The Carbohydrate-Insulin Model of Obesity: Beyond ‘Calories In-Calories Out’

A spate of recent reviews claim to refute the CIM,^1,32,33,48 or dismiss any special metabolic effects of macronutrients,⁴⁹ but these attacks are premised on a misunderstanding of physiological mechanisms, misinterpretation of feeding studies and disregard for much supportive data. In animals, dietary composition has been shown to affect metabolism and body composition, controlling for calorie intake, in a manner consistent with the CIM predictions. Admittedly, the evidence for these effects in humans remains inconclusive.

Limited evidence notwithstanding, the conventional model has an implicit conflict with modern research on the biological control of body weight. The rising mean BMI among genetically stable populations suggests that changing environmental factors have altered the physiological systems defending body weight. After all, inexorable weight gain is not the inevitable consequence of calorie abundance, as demonstrated by many historical examples (eg, the United States, Western Europe, and Japan from the end of World War II until at least the 1970s).

Diets of varying composition, apart from calorie content, have varying effects on hormones, metabolic pathways, gene expression, and the gut microbiome in ways that could potentially influence fat storage. By asserting that all calories are alike to the body, the conventional model rules out the environmental exposure with the most plausible link to body weight control. What other factors could be responsible for such massive changes in obesity prevalence? The conventional model offers no compelling alternatives.

High-quality research will be needed to resolve the debate, which has been ongoing for at least a century.⁵ In 1941, the renowned obesity expert Julius Bauer described a key component of the CIM (the reverse direction of causality depicted in Figure B), writing in this journal: “The current energy theory of obesity, which considers only an imbalance between intake of food and expenditure of energy, is unsatisfactory…. An increased appetite with a subsequent imbalance between intake and output of energy is the consequence of the abnormal anlage [fat tissue] rather than the cause of obesity.”⁵⁰ In view of the massive and rising toll of obesity-related disease, this research should be given priority.

https://bit.ly/2KIjZCG

At least 8 million IVF babies born in 40 years since historic first

The world’s first in-vitro fertilization baby was born in 1978 in the UK. Since then, 8 million babies have been born worldwide as a result of IVF and other advanced fertility treatments, an international committee estimates.

In-vitro fertilization involves removing eggs from a woman’s ovaries and mixing them with sperm outside the body, typically in a Petri dish; “in vitro” is Latin for “in glass.” Fertilized by this process, the eggs become embryos that can be placed in a woman’s uterus, where they can develop into a fetus and eventually a baby.

While IVF births have increased over the past four decades, rates of twins and multiple births have declined, according to the report from the International Committee Monitoring Assisted Reproductive Technologies, a nonprofit that disseminates global information on assisted reproductive technologies.

The committee presented its results Tuesday at the 34th annual Meeting of the European Society of Human Reproduction and Embryology in Barcelona, Spain.

Conception through science

The society was founded in 1985 by Robert Edwards, a Cambridge reproductive biologist who helped lead the first in-vitro conception with gynecologist Dr. Patrick Steptoe.

The historic birth of Louise Brown, known at the time as a “test tube baby,” 40 years ago at Oldham General Hospital was the first to result from IVF.

“I don’t think my mother, Lesley Brown, could ever have imagined how big IVF would become and how many babies would be born,” Brown said of the 8 million who followed her.

The presentation estimates that more than a half a million babies are now born each year from IVF and intracytoplasmic sperm injection, from more than 2 million treatment cycles performed.

Intracytoplasmic sperm injection, in which conception also takes place outside the body, involves a single sperm being injected directly into an egg as opposed to being allowed to naturally fertilize an egg in a Petri dish. It was developed in the early 1990s as a treatment for male infertility, though it is now used more generally.

European fertility clinics favor sperm injection over traditional IVF by nearly two-to-one, a pattern found throughout the world, according to the report.

The presentation is based on global data collected from regional registries by the International Committee Monitoring Assisted Reproductive Technologies.

The European Society of Human Reproduction and Embryology also collected national registry data of assisted reproductive technology cycles — a single attempt at accomplishing conception — performed in Europe from 1997 through 2015. It found that Spain leads the continent in assisted reproduction, with a record 119,875 treatment cycles; followed by Russia (110,723 cycles); Germany (96,512); and former front-runner France (93,918). The UK usually performs about 60,000 treatments a year.

By comparison, the US Centers for Disease Control and Prevention reports 263,577 total assisted reproductive technology cycles performed at 463 fertility clinics during a single year (2016), which resulted in 76,930 live-born infants.

Cycles monitored by the European Society of Human Reproduction and Embryology include treatments with IVF and intracytoplasmic sperm injection as well as egg donation, which involves using an egg that was not removed from the woman implanted with the resulting embryo.

In European nations, the rate of successful pregnancy per embryo transfer is about 36% for both IVF and intracytoplasmic sperm injection, according to the report. The rate of single embryo transfers also continues to rise in Europe — from 11% in 1997 to 38% in 2015 — while the rate of multiple births has declined to 14% as of 2015, according to the report.

“The number of [assisted reproductive technology] cycles continues to increase, but utilization is still very influenced by affordable access … which is related to insurance or public funding,” the report abstract stated.

Egg donation treatments and freezing eggs have become more widespread and embryo freezing more successful with the introduction of vitrification, a more efficient and safe fast-freezing technology, according to the report. Pregnancy rates from egg donation are now at about 50%, the researchers noted.

Though there is some unmet need in Europe, overall, the total number of cycles performed across the continent is increasing by about 7% per year, the report indicated.

‘Good news’

Dr. Gillian Lockwood, a consultant in reproductive medicine at IVI Midland, a fertility treatment center in the UK, said the report is a “real good-news story.”

However, Lockwood, who was not involved in the study, believes that 8 million is “quite a conservative estimate.”

“We know there’s a huge amount of IVF going on in China and India, which isn’t necessarily reported or recorded,” she said.

The good news includes a continued rise in the rate of successful pregnancy for each IVF attempt, she said: “When I started in IVF in 1990, we thought a 15% pregnant rate was quite good. Now, most competent clinics are looking at at least 40% for good prognosis patients.” Also, she noted, the multiple pregnancy rate is coming down and is now at 14%, with a goal of “less than 10%.”

Another point made by the European Society of Human Reproduction and Embryology presentation was “what a huge unmet need there is for fertility treatments,” she said. She noted the report’s finding that only one in every three couples who tries fertility treatments ends up with a baby. The reason for this is “limited cycles” of treatment, Lockwood said.

“After six funded cycles, 70% of couples will have a baby. The UK, despite having invented IVF 40 years ago, has one of the lowest rates of fertility interventions.”

Follow CNN Health on Facebook and Twitter

See the latest news and share your comments with CNN Health on Facebook and Twitter.

The one woman whose very existence is central to any discussion of reproductive technology remains both humble and hopeful.

Despite the acclaim of her birth, “we are just normal people, and I lead a normal life,” Brown said of herself and her mother. “There are so many people working in the IVF industry, and they do a fantastic job bringing hope and joy to people and creating families.”

https://cnn.it/2KICeVz

Ambulatory surgery centers, publish prices, boost bottom line

Publicly listing prices for common surgeries helped to boost revenue and patient satisfaction.

That’s the finding from a small study of ambulatory surgical centers across the country by researchers from Johns Hopkins University in Baltimore.

Consumers are increasingly demanding more control over their healthcare decisions, including how much they pay. As a result, many hospitals and health systems are placing strategic focus on their pricing strategies, including both disclosing prices upfront and offering competitively priced services.

As the researchers described in the study, published in The American Surgeon, they drew from a database held by the Free Market Medical Association, and identified eight ambulatory surgical centers that listed prices for surgical services on their websites. The team sent a data-collection form to the eight centers between April and May 2016.

Six of the centers returned completed forms, which asked for patient demographics; details of price transparency initiatives; and information on how patient volume, patient inquiries for services, patient satisfaction, and center revenue changed 1 year after the prices were made transparent.

The results showed:

• Five of the six centers reported increases in patient volume and revenue after adopting price transparency — specifically, there was a midrange or median patient volume increase of 50% 1 year after implementing price transparency
• Four centers reported a 30% midrange revenue increase
• Three centers had an average increase of seven new third-party administrator contracts
• Three centers had a reduction in their administrative burden
• Five centers reported an increase in patient satisfaction and patient engagement after price transparency.

Brian Unell, vice president of revenue cycle for Georgia-based Piedmont Healthcare, said that Piedmont is currently working on a price transparency initiative of its own. “There are studies that show that patients who are aware of what their payment expectations are, are more likely to pay,” he said. “And we believe that it’s important our charge structures are market competitive. As a result, we now generate around 15,000 patient estimates each month, which is a 650% increase from the end of 2017.”

Although the investigators said their findings don’t “categorically prove” that the price transparency directly boosted business for the surveyed centers, “the timing of the increases suggests the impact is positive.”

In addition, the centers’ leaders said they were happy with their price transparency initiatives.

Officials at all six centers reported they would recommend price transparency as a marketing strategy to other providers. Four of the centers reported a belief that price transparency increased both their annual revenue and the demand for their services.

• Primary Source

  The American Surgeon

  Source Reference: Mehta A, et al “The Impact of Price Transparency for Surgical Services” Amer Surg 2018; 84(4): 604-608.

https://bit.ly/2u1SniA

Zynerba rebounds after selloff driven by failed cannabis-based skin patch trial

Shares of Zynerba Pharmaceuticals Inc. rose 7% in Friday trade, recouping some of their prior-session losses that came after the company said an early-stage trial of a cannabinoid skin patch failed to meet its main goals.

Zynerba ZYNE, +6.00%  , which is developing cannabis-based therapies for rare neurospsychiatric disorders, said the trial of ZYN001, which delivers tetrahydrocannabinol (THC) through a transdermal patch, did not achieve its goal of target blood levels of 5 to 14 ng/ml THC in healthy volunteers. THC is the psychoactive ingredient in cannabis and the company was trying to find a way to deliver it without patients having to take it orally, which can make them high.

“This Phase 1 study was a single and multiple dose, placebo-controlled first-in-man study to assess the safety and pharmacokinetics of ZYN001 administered as a transdermal patch to healthy adult subjects,” Zynerba said in a statement. “Several formulations and patch wear times ranging from 24 hours to 14 days were assessed in in 60 healthy subjects who were randomized to ZYN001 or placebo.”

The company will now focus its efforts on its ZYN002 treatment for Fragile X syndrome, a genetic autism-spectrum disorder that causes intellectual disability, behavioral and learning challenges that can be accompanied by seizures.

The change will extend Zynerba’s cash runway to the second half of 2019. The company said it has $52.1 million in cash and cash equivalents.

The news disappointed those who have high hopes for medical applications for marijuana and its chemical compounds. In June, the U.S. Food and Drug Administration approved a drug developed by U.K. company GW PharmacueticalsGWPH, +0.38%  to treat two severe forms of childhood epilepsy, Lennox-Gastaut syndrome and Dravet syndrome.

That drug, called epidiolex, contains cannabidiol (CBD), as opposed to THC, which means it does not make patients high. However, the product remains a controlled substance and cannot be sold until the Drug Enforcement Administration makes a final scheduling decision, as MarketWatch’s Emma Court has reported.

Canaccord analyst Arlinda Lee reiterated her buy rating on Zynerba stock and $18 price target on Friday, and said her sum-of-the-parts valuation of the company did not include ZYN001.

Lee is optimistic about Zynerba’s pivotal Fragile X Syndrome trial of patients in the U.S., Australia and New Zealand, noting that the company has received U.S. Orphan Drug Designation for cannabinoid use to treat the disease.

“Following agreement with FDA, we expect rapid enrollment of a pivotal trial in 2018 to result in a positive outcome,” she wrote in a note.

A Phase 2b trial of ZYN002 in treating epilepsy that’s planned for the second half “is designed to show meaningful contrast in treated patients,” versus an earlier trial, she wrote. The new trial will explore higher doses after the first trial failed to meet its main goals.

Zynerba shares have fallen 22% in 2018, while GW Pharma has gained 7%. The S&P 500 SPX, +0.85%   has gained 3% and the Dow Jones Industrial AverageDJIA, +0.41%   has fallen about 1%.

https://on.mktw.net/2MZzXpo

Cash-rich startup Rubius to build $155M cell therapy manufacturing site in RI

After closing two mega-rounds of investment within eight months of each other, the booming team at Rubius is now putting some of that cash to work. The Cambridge startup is building out a 135,000 square-foot manufacturing site in Rhode Island for its cell therapies — just months before it files its first IND.

The company plans to renovate an existing property in Smithfield, RI to do the job, investing $155 million over the next 5 years for the project. Back in March, Rubius’ president Torben Straight Nissen told Endpoints News that he was pondering an in-house manufacturing process. Developing a new class of medicine calls early on for some pricey manufacturing capacity.

The big idea at Rubius is that researchers can take red blood cells — designed by nature to transport oxygen — hijack them through genetic engineering tech and get them to carry proteins needed to fight various diseases. It’s an off-the-shelf approach, rather than one personalized for each patient.

It’s a platform play — a particular favorite of Flagship Pioneering, the startup factory that churned out Rubius. Flagship chief Noubar Afeyan has been one of the leading proponents of a move to find new platform companies with big potential for some game-changing technology and then coming up with the big money needed to build a full pipeline of therapies, rather than one or two pilot projects to demonstrate their potential.

Rubius’ platform has already attracted big financial support, raising $220 million in two round since last summer.

The R&D plan at Rubius is to push ahead with some lead enzyme replacement therapies being spawned on a platform that seeks to develop a brand-new class of cell therapies. The company plans to file its first IND for lead candidate RTX-132 in early 2019.

Bursting at the seams, Rubius is also now moving into 45,000 square feet in new digs at 399 Binney. By this summer, Nissen said, the staff should be up to around 100.

https://bit.ly/2KQ5Xiu

Breathing Tubes Fail to Save Many Older Patients

Earlier this year, an ambulance brought a man in his 80s to the emergency room at Brigham and Women’s Hospital in Boston. He had metastatic lung cancer; his family had arranged for hospice care at home.

But when he grew less alert and began struggling to breathe, his son tearfully called 911.

“As soon as I met them, his son said, ‘Put him on a breathing machine,’” recalled Dr. Kei Ouchi, an emergency physician and researcher at the hospital.

Hospice patients know that they’re close to death; they and their families have also been instructed that most distressing symptoms, like shortness of breath, can be eased at home.

But the son kept insisting, “Why can’t you put him on a breathing machine?”

Dr. Ouchi, lead author of a new study of how older people fare after emergency room intubation, knew this would be no simple decision.

 

“I went into emergency medicine thinking I’d be saving lives. I used to be very satisfied putting patients on a ventilator,” he told me in an interview.

But he began to realize that while intubation is indeed lifesaving, most older patients came to the E.R. with serious illnesses. “They sometimes have values and preferences beyond just prolonging their lives,” he said.

Often, he’d see the same people he’d intubated days later, still in the hospital, very ill, even unresponsive. “Many times, a daughter would say, ‘She would never have wanted this.’”

Like all emergency doctors, he’d been trained to perform the procedure — sedating the patient, putting a plastic tube down his throat and then attaching him to a ventilator that would breathe for him.

But, he said, “I was never trained to talk to patients or their families about what this means.”

His study, published in the Journal of the American Geriatrics Society, reveals more about that.

 

 

 

Analyzing 35,000 intubations of adults over age 65, data gathered from 262 hospitals between 2008 and 2015, Dr. Ouchi and his colleagues found that a third of those patients die in the hospital despite intubation (also called “mechanical ventilation”).

Of potentially greater importance to elderly patients — who so often declare they’d rather die than spend their lives in nursing homes — are the discharge statistics.

Only a quarter of intubated patients go home from the hospital. Most survivors, 63 percent, go elsewhere, presumably to nursing facilities.The study doesn’t address whether they face short rehab stays or become permanent residents.

But it does document the crucial role that age plays.

After intubation, 31 percent of patients ages 65 to 74 survive the hospitalization and return home. But for 80- to 84-year-olds, that figure drops to 19 percent; for those over age 90, it slides to 14 percent.

At the same time, the mortality rate climbs sharply, to 50 percent in the eldest cohort from 29 percent in the youngest.

All intubated patients proceed to intensive care, most remaining sedated because intubation is uncomfortable. If they were conscious, patients might try to pull out the tubes or the I.V.’s delivering nutrition and medications. They cannot speak.

Intubation “is not a walk in the park,” Dr. Ouchi said. “This is a significant event for older adults. It can really change your life, if you survive.”

 

A study at Yale University in 2015 following older adults before and after an I.C.U. stay (average age: 83) confirmed what many geriatricians already understood. Depending on how disabled patients are before a critical illness, they’re likely to see a decline in their function afterward, or to die within a year.

Those who underwent intubation had more than twice the mortality risk of other I.C.U. patients. “You don’t get better, most of the time,” said Dr. Ouchi. While outcomes remain hard to predict, “a lot of times, you get worse.”

Intubation rates are projected to increase. But so has the use of alternatives known as “noninvasive ventilation” — primarily the bipap device, short for bi-level positive airway pressure.

A tightfitting mask over the nose and mouth helps patients with certain conditions breathe nearly as well as intubation does. But they remain conscious and can have the mask removed briefly for a sip of water or a short conversation.

When researchers at the Mayo Clinic undertook an analysis of the technique, reviewing 27 studies of noninvasive ventilation in patients with do-not-intubate or comfort-care-only orders, they found that most survived to discharge. Many, treated on ordinary hospital floors, avoided intensive care.

“There are cases where noninvasive ventilation is comparable or even superior to mechanical ventilation,” said Dr. Douglas White, a critical care physician and ethicist at the University of Pittsburgh School of Medicine.

Dr. Ouchi, for instance, explained to his patient’s distraught son that intubation would thwart his father’s desire to remain communicative. The patient, able to see though not to say much, died four days later in a hospital room with bipap and morphine to reduce his “air hunger.”

 

Most patients in the Mayo review died within a year, too. But bipap may provide an interim option, giving families and physicians time to decide together whether to intubate an ailing older patient, who at this point probably can’t direct his own care.

The harried emergency room environment, after all, hardly encourages thoughtful discussions about patients’ prognoses and wishes. Those can become fraught conversations anyway, as Dr. White’s previous research has demonstrated.

His 2016 study showed that when physicians and surrogate decision makers have very different expectations about a critically ill patient’s odds of recovery, it’s not merely because family members fail to grasp what the physician explained.

“Other things get in the way of making good decisions,” Dr. White pointed out. “A lot of this has to do with psychological and emotional factors” — like “optimism bias” (Most people with this condition will die, but not my mom) or “performative optimism” (If we maintain hope, our mom will get better).

In their most recent study, he and his colleagues experimented with a support program for families with relatives in I.C.U.s., nearly all intubated.

When a specially-trained nurse checked in daily to explain developments and answer questions, families rated their communications more highly and felt more satisfied with their loved ones’ care.

The University of Pittsburgh Medical Center’s health system has begun adopting the program in its 40 I.C.U.s.

 

But discussing how aggressively an older person wants to be treated remains a conversation — probably a series of them — best held before a crisis.

Intubation, for instance, is often something a physician can foresee. Older patients who have cardio-respiratory conditions (emphysema, lung cancer, heart failure), or who are prone to pneumonia, or who have entered the later stages of Alzheimer's or Parkinson's disease — any of them may be nearing this crossroads.

When they do, Dr. Michael Wilson, a critical care physician at the Mayo Clinic, opts for a particularly humane approach.

As he recently described in JAMA Internal Medicine, before he inserts the tube, he explains to the patient and family that while he and the staff will do everything they can, people in this circumstance may die.

“You may later wake up and do fine,” he tells his patient. “Or this may be the last time to communicate with your family,” because intubated patients can’t talk.

Since setting up intubation generally takes a few minutes, he encourages people to spend them sharing words of comfort, reassurance and affection. Without that pause, “I have stolen the last words from patients,” he told me.

His editorial has drawn attention from critical care physicians around the world.

Dr. Wilson has used this approach about 50 times in his I.C.U., so he has learned what patients and families, given this opportunity, tell one another.

“It’s nearly always, ‘I love you,’” he said. “‘I hope you do well.’”

https://tinyurl.com/y9o6qjeh

Educational Development 7.7% Holder to Board: ‘Little to No Economic Alignment’

Red Oak Partners, LLC, a long-term investor in Educational Development Corporation (NASDAQ: EDUC) and the largest outside investor with a 7.7% ownership stake, announced today that it has issued a letter to the Board of Directors (“BOD” or the “Board”) of EDUC expressing serious concerns with the Company’s troubling corporate governance practices, Board composition, and misaligned management incentive plan proposal and Red Oak’s intention to oppose the election of the Class II directors and the proposed management equity incentive plan at the upcoming 2018 Annual Meeting scheduled to be held on July 24th. Red Oak has also called upon EDUC’s Board to work with its shareholders to address the significant concerns regarding EDUC’s corporate governance practices.

https://bit.ly/2KYnLF2