Soros To End 'Most EU Operations' In 'Radical Shift'

 George Sorors' Open Society Foundations, which are now controlled by his son Alexander, will cease most of its operations in the European Union.

The move, which comes after foundation-funded NGOs ferried migrants to Europe for over a decade (mission accomplished?), comes after the $25 billion family foundation announced a headcount reduction of at least 40% following Alexander's ascent.

Citing a "radical shift of strategic direction," OSF says that their new operating model will require "significant further restructuring," and "closing all regional and global programs," according to a letter sent to grantees in Hungary which was seen by Bloomberg.

"Ultimately, the new approved strategic direction provides for withdrawal and termination of large parts of our current work within the European Union, shifting our focus and allocation of resources to other parts of the world," reads the message, which cites another note sent to staff at OSF's Berlin headquarters.

"OSF will largely terminate funding within the European Union, and further funding will be extremely limited," it reads, without elaborating, except to say that the organization is pivoting because "EU institutions and governments were already allocating significant resources to human rights, freedom and pluralism" inside the bloc.

And of course, Bloomberg sings OSF's praises:

In the EU, OSF financed a wide range of philanthropic programs in the bloc’s eastern former communist members, including Hungary, Poland, Slovakia, Romania, the Czech Republic, Bulgaria and elsewhere. They included initiatives aimed at strengthening democracy, promoting human rights and alleviating the poverty and discrimination faced by the Roma minority.

It also funds projects in non-EU European countries such as in the Balkans and further afield in central Asia.

The organization based its European headquarters in Budapest until 2018, when it moved to Berlin following a years-long campaign against Soros and the OSF’s liberal values by nationalist Prime Minister Viktor Orban’s government in Hungary. It also has offices in Barcelona, Brussels and Belgium. -Bloomberg

Over the past three decades, OSF has spent over $19 billion on various projects, including $209 million in 2021 towards projects in Europe and the central Asia region. 

https://www.zerohedge.com/geopolitical/soros-end-most-eu-operations-radical-shift

First-Line Therapy in T2D: Has Metformin Been 'Dethroned'?

 Initially approved by the US Food and Drug Administration (FDA) in 1994, metformin has been the preferred first-line glucose-lowering agent for patients with type 2 diabetes (T2D) owing to its effectiveness, low hypoglycemia risk, weight neutrality, long clinical track record of safety, and affordability. However, the advent of newer glucose-lowering agents with evidence-based cardiovascular (CV) and renal benefits calls into question whether metformin should continue to be the initial pharmacotherapy for all patients with T2D. To help determine whether metformin has been "dethroned" as first-line treatment for T2D, here is a brief review of recent evidence and current guideline recommendations.

Cardiovascular Outcome Trials Transform Standard of Care

In 2008, the FDA issued guidance to industry to ensure that CV risk is more thoroughly addressed during development of T2D therapies. This guidance document required dedicated trials to establish CV safety of new glucose-lowering therapies. Findings from subsequent cardiovascular outcome trials (CVOTs) and subsequent large renal and heart failure (HF) outcome trials have since prompted frequent and substantial updates to major guidelines. On the basis of recent evidence from CVOT and renal trials, contemporary clinical practice guidelines have transitioned from a traditional glucocentric treatment approach to a holistic management approach that emphasizes organ protection through heart-kidney-metabolic risk reduction.

Per the 2008 FDA guidance, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagonlike peptide-1 (GLP-1) receptor agonists, and sodium-glucose cotransporter-2 (SGLT2) inhibitors, were evaluated in large dedicated CVOTs. Findings from several CVOTs established GLP-1 receptor agonist and SGLT2 inhibitor CV safety, and unexpectedly demonstrated reduced rates of major adverse cardiovascular events (MACE) relative to placebo. The LEADER and EMPA-REG OUTCOME trials were the first CVOTs to report cardioprotective benefits of the GLP-1 receptor agonist liraglutide and the SGLT2 inhibitor empagliflozin, respectively. The LEADER trial reported a 13% significant relative risk reduction for its primary composite MACE outcome, and the EMPA-REG OUTCOME trial similarly reported a 14% relative risk reduction for MACE. After CVOTs on other GLP-1 receptor agonists and SGLT2 inhibitors reported CV benefit, clinical practice guidelines began to recommend use of these agents in at-risk patients to mitigate CV risk.

During the period when most CVOTs were designed and conducted, a majority of trial participants were receiving metformin at baseline. Inclusion of a small subset of metformin-naive participants in these trials allowed for several post hoc– and meta-analyses investigating the impact of background metformin use on the overall CV benefits reported. Depending on the trial, baseline metformin use in large GLP-1 receptor agonist CVOTs ranged from 66% to 81%. For instance, 76% of participants in the LEADER trial were receiving metformin at baseline, but a post hoc analysis found no heterogeneity for the observed CV benefit based on background metformin use. Similarly, a subgroup analysis of pooled data from the SUSTAIN-6 and PIONEER 6 trials of injectable and oral formulations of semaglutide, respectively, reported similar CV outcomes for participants, regardless of concomitant metformin use. When looking at the GLP-1 receptor agonist class overall, a meta-analysis of seven CVOTs, which included participants with established atherosclerotic cardiovascular disease (ASCVD) and those with multiple ASCVD risk factors, concluded that GLP-1 receptor agonist therapy reduced the overall incidence of MACE in participants not receiving concomitant metformin at baseline.

Similar analyses have examined the impact of background metformin use on CV outcomes with SGLT2 inhibitors. An analysis of EMPA-REG OUTCOME found that empagliflozin improved CV outcomes and reduced mortality irrespective of background metformin, sulfonylurea, or insulin use. Of note, this analysis suggested a greater risk reduction for incident or worsening nephropathy in patients not on concomitant metformin (hazard ratio [HR], 0.47; 95% CI, 0.37-0.59; P = .01) when compared with those taking metformin at baseline (HR, 0.68; 95% CI, 0.58-0.79; P = .01). In addition, a meta-analysis of six large outcome trials found consistent benefits of SGLT2 inhibition on CV, kidney, and mortality outcomes regardless of background metformin treatment. Therefore, although CVOTs on GLP-1 receptor agonists and SGLT2 inhibitors were not designed to assess the impact of background metformin use on CV outcomes, available evidence supports the CV benefits of these agents independent of metformin use.

Individualizing Care to Attain Cardiorenal-Metabolic Goals

Three dedicated SGLT2 inhibitor renal outcome trials have been published to date: CREDENCE, DAPA-CKD, and EMPA-KIDNEY. All three studies confirmed the positive secondary renal outcomes observed in SGLT2 inhibitor CVOTs: reduced progression of kidney disease, HF-associated hospital admissions, and CV-related death. The observed renal and CV benefits from the CREDENCE trial were consistent across different levels of kidney function. Similarly, a meta-analysis of five SGLT2 inhibitor trials of patients with HF demonstrated a decreased risk for CV-related death and admission for HF, irrespective of baseline heart function. The ongoing FLOW is the first dedicated kidney-outcome trial to evaluate the effectiveness of a GLP-1 receptor agonist (semaglutide) in slowing the progression and worsening of chronic kidney disease (CKD) in patients with T2D.

As previously noted, findings from the LEADER and EMPA-REG OUTCOME trials demonstrated the beneficial effects of GLP-1 receptor agonists and SGLT2 inhibitors not only on MACE but also on secondary HF and kidney disease outcomes. These findings have supported a series of dedicated HF and kidney outcome trials further informing the standard of care for patients with these key comorbidities. Indeed, the American Diabetes Association's (ADA) 2023 Standards of Care in Diabetes updated its recommendations and algorithm for the use of glucose-lowering medications in the management of T2D. The current ADA recommendations stress cardiorenal risk reduction while concurrently achieving and maintaining glycemic and weight management goals. On the basis of evolving outcome trial data, GLP-1 receptor agonists and SGLT2 inhibitors with evidence of benefit are recommended for patients with established or at high risk for ASCVD. Further, the Standards preferentially recommend SGLT2 inhibitors for patients with HF and/or CKD. Because evidence suggests no heterogeneity of benefit based on A1c for MACE outcomes with GLP-1 receptor agonists and no heterogeneity of benefit for HF or CKD benefits with SGLT2 inhibitors, these agents are recommended for cardiorenal risk reduction regardless of the need to lower glucose.

The 2023 update to the American Association of Clinical Endocrinology (AACE) Consensus Statement: Type 2 Diabetes Management Algorithm similarly recommends the use of GLP-1 receptor agonists and SGLT2 inhibitors to improve cardiorenal outcomes. To further emphasize the importance of prescribing agents with proven organ-protective benefits, the AACE consensus statement provides a complications-centric algorithm to guide therapeutic decisions for risk reduction in patients with key comorbidities (eg, ASCVD, HF, CKD) and a separate glucocentric algorithm to guide selection and intensification of glucose-lowering agents in patients without key comorbidities to meet individualized glycemic targets. Within the complications-centric algorithm, AACE recommends GLP-1 receptor agonists and SGLT2 inhibitors as first-line treatment for cardiorenal risk reduction regardless of background metformin use or A1c level.

In addition to the emphasis on the use of GLP-1 receptor agonists and SGLT2 inhibitors for organ protection, guidelines now recommend SGLT2 inhibitors as the standard-of-care therapy in patients with T2D and CKD with an estimated glomerular filtration rate ≥ 20 mL/min/1.73 m², and irrespective of ejection fraction or a diagnosis of diabetes in the setting of HF. Overall, a common thread within current guidelines is the importance of individualized therapy based on patient- and medication-specific factors.

Optimizing Guideline-Directed Medical Therapy

Results from the DISCOVER trial found that GLP-1 receptor agonist and SGLT2 inhibitor use was less likely in the key patient subgroups most likely to benefit from therapy, including patients with peripheral artery disease and CKD. Factors contributing to underutilization of newer cardiorenal protective glucose-lowering therapies range from cost and access barriers to clinician-level barriers (eg, lack of knowledge on CKD, lack of familiarity with CKD practice guidelines). Addressing these issues and helping patients work through financial and other access barriers is essential to optimize the utilization of these therapies and improve cardiorenal and metabolic outcomes.

So, has metformin been "dethroned" as a first-line therapy for T2D? As is often the case in medicine, the answer depends on the individual patient and clinical situation. Metformin remains an important first-line treatment in combination with lifestyle interventions to help patients with T2D without key cardiorenal comorbidities achieve individualized glycemic targets. However, based on evidence demonstrating cardiorenal protective benefits and improved glycemia and weight loss, GLP-1 agonists and SGLT2 inhibitors may be considered as first-line treatment for patients with T2D with or at high risk for ASCVD, HF, or CKD, regardless of the need for additional glucose-lowering agents and independent of background metformin. Ultimately, the choice of first-line therapy for patients with T2D should be informed by individualized treatment goals, preferences, and cost-related access. Continued efforts to increase patient access to GLP-1 receptor agonists and SGLT2 inhibitors as first-line treatment when indicated are essential to ensure optimal treatment and outcomes.

https://www.medscape.com/viewarticle/995230

'Fewer People Are Reporting They Have Long COVID'

 The rate of people experiencing long COVID appears to be stabilizing at about 1 in 10 adults who have ever been infected with the virus, new government tracking data shows. 

When taking into account people who've never had COVID-19, an estimated 6% of the U.S. adult population had long COVID as of June 2023, down from 7.5% in June 2022. That's according to a new CDC report analyzing data from the monthly online Household Pulse Survey. The survey tracks pandemic related health data, including mental health indicators and insurance coverage.

Among people who have ever had COVID, the percentage of people reporting they have long COVID has fallen from 19% last summer to around 11% in January and that rate has held steady throughout 2023. The report authors said the reason for the stabilization could be a combination of factors, including fewer people being infected, less severe infections, better treatments such as antivirals, and protection by vaccines.

As part of the survey, people are asked if they've had symptoms lasting at least 3 months that they didn't have prior to COVID-19 infection. Symptoms could include tiredness or fatigue, difficulty thinking or concentrating, memory problems, difficulty breathing, joint or muscle pain, fast heartbeat, chest pain, dizziness on standing, menstrual changes, changes to taste or smell, or inability to exercise.

More than 1 in 4 people who have long COVID said in the survey that the condition significantly limits their ability to carry out day-to-day activities, compared to the time before they had COVID-19. The rate of people reporting significant limitations has remained steady over time, the authors wrote.

Last month, the federal government announced the formation of the Office of Long COVID Research and Practice to head up the government's response to aiding the estimated 7.7 million to 23 million people in the U.S. who have long COVID. The cornerstone of the office's work is coordinating a $1.15 billion research program, which includes clinical trials, called the RECOVER Initiative.

Sources

CDC: "Long COVID and Significant Activity Limitation Among Adults, by Age — United States, June 1–13, 2022, to June 7–19, 2023."

National Center for Health Statistics: "Household Pulse Survey."

DHHS: "HHS Announces the Formation of the Office of Long COVID Research and Practice and Launch of Long COVID Clinical Trials Through the RECOVER Initiative."

https://www.medscape.com/s/viewarticle/995437

Better Than Dialysis? Artificial Kidney Could Be the Future

 Nearly 90,000 patients in the United States are waiting for a lifesaving kidney transplant, yet only about 25,000 kidney transplants were performed last year. Thousands die each year while they wait. Others are not suitable transplant candidates.

Half a million people are on dialysis, the only transplant alternative for those with kidney failure. This greatly impacts their work, relationships, and quality of life.

Researchers from The Kidney Project hope to solve this public health crisis with a futuristic approach: an implantable bioartificial kidney. That hope is slowly approaching reality. Early prototypes have been tested successfully in preclinical research and clinical trials could lie ahead.

Medscape Medical News spoke with two researchers who came up with the idea: nephrologist William Fissell, MD, of Vanderbilt University in Nashville, and Shuvo Roy, PhD, a biomedical engineer at the University of California at San Francisco. This interview has been edited for length and clarity.

Medscape: Could you summarize the clinical problem with chronic kidney disease?

William Fissell: Dialysis treatment, although lifesaving, is incomplete. Healthy kidneys do a variety of things that dialysis cannot provide. Transplant is absolutely the best remedy, but donor organs are vanishingly scarce. Our goal has been to develop a mass-produced, universal donor kidney to render the issue of scarcity — scarcity of time, scarcity of resources, scarcity of money, scarcity of donor organs — irrelevant.

Do you envision your implantable, bioartificial kidney as a bridge to transplantation? Or can it be even more, like a bionic organ, as good as a natural organ and thus better than a transplant?

Shuvo Roy: We see it initially as a bridge to transplantation, or as a better option than dialysis for those who will never get a transplant. We're not trying to create the 'six million dollar man.' The goal is to keep patients off dialysis — to deliver some, but probably not all, of the benefits of a kidney transplant in a mass-produced device that anybody can receive.

Fissell: The technology is aimed at people in stage 5 renal disease, the final stage, when kidneys are failing, and dialysis is the only option to maintain life. We want to make dialysis a thing of the past, put dialysis machines in museums like the iron lung, which was so vital to keeping people alive several decades ago but is mostly obsolete today.

How did you two come up with this idea? How did you get started working together?

Roy: I had just begun my career as a research biomedical engineer when I met Dr William Fissell, who was then contemplating a career in nephrology. He opened my eyes to the problems faced by patients affected by kidney failure. Through our discussions, we quickly realized that while we could improve dialysis machines, patients needed and deserved something better — a treatment that improves their health while also allowing them to keep a job, travel readily, and consume food and drink without restrictions. Basically, something that works more like a kidney transplant.

How does the artificial kidney differ from dialysis?

Fissell: Dialysis is an intermittent stop-and-start treatment. The artificial kidney is continuous, around-the-clock treatment. There are a couple of advantages to that. The first is that you can maintain your body's fluid balance. In dialysis, you get rid of 2-3 days' worth of fluid in a couple of hours, and that's very stressful to the heart and maybe to the brain as well. Second advantage is that patients will be able to eat a normal diet. Some waste products that are byproducts of our nutritional intake are slow to leave the body. So in dialysis, we restrict the diet severely and add medicines to soak up extra phosphorus. With a continuous treatment, you can balance excretion and intake.

The other aspect is that dialysis requires an immense amount of disposables. Hundreds of liters of water per patient per treatment, hundreds of thousands of dialysis cartridges and IV bags every year. The artificial kidney doesn't need a water supply, disposable sorbent, or cartridges.

How does the artificial kidney work?

Fissell: Just like a healthy kidney. We have a unit that filters the blood so that red blood cells, white blood cells, platelets, antibodies, albumin — all the good stuff that your body worked hard to synthesize — stays in the blood, but a watery soup of toxins and waste is separated out. In a second unit, called the bioreactor, kidney cells concentrate those wastes and toxins into urine.

Roy: We used a technology called silicon micro-machining to invent an entirely new membrane that mimics a healthy kidney's filters. It filters the blood just using the patient's heart as a pump. No electric motors, no batteries, no wires. This lets us have something that's completely implanted.

We also developed a cell culture of kidney cells that function in an artificial kidney. Normally, cells in a dish don't fully adopt the features of a cell in the body. We looked at the literature around 3-D printing of organs. We learned that, in addition to fluid flow, stiff scaffolds, like cell culture dishes, trigger specific signals that keep the cells from functioning. We overcame that by looking at the physical microenvironment of the cells —  not the hormones and proteins, but instead the fundamentals of the laboratory environment. For example, most organs are soft, yet plastic lab dishes are hard. By using tools that replicated the softness and fluid flow of a healthy kidney, remarkably, these cells functioned better than on a plastic dish.

Would patients need immunosuppressive or anticoagulation medication?

Fissell: They wouldn't need either. The structure and chemistry of the device prevents blood from clotting. And the membranes in the device are a physical barrier between the host immune system and the donor cells, so the body won't reject the device.

What is the state of the technology now?

Fissell: We have shown the function of the filters and the function of the cells, both separately and together, in preclinical in vivo testing. What we now need to do is construct clinical-grade devices and complete sterility and biocompatibility testing to initiate a human trial. That's going to take between $12 million and $15 million in device manufacturing.

So it's more a matter of money than time until the first clinical trials?

Roy: Yes, exactly. We don't like to say that a clinical trial will start by such-and-such year. From the very start of the project, we have been resource limited.

Sources:

William Fissell, MD, nephrologist, Vanderbilt University

Shuvo Roy, PhD, biomedical engineer, University of California at San Francisco

https://www.medscape.com/viewarticle/995477

Jasper started at Overweight by CapitalOne

 Target $7

https://finviz.com/quote.ashx?t=JSPR&ty=c&ta=1&p=d

U.S. bank stocks drop after Fitch downgrade warning

 Shares of U.S. banks dropped in premarket trading after a Fitch Ratings analyst told CNBC that the agency could downgrade several lenders, while a proposed rule change by a top banking regulator added to investor worries.

Big banks JPMorgan Chase, Wells Fargo and Bank of America fell between 1.5% and 1.6%.

Among the mid-sized lenders, Western Alliance Bancorp , Zions Bancorp and PacWest Bancorp fell between 2% and 5%.

https://www.marketscreener.com/quote/stock/BANK-OF-AMERICA-CORPORATI-11751/news/U-S-bank-stocks-drop-after-Fitch-downgrade-warning-44618765/

UAW workers may vote on strike at Detroit Three automakers next week

 Union members are planning to vote on a strike at Detroit Three automakers next week, the United Auto Workers (UAW) said on Tuesday, as it pushes the companies to reach new contract terms by Sept. 14 deadline.

The UAW's warning comes as the two sides have made little headway with their negotiations. U.S. President Joe Biden has already called on the automakers and union members to reach a new agreement before the contracts expire next month.

"Whether or not there's a strike next month is entirely up to the Big Three automakers," UAW president Shawn Fain said in a statement.

Fain will address the pace of negotiations and announce preparations for strike authorization votes to be held next week by 150,000 UAW members at Ford, General Motors and Stellantis on Facebook Live later in the day, the union said.

The announcement comes after workers at aerospace supplier Spirit AeroSystems rejected a contract that their leaders negotiated with their employer, joining freight railroad employees, airline pilots and others who are growing more fed up with stagnant pay, high healthcare costs, scanty sick time and uncertain scheduling.

https://www.marketscreener.com/quote/stock/GENERAL-MOTORS-COMPANY-6873535/news/UAW-workers-may-vote-on-strike-at-Detroit-Three-automakers-next-week-44620324/