemed 76  organizations and 388 individuals as enemies of Ukraine - including ZeroHedge and prominent American politicians opposed to the war in Ukraine.

"Federal bureaucrats should not support or partner with foreign groups that attempt to intimidate and silence U.S. citizens and lawmakers," Banks wrote in his letter. "I am urging the Appropriations Committee majority to support efforts in the Fiscal Year 2025 SFOPS bill to force the State Department and USAID to end all relations with foreign NGOs like TEXTY that seek to silence the speech of Americans they dislike and to sway U.S. policymakers to serve their own interests."

Texty.org.ua was founded by Anatoly Bondarenko, a participant in the State Department's TechCamp program, which aims to train foreign journalists and activists in digital skills. The relationship between Bondarenko and the State Department has been publicly acknowledged, adding layers to the debate over the NGO's activities and its impact on U.S. interests.

This legislative action occurs amidst broader discussions about foreign influence in American politics, with increasing scrutiny on how foreign entities may use U.S.-linked platforms or resources to sway public and political opinion in the United States. As this bill moves forward, it sets the stage for further debates on the balance between global cooperation and safeguarding national sovereignty in the realm of information and policy.

On Tuesday, Banks sent a letter to journalist Jack Posobiec informing him that his name appears on the TEXTY list, and notifying him of his intent to put a stop to US taxpayers funding the organization.

"I’m not bothered by what foreign nations think of me," Banks said after the Appropriations Committee moved forward with his suggested provision. "But it’s shameful for our agencies to be using Hoosiers’ tax dollars to collaborate with foreign groups that attempt to intimidate U.S. citizens and lawmakers. I’d like to thank the Republicans on the Appropriations Committee for defunding any such work with the Data Journalism Agency."

https://www.zerohedge.com/political/house-moves-defund-ukrainian-ngo-issued-enemies-list-after-rep-jim-banks-takes-action

Bank of Mexico says it could act to restore 'order' in markets

 The Bank of Mexico is monitoring recent volatility in domestic financial markets, including foreign exchange markets, and could act to restore order in the event of "atypical" or "extreme" behavior, the bank's governor Victoria Rodriguez said on Wednesday.

Mexico's central bank "will be very attentive to the development of our markets, and if they show atypical behavior or extreme volatility, and if warranted, it could take the necessary measures to restore their orderly behavior," Rodriguez said during a presentation of the bank's biannual financial stability report.

Banxico, as the Mexican central bank is known, could act on its own or with Mexico's foreign exchange commission, comprised of officials from the finance ministry and the Banxico board members, Rodriguez said.

Mexico's peso, one of the world's best performing emerging market currencies in recent years, has weakened over 10% since the Morena ruling party coalition dominated the June 2 general elections, emboldening politicians to pursue controversial reforms to the constitution. That has shaken investor confidence.

"It is normal for financial markets to present adjustments by incorporating scenarios that had not been anticipated, as is happening in the recent episode," Rodriguez said of the peso's sharp depreciation.

Rodriguez underscored that Banxico does not have a fixed goal for the exchange rate, like it does for the inflation rate, but that the board is monitoring the peso's impact on inflation and that it could be some time before the exchange rate volatility reflects on inflation.

Wednesday's report found that the Mexican financial system is solid and resilient, with the banking system showing resilience in stress tests probing its solvency and liquidity.

While market volatility is one of four main risks to Mexico's macro-financial stability, according to the report, directors on Wednesday urged calm amid the turbulence of recent days.

"Mexico's solid economic fundamentals that led to the good performance of our markets prior to the aforementioned episode remain in force," Rodriguez said.

Mexico's President-elect Claudia Sheinbaum has sought to reassure nervous investors after her landslide victory this month, in which Morena secured a super-majority required to pass the constitutional reforms unopposed in the lower house of Congress, while coming just shy of the super-majority in the Senate.

https://finance.yahoo.com/news/bank-mexico-says-could-act-215150181.html

The Tyranny of Beta-Blockers

 Beta-blockers are excellent drugs. They're cheap and effective; feature prominently in hypertension guidelines; and remain a sine que non for coronary artery disease, myocardial infarction, and heart failure treatment. They've been around forever, and we know they work. Good luck finding an adult medicine patient who isn't on one.

Beta-blockers act by slowing resting heart rate (and blunting the heart rate response to exercise. The latter is a pernicious cause of activity intolerance that often goes unchecked. Even when the adverse effects of beta-blockers are appreciated, providers are loath to alter dosing, much less stop the drug. After all, beta-blockers are an integral part of guideline-directed medical therapy (GDMT), and GDMT saves lives.

Balancing Heart Rate and Stroke Volume Effects

The pulmonologist sees beta-blockers differently. To augment cardiac output and optimize oxygen uptake (VO₂) during exercise, we need the heart rate response. In fact, the heart rate response contributes more to cardiac output than augmenting stroke volume (SV) and more to VO₂ than the increase in arteriovenous (AV) oxygen difference. An inability to increase the heart rate commensurate with physiologic work is called chronotropic incompetence (CI). That's what beta-blockers do ─ they cause CI.

Physiology dictates that CI will cause activity intolerance. That said, it's hard to quantify the impact from beta-blockers at the individual patient level. Data suggest the heart rate effect is profound. A study in patients without heart failure found that 22% of participants on beta-blockers had CI, and the investigators used a conservative CI definition (≤ 62% of heart rate reserve used). A recent report published in JAMA Cardiology found that stopping beta-blockers in patients with heart failure allowed for an extra 30 beats/min at max exercise. 

Wasserman and Whipp's textbook, the last word on all things exercise, presents a sample subject who undergoes two separate cardiopulmonary exercise tests (CPETs). Before the first, he's given a placebo, and before the second, he gets an intravenous beta-blocker. He's a 23-year-old otherwise healthy male — the perfect test case for isolating beta-blocker impact without confounding by comorbid diseases, other medications, or deconditioning. His max heart rate dropped by 30 beats/min after the beta-blocker, identical to what we saw in the JAMA Cardiology study (with the heart rate increasing by 30 beats/min following withdrawal). Case closed. Stop the beta-blockers on your patients so they can meet their exercise goals and get healthy!

Such pithy enthusiasm discounts physiology's complexities. When blunting our patient's heart rate response with beta-blockers, we also increase diastolic filling time, which increases SV. For the 23-year-old in Wasserman and Whipp's physiology textbook, the beta-blocker increased O₂ pulse (the product of SV and AV difference). Presumably, this is mediated by the increased SV. There was a net reduction in VO₂ peak, but it was nominal, suggesting that the drop in heart rate was largely offset by the increase in O₂ pulse. For the patients in the JAMA Cardiology study, the entire group had a small increase in VO₂ peak with beta-blocker withdrawal, but the effect differed by left ventricular function. Across different studies, the beta-blocker effect on heart rate is consistent but the change in overall exercise capacity is not. 

Patient Variability in Beta-Blocker Response

In addition to left ventricular function, there are other factors likely to drive variability at the patient level. We've treated the response to beta-blockers as a class effect — an obvious oversimplification. The impact on exercise and the heart will vary by dose and drug (eg, atenolol vs metoprolol vs carvedilol, and so on). Beta-blockers can also affect the lungs, and we're still debating how cautious to be in the presence of asthma or chronic obstructive pulmonary disease. 

In a world of infinite time, resources, and expertise, we'd CPET everyone before and after beta-blocker use. Our current reality requires the unthinkable: We'll have to talk to each other and our patients. For example, heart failure guidelines recommend titrating drugs to match the dose from trials that proved efficacy. These doses are quite high. Simple discussion with the cardiologist and the patient may allow for an adjustment back down with careful monitoring and close attention to activity tolerance. With any luck, you'll preserve the benefits from GDMT while optimizing your patient's ability to meet their exercise goals.

Aaron B. Holley, MD, is a professor of medicine at Uniformed Services University in Bethesda, Maryland, and a pulmonary/sleep and critical care medicine physician at MedStar Washington Hospital Center in Washington, DC. He covers a wide range of topics in pulmonary, critical care, and sleep medicine. 

https://www.medscape.com/viewarticle/tyranny-beta-blockers-2024a1000apc

Continuous Glucose Monitors Should Not Be Normalized

 Hello. I am Boris Hansel, a diabetologist and nutritionist at Bichat Hospital in Paris. Should we now recommend continuous glucose monitoring to all our patients, even those without diabetes? Most of us would instinctively say "no" to this question, but we are seeing opinions from doctors recommending it, and in recent years, scientific literature has focused on the subject. 

Today, anyone can get an arm patch that continuously measures interstitial glucose, which is closely related to blood sugar. The information can be read on a dedicated reader or on a mobile phone by scanning the patch or, with some models, without even doing anything.

There is a consensus for prescribing continuous glucose monitoring for patients with type 1or type 2 diabetes who are treated with at least three insulin injections. Not only is the use of continuous glucose monitoring much more comfortable than self-monitoring with finger sticks, but continuous monitoring also helps reduce glycosylated hemoglobin while decreasing the risk for hypoglycemia. Recently, another indication has begun to be reimbursed in France: type 2 diabetes under mono-insulin injection when the diabetes is not well controlled.

But alongside these situations, there are two questions that are worth considering.

Untreated Type 2 Diabetes 

First, is continuous glucose monitoring desirable for all patients with diabetes, even those not treated with insulin and even when blood sugar levels are well managed? Intuitively, one might think that it can't hurt and that continuous monitoring of blood sugar can only improve things. We have some evidence supporting this idea, but the level of proof is quite weak. It is not clear that continuous monitoring can improve patients' awareness of the impact of dietary choices or physical activity on blood sugar. Obviously, one can imagine that continuously monitoring glucose will encourage a shift toward more beneficial behaviors. But honestly, today, we do not have proof that wearing a continuous glucose monitor can improve behaviors in patients with type 2 diabetes who are treated with noninsulin antidiabetic medications.

Furthermore, a significant study has shown that while the effectiveness is more evident in patients treated with insulin, strong evidence suggests that continuous glucose monitoring could also reduce glycosylated hemoglobin in patients with type 2 diabetes who are not treated with insulin. A close examination of the results suggests that the benefits generally are less than those observed in insulin-treated patients with diabetes.

When we look at the scientific literature, two factors seem particularly important to consider if choosing to prescribe a continuous glucose monitoring sensor. The first is the method used, because the results can vary depending on the method. It appears that only self-monitoring that allows the patient to follow glucose in real time is effective, unlike blind monitoring that allows only a retrospective analysis of blood sugar levels. In the latter case, the patient wears the sensor, and after a week, 10 days, or 15 days, the results are analyzed, possibly with a healthcare provider. It seems that this is not very effective in improving glycosylated hemoglobin and dietary and physical activity behavior.

The second essential factor to consider is the need for an education program for the use of these sensors to be helpful. If sensors are used but nothing else is done, it does not seem logical. Seeing blood sugar levels without being able to understand them and act accordingly seems of little use. Scientific literature seems to confirm this idea. 

Patients Without Diabetes 

Now there is another question. We have discussed patients with type 2 diabetes without insulin. It’s trendy to talk about the potential benefits of continuous glucose monitors in patients without diabetes. The idea is emerging that these monitors could be used to refine the diagnosis of diabetes or to better predict the onset of diabetes in the subsequent years.

Others claim that continuous glucose monitors are an effective way to induce a change in dietary and physical activity behaviors in patients with prediabetes. One can, for example, tell a patient, "You are at risk of developing diabetes, so by monitoring your glucose, you will change your behavior." Honestly, the scientific data we have today do not support these ideas, and I sincerely believe that it is not advisable today to recommend, as some would like, the mass use of monitors, whether in patients with overweight or obesity, or whether in patients with prediabetes. This goes for suggestions for using the monitor for 7-10 days per year, in the form of a session to try to reduce the risk for diabetes by motivating patients to change their behavior. We have no evidence at all that this can work. And in my opinion, with this kind of discourse, we ultimately risk, as usual, encouraging patients who are already "fans" of self-checks and self-monitoring to get health data, even if they do not know how to interpret it. Maybe even the doctor they ask for interpretation will not be trained to interpret the results of these monitors.

Spreading the idea that monitors are useful for preventing diabetes has a side effect: It hinders progress on the essential issue. Today, one of the problems in diabetes and prediabetes is that screening is not done often enough, and 20% of patients with diabetes are still unaware of their diagnosis. The management of early diabetes or prediabetes, in my opinion, is not optimal in routine care today. So, I think that adding the idea that using monitors could be beneficial dilutes the main information.

Having said that, I sometimes offer continuous glucose monitoring to some of my patients on a case-by-case basis. I believe that with proper support and an educational program, it can be beneficial for certain patients.

In Practice

In summary, I am totally opposed to the normalization of the use of monitors. I think it is our role as healthcare professionals to warn the public that even if it is accessible — anyone can buy a reader, a sensor — it is not necessarily beneficial, and it may even distract us from what is essential. But as a specialist, I think that using a monitor within a genuine care plan seems reasonable. Ultimately, it's just personalized medicine.

https://www.medscape.com/viewarticle/continuous-glucose-monitors-should-not-be-normalized-2024a1000avm