“Our Gene-Edited Future”

NPR: He Inherited A Devastating Disease. A CRISPR Gene-Editing Breakthrough Stopped It

Previously the CRISPR gene-editing has been used to counter genetic defects in conditions like sickle cell and thalasemia. This has involved taking cells out of the body, editing them in the lab, and infusing them back in or injecting CRISPR directly into cells that need fixing.

Now, scientists are directly injecting nanoparticles with the CRISPR gene-editing tools. Here’s an excerpt:

Doctors infused billions of microscopic structures known as nanoparticles carrying genetic instructions for the CRISPR gene-editor into four patients in London and two in New Zealand. The nanoparticles were absorbed by their livers, where they unleashed armies of CRISPR gene-editors. The CRISPR editor honed in on the target gene in the liver and sliced it, disabling production of the destructive protein.

Within weeks, the levels of protein causing the disease plummeted, especially in the volunteers who received a higher dose. Researchers reported at the Peripheral Nerve Society Annual Meeting and in a paper published in The New England Journal of Medicine.

“This is really opening a new era as we think about gene-editing where we can begin to think about accessing all kinds of different tissue in the body via systemic administration

Related study: JD Gilmore et al. NEJM. 2021. DOI: 10.1056/NEJMoa2107454. CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis.

My take: This type of discovery could dramatically improve the treatment of many diseases including heart disease, muscular dystrophy and brain diseases such as Alzheimer’s.

Related blog post: Genetically Modified Humans: Genome Editing 101

Steroids for Some with Short Gut, Poor Agreement on Endoscopy Findings, and Ending Surprise Bills

Briefly noted:

  1. F Wang et al JPGN 2021; 73: 17-22. Glucocorticoids Improve Enteral Feeding Tolerance in Pediatric Short Bowel Syndrome With Chronic Intestinal Inflammation In this retrospective study with 15 patients who had histologically-confirmed chronic intestinal inflammation, glucocorticoids (budesonide or prednisone) were associated with clinical improvement. Key findings: 7 of the 15 patients gained enteral autonomy. 6 of 7 of those had eosinophilic infiltrates as part of their histologic findings. 11 of 15 had a reduction in parenteral calories.
  2. L Norsa et al JPGN 2021; 73: 48-53. Scoring Endoscopy in Pediatric Inflammatory Bowel Disease: A Way to Improve Quality This study showed very poor agreement between 11 pediatric GIs in evaluating videos of 15 endoscopies (see below). Key finding: Intraclass correlation was 0.298 (95% confidence interval [CI]: 0.13–0.55) for ulcerative colitis (UC) and 0.266 (0.11–0.52) for Crohn disease (CD). My take: This study indicates either a need for rigorous training of endoscopists and/or need for AI review of endoscopy.
  3. NY Times 7/2/21: Full text: For Surprise Medical Bills, It’s the Beginning of the End Key issues for regulators: define a standard price for out-of-network care, determine what hospitals and doctors will need to do to notify patients they are not in their insurance network, and establish a complaint system for consumers who believe they were illegally billed.

Related blog posts:

From JGPN twitter feed

Risks of Vaccines Compared to COVID-19 Infection in 12-17 Year Olds

NY Times: Covid Is a Greater Risk to Young People Than the Vaccines (July 4, 2021)

This article elaborates on the risks of vaccination, especially due to myocarditis, compared to the risks posed by COVID-19 infection. Even using very cautious estimates, the authors find that the risks of hospitalizations, cardiac morbidity, and deaths are likely to be much lower in those who receive the vaccine.

Key points:

  • “Among the 6.14 million Americans 17 and under who have been fully vaccinated, there have been 653 possibly related hospitalizations lasting a day or longer…. If that rate holds, it means that if all 73 million Americans ages 17 and under are eventually vaccinated, there will be around 7,700 hospitalizations.”
  • “So far, 326 Americans age 17 and younger have died of Covid-19.”
  • “If the coronavirus were eventually to infect all 73 million children in the United States, we would conservatively expect Covid-19 to be responsible for around 14,600 hospitalizations….[and] lead to over 27,000 additional hospitalizations from the [MIS-C] syndrome.”
  • Unlike hospitalizations related to vaccines which have typically been brief and uneventful, “Covid-related hospitalizations in adolescents can be long and complicated, with nearly one-third requiring patients to enter the intensive care unit.”
  • “Bad things inevitably happen to a small number of people after any vaccination, a few caused by the vaccines, but most not…The virus is more dangerous.”

My take: 12-17 year olds are at less risk from COVID-19 infection than other age groups, however, this risk is still greater risk than the risk of vaccination. Protecting them with immunizations also protects other vulnerable populations and may decrease the risk of vaccine-resistant variants.

Related article: Eric Topol NY Times: It’s Time for the F.D.A. to Fully Approve the mRNA Vaccines An excerpt: “Now more than 180 million doses of the Pfizer vaccine and 133 million of Moderna’s have been administered in the United States, with millions more doses distributed worldwide. In the history of medicine, few if any biologics (vaccines, antibodies, molecules) have had their safety and efficacy scrutinized to this degree…it’s frankly unfathomable that mRNA vaccines have been proved safe and effective in hundreds of millions of people and yet still have a scarlet “E”.”

Pediatric Gastroenterology Hospitalists –Job Wanted?

A recent article (M Latorre et al. Clin Gastroenterol Hepatol 2021; 19: 871-875) describes “A Practical Guide to Establishing a Gastroenterology Hospitalist Program (in adult GI)”

Our group had flirted with the idea of a GI Hospitalist (GIH) many years ago when one of the partners expressed some interest. To establish this type of job takes a lot of planning.

Some of the key points:

  • “Proactively incorporating scheduling measures to provide the GIH with coverage and backup is important; otherwise the job can become easily overwhelming.” Outpatient faculty have to provide coverage to assure the individual is protected and covered for emergencies, weekends, and holidays. “Creating dedicated shifts with daily start and stop times allow for more control over the GIH’s hours.”
  • The authors note that when they began their GIH, the outpatient faculty rotated and assisted with afternoon consults/procedures to protect GIH from long days and burnout.
  • In adult medicine, a GIH can help improve GI practice profitability by allowing outpatient doctors to increase office revenue and endoscopic procedures. In pediatrics, it is possible that a GIH would generate more billings than outpatient counterparts due to increased procedural demands for inpatients.
  • GIH can improve patient care (timely endoscopy, focus on inpatient problems), improve continuity, and reduce costs similar to other hospitalists.

My take: If there is adequate help, especially to prevent long days and increased night call, this model could work in pediatric GI as well.

Related blog posts:

This story below was NOT from ‘The Onion.’ NPR 6/10/21:

How Insurance Companies Can Help Stop the Pandemic in the U.S.

From AJC, Hashem Dezhbakhsh: An incentive to encourage vaccination

This is a good read. An excerpt:

Vaccine hesitancy, which can prolong the pandemic, is a textbook example of a negative consumption externality, where an individual’s choice can harm or impose costs on others. Indoor smoking, drunk driving, or littering are other examples…

One policy option is to use the insurance mechanism, with risk assessment and risk pricing as its enforcing arms….

For example, a risky driver has a higher auto insurance premium than a safe driver, a smoker has a higher health insurance premium than a non-smoker,…Similarly, health insurance premiums, deductibles, and co-pays can be set higher for those who are unvaccinated...

Using risk pricing to set insurance premiums and co-pays for these individuals makes good sense and is fair policy. It incentivizes individuals to vaccinate, while also providing a fairer insurance pricing system by charging those with self-selected higher risk a higher price, instead of shifting their medical costs to others through uniform insurance pricing.


This and That: Ear Tubes and Addiction Medicine

Interesting articles from recent NEJM:

A Hoberman et al. NEJM 2021; 384: 1789-99. Tympanostomy Tubes or Medical Management for Recurrent Acute Otitis Media

A quick read of this article suggested very bad news for our ENT colleagues. In this prospective, randomized trial (n=250), the authors did not find a significant advantage of tympanostomy tubes over medical management of acute otitis media (OM) among 6-35 month olds with recurrent OM in an intention-to-treat analysis, the rate (±SE) of episodes of acute otitis media per child-year during a 2-year period was 1.48±0.08 in the tympanostomy-tube group and 1.56±0.08 in the medical-management group (P=0.66).

In an associated editorial (pg 1859-60), (Ellen Wald notes that only 55% of children in the medical management group were actually treated medically throughout the trial making the sample size too small. Her advice: “In a child older than 2 years of age, we can forecast that infections will be fewer in the coming year and that medical treatment should be continued. In the younger child, there is a nearly 50% likelihood that the frequency of infections will continue; the child is likely to have fewer and less severe episodes of acute otitis media with less exposure to antibiotics if tympanostomy-tube placement is undertaken.”

Time to first recurrent episode of acute otitis media (Figure 2). Cumulative percentage of children with recurrent OM with one minus Kaplan-Meier survival estimates according to trial group.

E Poorman. NEJM 2021; 384: 1783-1784. The Number Needed to Prescribe — What Would It Take to Expand Access to Buprenorphine?

This article describes how many physicians are reluctant to treat opioid use disorder. The author notes that “prescribing buprenorphine is one of the most effective ways to save a life. In one study, buprenorphine treatment was associated with a 37% reduction in all-cause mortality during the year after a nonfatal overdose. This reduction is larger than the reduction in mortality associated with any blood-pressure medication, diabetic agent, or statin….But much…will depend on physicians believing that people with a substance use disorder aren’t just “addicts” but are people with a chronic medical disease that we can and should treat.”

Are We On the Verge of Pharmacologic Management of Obesity (Again)?

In the 1990s, the combination of fenfluramine/phentermine was popularized as a treatment for obesity. Fenfluarmine, though, was shown to cause potentially fatal pulmonary hypertension and heart valve problems, which eventually led to its withdrawal and legal damages of over $13 billion (per Wikipedia: fenfluramine/phentermine).

Now, glucagon-like peptide-1 (GLP-1) receptor agonists, like liraglutide, are showing promise as agents to promote weight loss, primarily by inhibiting appetite. JR Lundrgen et al (NEJM 2021; 384: 1719-1730. Healthy Weight Loss Maintenance with Exercise, Liraglutide, or Both Combined) show that liraglutide can promote weight loss, especially if combined with exercise.

Methods: After an 8-week low-calorie diet, participants were randomly assigned for 1 year to one of four strategies: a moderate-to-vigorous–intensity exercise program plus placebo (exercise group); treatment with liraglutide (3.0 mg per day-SC injection) plus usual activity (liraglutide group); exercise program plus liraglutide therapy (combination group); or placebo plus usual activity (placebo group)

Key findings:

  • After the 8-week low-calorie diet, 195 participants had a mean decrease in body weight of 13.1 kg.
  • At 1 year, all the active-treatment strategies led to greater weight loss than placebo: difference in the exercise group, −4.1 kg (95% confidence interval [CI], −7.8 to −0.4; P=0.03); in the liraglutide group, −6.8 kg (95% CI, −10.4 to −3.1; P<0.001); and in the combination group, −9.5 kg (95% CI, −13.1 to −5.9; P<0.001). The combination strategy led to greater weight loss than exercise (difference, −5.4 kg; 95% CI, −9.0 to −1.7; P=0.004) but not significantly more than monotherapy with liraglutide (−2.7 kg; 95% CI, −6.3 to 0.8; P=0.13)
  • The side effects of decreased appetite, dizziness, increased heart rate and palpitations were more common in those receiving liraglutide; palpitations were evident in 12% of the liraglutide monotherapy group and 4% of the combination (with exercise) group.

The details of the exercise program are detailed in the methods section; all participants were assigned an instructor and expected to do a minimum of 150 minutes per week of moderate-intensity aerobic physical activity or 75 minutes per week of vigorous-intensity aerobic physical activity.

These results are similar to the 15% weight loss noted at 68 weeks with the GLP-1 receptor agonist semaglutide.

My take: GLP-1 receptor agonists help individuals lose weight. However, we’ve seen the promise of medical therapy before so we will have to see how the story ends.

Related blog post: Semaglutide: Potential or Problematic New Treatment for Fatty Liver Disease/NASH

Briefly noted: YY Gibbens et al. American Journal of Gastroenterology 2021 April 22. Effects of Central Obesity on Esophageal Epithelial Barrier Function. Key finding:  Obesity+/GER- group demonstrated increased intercellular space, reduced desmosome density, and increased fluorescein leak compared with control subjects. Thus, obesity may worsen esophageal disease by  impairing the structural and functional integrity of the esophageal barrier independent of GER. (Thanks to Mike Hart for this reference)