CDC study seeks to provide clues to seeming surge of hepatitis cases in kids

 When previously healthy little kids started showing up in hospitals with failing livers last fall and this spring, startled doctors and public health authorities didn’t know what was behind what they were seeing. They also didn’t know if what they were seeing was new.

There have always been cases of hepatitis in children for which a cause cannot be found — such cases are labeled pediatric hepatitis of unknown etiology. But these cases occur in very low numbers and they aren’t well-studied or tracked. So when doctors in Alabama and Scotland reported seeing more of these cases over a few weeks then they would normally see in a year, they didn’t have reliable statistics against which to compare the seeming surge.

Now scientists at the Centers for Disease Control and Prevention have come up with some estimates for the normal rate of this condition, at least in the United States. Their findings, published earlier this week in the online journal Morbidity and Mortality Weekly Report, may come as a surprise.

Their research suggests there has not been an increase in cases of pediatric hepatitis of unknown origin, at least in the United States. Nor has there been a rise in the number of pediatric liver transplants, which a portion of these children have needed. Likewise, the rate of detections of infections caused by adenovirus 41 — a stomach bug virus that has been implicated as a potential trigger of these hepatitis cases — has not changed over time, the CDC scientists reported.

(They note that authorities in the United Kingdom believe they may have seen a small increase in pediatric hepatitis cases, but the report they point to says the lack of pre-pandemic data there makes it hard to be certain.)

The CDC findings don’t identify what is causing the cases of pediatric hepatitis of unknown origin, 290 of which are under investigation in this country. Elsewhere, about three dozen countries have detected cases since the United Kingdom raised the alarm in early April. As of June 6, the World Health Organization had been notified of over 800 probable and suspected cases.

But the CDC findings may help to rule some things out. With rates unchanged since before the Covid-19 pandemic, a theory espoused by scientists from Israel — that this is some sort of post-Covid condition — becomes harder to argue.

“It doesn’t mean that Covid still can’t have some collateral role with all of this. But I think these kind of data helps support that that’s probably not the cause,” explained veteran epidemiologist Michael Osterholm, who was not involved in the CDC work.

The CDC researchers drew data from four different sources looking at emergency department visits and hospitalizations for hepatitis of unknown etiology in kids under age 11, from January 2018 to March 2022 for the former and January 2019 and March 2022 for the latter.

They also compared monthly liver transplant figures for children under the age of 18 for whom the diagnosis was hepatic necrosis — liver failure — of unknown etiology from October 2017 through March 2022. Finally, they studied lab data on stool samples tested for adenovirus 40 or 41 during the period from October 2017 to March 2022 from Labcorp, a large commercial laboratory network.

There were no statistically significant increases in hospitalizations for hepatitis of unknown origin in the period after the start of the Covid-19 pandemic; nor was there a statistically significant increase in the number of liver transplants per month, the researchers found. The number of positive adenovirus stool tests varied — within a range — before the pandemic and it did after the pandemic as well. But the positivity rate from last October, when the Alabama cases were detected through March, when Scotland started to report cases, did not exceed pre-pandemic rates.

“The cases that we’re currently describing, at least the trends, do not seem to be different to what we described prior to the pandemic,” senior author Jacqueline Tate, lead of the epidemiology team in CDC’s viral gastroenterology branch, told STAT in an interview.

“I think that does point out that with all the changes that we’ve undergone with the pandemic … that does not seem to have had the same impact on the trends in hepatitis, if it was a driving factor.”

The work was done to establish baseline rates, she said.

“We’re trying to look at what the landscape is. Is there something that’s dramatically changed? We don’t think so. But I think in looking at this and just realizing that we have improved diagnostics, improved accessibility to information, we may be able to explain better what’s going on with this hepatitis,” Tate said.

The fact that baseline rates haven’t changed doesn’t mean there’s nothing going on with pediatric hepatitis of unknown etiology, said Osterholm, director of the University of Minnesota’s Center for Infectious Diseases Research and Policy. Rather, a couple of clusters of cases — in Alabama and in Scotland — may be giving the scientific community an opportunity to figure out what has been responsible for some of the cases all along.

In disease detective work, having baseline data is crucial to differentiate something new from something newly recognized, said Jeffrey Duchin, health officer for the Seattle and King County public health department and an infectious diseases professor at the University of Washington.

The seeming increase in cases could be “enhanced ascertainment” — increased detection, he said, adding that the CDC analysis is reassuring, suggesting we’re not seeing a major increase in pediatric hepatitis.

When medical events happen at very low levels — an unexplained case here, another there — it can be very tough to get to the bottom of what is going on, said Osterholm, who has been involved in cracking a number of public health mysteries.

But sooner or later, by fluke, there will be a cluster of cases. And if the cluster is spotted and the clinicians involved work it up thoroughly and report their findings, as both groups did, other physicians will start looking and realizing that they too saw cases that fit that definition, he said.

“It’s not unusual at all to see new conditions where somebody gets a case series of five or six cases, somebody else will look carefully and get a case series of five or six and pretty soon those five and six and five and six grow to 700,” Osterholm said.

“With really comprehensive information, like the CDC just presented here … the bottom line is this very well could have been going on for some time before Covid ever occurred at this low level,” he said.

The current attention to pediatric hepatitis may help to move some of these cases out of the “unknown etiology” column. But it will take more and different types of studies to identify what is causing them. Tate said the CDC currently has such a study underway. So does the U.K. Health Security Agency, which has repeatedly said that adenovirus infection — possibly in combination with some other factor — appears to be linked to these cases.

https://www.statnews.com/2022/06/17/a-cdc-study-seeks-to-provide-clues-to-seeming-surge-of-hepatitis-cases-in-kids/

Gottlieb predicts slow start for kids’ vaccines

 Former U.S. Food and Drug Administration (FDA) Commissioner Scott Gottlieb said on Sunday that he anticipates a slow rollout for COVID-19 vaccines for children under age 5. 

“I think it’s going to be a little bit more of a slow rollout relative to what we’ve seen in past rollouts with the other age groups,” Gottlieb said of vaccinating the youngest Americans during an interview on CBS’s “Face the Nation.” 

Gottlieb specifically pointed to some of the differences in distribution, as some children under age 3 cannot be vaccinated at mass distribution sites.

“There are going to be pharmacies that are vaccinating children. CVS is going to move it into their pharmacies, but they’re only moving in to the pharmacies with advanced care providers with their MinuteClinics,” he explained

“Maybe around children’s hospitals, you’ll see some clinics stood up, but most people are probably going to get vaccinated in their pediatricians’ offices, and it’s going to take a little bit more time to get the vaccine into those local settings because it’s more difficult to vaccinate a child who is very young,” Gottlieb continued.

“You need people who are specially trained to do that, and so you want the settings to be appropriate,” he added.

The former FDA commissioner also cited surveys that indicated that roughly 20 percent of parents with children under 5 planned to vaccinate their children but said he anticipated a possibly lower rate.

“As prevalence declines going into the summer, a lot of parents may choose to take a wait-and-see attitude and reconsider this in the fall. I think uptick will be pretty slow,” he explained.

His remarks come after Centers for Disease Control and Prevention Director Rochelle Walensky on Saturday endorsed an advisory committee’s recommendation to permit children under the age 5 to receive the Pfizer and Moderna COVID-19 vaccines.

President Biden called the move a “monumental step.”

“For parents all over the country, this is a day of relief and celebration,” he said in a statement Saturday.

https://thehill.com/policy/healthcare/3529201-gottlieb-predicts-slow-start-for-kids-vaccines/

Inflation will not fall to 2% target for two years: Fed’s Mester

 Cleveland Federal Reserve Bank President Loretta Mester said it will take two years for inflation to fall to the central bank’s 2% target, adding that it will be “moving down” gradually from the current level.

A surge in inflation, which is at its highest level in 40 years, has made hawks of nearly all Fed policymakers, only one of whom dissented earlier this week against what was the central bank’s biggest rate increase in more than a quarter of a century.

“It isn’t going to be immediate that we see 2% inflation. It will take a couple of years, but it will be moving down,” Mester said in an interview with CBS News on Sunday.

Mester said she was not predicting a recession despite slowing growth.

“We do have growth slowing to a little bit below-trend growth and we do have the unemployment rate moving up a little bit. And that is OK, we want to see some slowing in demand to get it in line with supply,” Mester added, referring to forecasts submitted in the past week by participants of the Federal Open Market Committee’s meeting.

Policymakers currently expect to raise the Fed’s benchmark overnight interest rate, now in a range of 1.50%-1.75%, to at least 3.4% in the next six months. A year ago, the majority thought the rate would need to stay near zero until 2023.

On Friday, the Fed called its fight against inflation “unconditional.”

https://www.cnbc.com/2022/06/19/inflation-will-not-fall-to-2percent-target-for-two-years-feds-mester-says.html

Finding Success By Diversifying Your Trading

 

A lot of trading wisdom repeated by traders is surprisingly unintelligent.  A good example is the mantra that it is important to "have a process" for your trading and follow that process religiously.  Sounds great--until markets change and the process that worked in one kind of market no longer works.  If a business repeated a process endlessly, it would never adapt to changes in consumer tastes, new opportunities, etc.  Similarly, a singular focus on "discipline" is shorthand for a failure to innovate.

Which brings us to yet another piece of common wisdom that masquerades as wisdom:  Be patient and only put on your very best trade ideas.  Sounds great!  Don't overtrade and wait for the really good "A+" opportunities.

Not so.

In the most recent post, I outlined my approach to trading, highlighting finding opportunities in which detecting market cycles allows for good risk/reward entries in established trends.  What is interesting about this approach is that it applies across a very wide range of time frames.  Thus, one could look at long-term data and trade dominant cycles within broad trends, or one could implement the approach intraday.  As a rule, variability of price action increases as time frames increase, so it's unlikely that one would obtain the same risk-adjusted returns trading long-term vs. intraday.  By the logic of the idea of "be patient and only put on your very best trade ideas", we should only trade the time frame that yields the best results.

The problem with that view is that opportunities differ across time frames, as well as across instruments.  While it could make sense to trade a short-term pattern from the long side, this might be a mere blip for a good longer-term short trade.  When we trade multiple patterns that are relatively uncorrelated (or perhaps even negatively correlated), we as traders achieve the diversification normally associated with investing.

We can think of it this way:  an investor diversifies holdings at a given point in time.  The investor might hold in a portfolio relatively uncorrelated positions in currencies, rates, stocks, etc.  That diversification allows trades with a decent Sharpe ration to create a portfolio with a truly superior Sharpe.  If you put enough different edges together in a portfolio, the portfolio will show relatively smooth positive returns, because some ideas are always working when others aren't.  That's the beauty of diversification.

The active trader tends to participate in fewer opportunities at any given point in time, but over time will trade multiple cycles and trends, some shorter-term, some longer-term, some in one instrument, some in another.  Note:  A flexible trader might put on multiple long and short trades during the day, achieving over time what the investor structures all at once:  diversification!  

The successful active trader will have multiple, promising patterns ("setups") to trade, creating multiple, independent edges.  That is the beauty of Mike Bellafiore's idea of "playbooking".  Like a football or basketball team, the trader practices many different "plays" and thus can adapt to any environment.  Can you imagine a basketball team consisting of players that won't take shots because they don't have the wide-open look at the basket?  Any team--and any trader--is competitive only if they can find multiple ways to win.

Sitting passively and not trading until the perfect trade presents itself is not discipline; it's the essence of being a one-trick pony.  And when the market changes, the one-trick pony becomes a lame horse.  Many different edges of different quality and different instruments and different time frames creates what we might call a "trader's portfolio".  It's a lot harder to lose when we have many ways to win.  

Good traders have an edge.  Great ones constantly find new ones.

Further Resources:

The Daily Trading Coach - Trading psychology self-help methods

The Three Minute Trading Coach - Short videos on trading psychology

*

 Brett Steenbarger, Ph.D

http://traderfeed.blogspot.com/2022/06/finding-success-by-diversifying-your.html

Efficacy Estimates For Pfizer’s Vaccine For Young Children Come Under Scrutiny

 by Zachary Stieber via The Epoch Times (emphasis ours),

The efficacy estimates Pfizer has offered for its COVID-19 vaccine for young children are being dismissed as unreliable even as the shot is being readied to be administered to millions of American toddlers and babies.

A Pfizer clinical trial for children aged 6 months to 5 years pegged the efficacy at 80.3 percent overall—82.3 percent for children aged 2 to 5, and 75.5 percent for kids 6 months to 2 years.

But those estimates were determined “not to be reliable due to the low number of COVID-19 cases that occurred in study participants,” the Food and Drug Administration (FDA) said in a statement on June 17.

The estimates were based on just 10 COVID-19 cases—seven among kids who received a placebo, and three among those who received the vaccine. All occurred after Feb. 7.

But they were portrayed as evidence the vaccine should be given to children across the country during meetings with vaccine advisory panels for the FDA and Centers for Disease Control and Prevention (CDC) this week.

“High efficacy was observed in the course of this trial,” Dr. William Gruber, a senior vice president for vaccine clinical research and development at Pfizer, told panelists during a meeting on Friday.

Gruber also showed a slide presenting the data.

The low number of cases resulted in wide-ranging confidence intervals, which indicate how confident one can be in the numbers.

The claimed efficacy is “a meaningless statistic,” Dr. Harvey Risch, a professor of epidemiology at the Yale School of Public Health, told The Epoch Times in an email.

Read more here...

https://www.zerohedge.com/covid-19/efficacy-estimates-pfizers-vaccine-young-children-come-under-scrutiny

Revolutionizing Digital Pain Management

 

In a video, Beth Darnall, PhD, of Stanford University's Pain Relief Innovations Lab, discusses her research into the effectiveness of digital pain management interventions and their potential for improving equitable care and access.

The following is a transcript of her remarks:

In this study, we were examining the benefit of a brief digital pain education intervention that might help people recover from surgery with less pain. Most pain after surgery is treated with medications, and we want to deliver a whole-person pain care approach.

Our intervention is called "My Surgical Success" (MSS), and we compared MSS to a digital health education control group. We enrolled patients who were undergoing orthopedic trauma surgery at Stanford University. After orthopedic trauma surgery, patients often have quite a bit of pain that they can manage for months, and up to 10% of people have moderate to severe pain for 2 years later. So, having multimodal pain management approaches are really important.

We enrolled 84 patients undergoing orthopedic trauma surgery, randomized them either to MSS or our digital control intervention, and we followed them after surgery for 3 months to understand how our intervention might change pain intensity, as well as use of medication.

What we found was that people who were assigned to MSS had pretty good engagement rates with a fully digital treatment, which is important. Most importantly, we found that people in MSS reported reductions in pain proximal to the surgery and also durability of analgesia to 3 months later. Now, what we didn't find was changes in opioid use. Opioid use after surgery remained the same in both treatment groups. But we feel that showing that people have reduced pain from a brief self-administered, on-demand intervention is a really nice result, suggesting that other programs might be able to implement this type of a program wherein behavioral health and pain management could be vastly more accessible than it is now.

This current study builds on prior work. We previously showed that when women undergoing breast cancer surgery receive MSS, we found that they needed less opioid medication after breast cancer surgery. So that was an interesting finding, and that combined with our new results where we show sustained analgesia after orthopedic trauma surgery really suggests that there's true heterogeneity and treatment effects based on the surgical population.

There is much to be studied about how this intervention might impart therapeutic benefits across patients, across surgical populations, but we're very excited for the future. I think one next step in this line of research might be applying for NIH funding to do broader and more extensive research to understand how these brief digital therapeutics could truly transform our ability to enhance recovery after surgery broadly.

Myself and my colleagues are very focused on digital health and digital interventions to improve access to evidence-based pain treatment. Historically, we have seen massive pain treatment disparities, and this was pre-existing before COVID, but COVID itself has only brought to light these disparities in treatment.

It also revealed an opportunity to better level the field to ensure equitable access to these evidence-based treatments -- this whole-person pain care. So, It's truly an exciting time to be able to envision how people all over the world might have ease of access to care from the comfort of their own home, whether that's acute pain or chronic pain. And we have a whole portfolio of treatment options that are digitally-based and brief or single-session so that people can access the treatment that they need in the format that they want.

One of the greatest difficulties that we have been facing in pain care, whether that's care of people with chronic pain or the care of individuals who have post-surgical pain, is that we do not have enough trained therapists and clinicians to meet the needs of varied populations and varied individual circumstances. This access issue has been pervasive over the past decades. We know what works and we talk a lot about efficacy, but without access, efficacy is meaningless.

What I love most about these brief single-session, digital interventions is that they transform the largest barrier that we have in pain care, in this behavioral pain care space, which is access. I'm personally excited for the future, because we're bringing forward the evidence to truly transform how pain care is delivered.

https://www.medpagetoday.com/painmanagement/painmanagement/99316

Transplant Success Without Immune Suppressive Drugs

 For three children, their newly transplanted kidneys might never require them to take immunosuppressive drugs.

Along with the kidney they got from a parent due to the rare T-cell immunodeficiency and primary kidney failure syndrome they had (Schimke immuno-osseous dysplasia), the children got reduced-intensity conditioning and αβ T-cell–depleted and CD19 B-cell–depleted hematopoietic bone marrow from that haploidentical parent.

"Full donor hematopoietic chimerism and functional ex vivo T-cell tolerance was achieved, and the patients continued to have normal renal function without immunosuppression at 22 to 34 months after kidney transplantation," reported Alice Bertaina, MD, PhD, of Stanford University in California, and colleagues in the New England Journal of Medicine.

It's a notable step forward, stated Thomas Spitzer, MD, of Massachusetts General Hospital in Boston, and David Sachs, MD, of Columbia University in New York City, in an accompanying editorial.

"The separation of [graft-versus-host disease or GVHD] from the graft-versus-tumor effect and the induction of functional immune tolerance, defined by the absence of a destructive immune response in the absence of systemic immunosuppression, have been considered the 'Holy Grail' of HSCT [hematopoietic stem-cell transplantation] and solid-organ transplantation, respectively," they wrote.

"Freedom from immunosuppression after organ transplantation has a tremendous potential upside, since lifelong immunosuppressive therapy is sometimes complicated by debilitating or life-threatening complications, including but not limited to serious infections and secondary cancers," Spitzer and Sachs added.

Some prior success in that regard has accrued in adult transplant clinical trials. Immune tolerance and long-term antitumor responses were seen in seven of 10 cases of HLA-matched and haploidentical combined bone marrow and kidney transplants performed in patients with multiple myeloma and end-stage renal disease. Outside of the cancer setting, other small studies have combined HSCT and kidney transplantation with durable immune tolerance in the majority of patients.

The case series from Bertaina's group was a "remarkable experience" that shows the "potential of combined or sequential HSCT and kidney transplantation to correct disorders of hematopoiesis and immunodeficiency and to induce tolerance of the kidney allograft," according to the editorialists.

The way the stem cells were processed, with αβ T-cell depletion, removes the type of immune cells that cause GVHD and enables genetically half-matched transplants.

The immunodeficiency of Schimke immuno-osseous dysplasia "undoubtedly contributed to the achievement of successful donor HSCT engraftment without GVHD across an HLA barrier, despite T-cell depletion of the donor inoculum," Spitzer and Sachs noted. "Therefore, the specifics of this strategy may not be applicable to all tolerance induction approaches. Nevertheless ... it is a strategy that could also be considered for patients with other conditions in which sustained full donor chimerism is desirable."

The researchers noted that another group had previously tried something similar in Schimke immuno-osseous dysplasia but four of the five patients died from HSCT-related causes, potentially due to increased sensitivity to DNA-damaging agents used in myeloablative conditioning regimens.

In their series of the first three patients treated with what they called "dual immune/solid organ transplant," the patients got antithymocyte globulin (7.5 mg/kg), then fludarabine (1 mg/kg/day for 4 days) and cyclophosphamide (1,200 mg/m²), followed by total-body irradiation (200 cGy) and rituximab (200 mg/m²) to prepare for the HSCT.

Once donor myeloid and lymphoid chimerism after HSCT had been confirmed (at 5, 5.5, and 10 months for the individual patients), the living-donor kidney was transplanted from the haploidentical parent who had donated the HSCT. The patients received intraoperative methylprednisolone and postoperative low-dose oral prednisone and tacrolimus to reduce reperfusion inflammation, which were tapered off by day 30 and no further immunosuppression given.

No clinical signs of rejection were seen in the patients. Renal function is normal at 22 to 34 months post-transplantation. Two patients have had a protective response to subsequent vaccinations, and the third was awaiting titer data at the time of publication.

Peripheral blood mononuclear cells at 1 year after kidney transplantation showed functional tolerance to stimulator cells derived from their donor parent -- "and, therefore, potentially unable to mediate graft rejection even in the absence of immune suppression," the researchers noted. But their immune cells reacted as normal and proliferated in the presence of stimulator cells derived from their non-donor parent or a healthy, unrelated control.

"Further studies will be needed to determine whether these outcomes can be achieved in allograft recipients with intact pretransplantation T-cell immunity and hematopoiesis," Bertaina's group said.

They are now expanding the protocol to children who have had an initial kidney transplant that was rejected and plan to look at how to extend it to other solid organ transplants, including from deceased donors.

"That's a challenge, but it's not impossible," Bertaina said in a statement. "We'll need 3 to 5 years of research to get that working well."

Disclosures

The study was supported by the Kruzn for a Kure Foundation.

Bertaina disclosed no relationships with industry.

Sachs disclosed relationships with IBT-Med. Spitzer disclosed Bluebird Bio, Qihan Biotech, Syneos Health, Parexel (now Perceptive Informatics), Shire North American Group, Focus Diagnostic Medicine, Jazz Pharmaceuticals, Thompson, Miller and Simpson, the Bone Marrow Foundation Medical Advisory Board, and Ossium Health.

Primary Source

New England Journal of Medicine

Source Reference: Bertaina A, et al "Sequential stem cell-kidney transplantation in schimke immuno-osseous dysplasia" N Engl J Med 2022; DOI: 10.1056/NEJMoa2117028.

Secondary Source

New England Journal of Medicine

Source Reference: Spitzer TR and Sachs DH "Transplantation tolerance through hematopoietic chimerism" N Engl J Med 2022; DOI: 10.1056/NEJMe2204651.

https://www.medpagetoday.com/nephrology/kidneytransplantation/99255