“Our Gene-Edited Future”

Posted on July 26, 2021 by gutsandgrowth

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

Orbeez Ball Obstruction

Posted on July 25, 2021 by gutsandgrowth

Z Patel et al. Gastroenterol 2021: 161. https://doi.org/10.1053/j.gastro.2020.10.051. Full text: An Unusual Case of Small Bowel Obstruction

Case report of a 10 month old who developed a small bowel obstruction due to an “Orbeez” ball. “Orbeez balls are small polymer beads that absorbs water and expands, it can get up to 150 times their original size. When left out of water, the beads shrink back down to its original size. They were originally invented as a way to keep moisture in soil for plants. They are hugely popular with children and often used as toys, flower holders, air fresheners, light jars, and objets d’art in the house.”

Related blog post: Foreign Bodies in Children –Expert Guidance

Predicting Bad Outcomes with Ascites

Posted on July 24, 2021 by gutsandgrowth

T Ingviya et al. JPGN 2021; 73: 86-92. Clinical Predictors of Morbidity and Mortality in Hospitalized Pediatric Patients With Ascites

Methods: A retrospective cohort study was performed on patients (n=518) ages 0 to 21 hospitalized at Johns Hopkins Hospital between 1983 and 2010 with an ICD-9 discharge diagnosis of ascites

Key findings:

Among the 3 age groups (0–5, 6–12, and 13–21), the 0 to 5 age group experienced significantly increased length of stay (LOS) (P < 0.001) and mortality (P = 0.027).
Ascites etiology of veno-occlusive disease (VOD) and the presence of hydrothorax or thrombocytopenia was also significantly associated with increased LOS.
Ascites with the etiology of congestive hepatopathy and the presence of grade 3 ascites, hepatic encephalopathy, hepatorenal syndrome, hydrothorax, hyponatremia, and thrombocytopenia were associated with increased mortality.
Black pediatric patients with ascites have an increased risk of mortality

Related blog post: #NASPGHAN19 Liver Symposium (part 3)

Worse Outcomes After Hospital Mergers

Posted on July 23, 2021 by gutsandgrowth

NPR: The Untamed Rise Of Hospital Monopolies

An excerpt:

Zack Cooper, an economist at Yale School of Public Health, and his colleague, Martin Gaynor, have crunched the numbers on hospitals using the government’s preferred way of measuring market concentration, and they’ve found that about 80% of America’s hospital markets are now “highly concentrated.”…

The research clearly shows, Cooper says, that growing monopolization has raised prices for patients. Less competition means hospitals can charge higher prices and get away with it. They can pay lower wages and get away with it. And they can provide worse care and get away with it. “We want firms to compete and be incentivized to raise their quality to attract more consumers, and the more that hospitals merge, the less sharp those incentives become,” Cooper says. “We have evidence that death rates are literally higher in markets where hospitals face less competition.”…

The bizarre part of all this is that many of these monopolizing hospitals are technically considered “nonprofits.” … instead of making profits that are distributed to shareholders, nonprofit hospitals take the extra money they make and use it for executive compensation and buying shiny stuff.

Related blog posts:

Anti-TNF Therapy and Lower Rates of Colon Cancer & Financial Hardship Due to IBD

Posted on July 22, 2021 by gutsandgrowth

M Aklkhayyat et al. Inflamm Bowel Dis 2021; 27: 1052-1060. Lower Rates of Colorectal Cancer in Patients With Inflammatory Bowel Disease Using Anti-TNF Therapy

Using a selected sample from a database with >62 million patients, this retrospective cohort study determined the rates of colorectal cancer among patients with IBD. Key finding:

Among the IBD cohort, patients treated with anti-TNF agents were less likely to develop CRC; patients with Crohn’s disease: odds ratio, 0.69; 95% confidence interval, 0.66-0.73; P < 0.0001 vs patients with ulcerative colitis: odds ratio, 0.78; 95% confidence interval, 0.73-0.83; P < 0.0001.

My take: This study found an association between anti-TNF therapy and a reduced risk of CRC in patients with IBD.

Related blog posts:

NH Nguyen et al. Inflamm Bowel Dis 1068-1078. National Estimates of Financial Hardship From Medical Bills and Cost-related Medication Nonadherence in Patients With Inflammatory Bowel Diseases in the United States

Using the National Health Interview survey (2015), the authors identified individuals with self-reported IBD and assessed national estimates of financial toxicity. Key findings:

23% reported financial hardships due to medical bills, 16% of patients reported cost-related medication nonadherence, and 31% reported cost-reducing behaviors
Approximately 62% of patients reported personal and/or health-related financial distress, and 10% of patients deemed health care unaffordable
Inflammatory bowel disease was associated with 1.6 to 2.6 times higher odds of financial toxicity across domains compared with patients without IBD

My take: In addition to the physical and emotional toll of having IBD, there is also significant financial hardships for many.

Encouraging Safety Data for Ustekinumab & ESPGHAN Obesity Position Paper

Posted on July 21, 2021 by gutsandgrowth

WJ Sandborn et al. Inflamm Bowel Dis 2021; 27: 994-1007. Full text: Safety of Ustekinumab in Inflammatory Bowel Disease: Pooled Safety Analysis of Results from Phase 2/3 Studies

Methods: Data from 6 ustekinumab phase 2/3 CD and UC studies were pooled, and safety was evaluated through 1 year; this included 2574 patients (1733 patient-years of follow-up)

Key Safety findings –Events per 100 patient years -placebo vs ustekinumab respectively:

Adverse events: 165.99 [95% CI, 155.81–176.67] vs 118.32 [95% CI, 113.25–123.55])
Serious AEs: 27.50 [95% CI, 23.45–32.04] vs 21.23 [95% CI, 19.12–23.51])
Infections 80.31 [95% CI, 73.28–87.84] vs 64.32 [95% CI, 60.60–68.21])
Serious infections: 5.53 [95% CI, 3.81–7.77] vs 5.02 [95% CI, 4.02–6.19])
Malignancies excluding nonmelanoma skin cancer: 0.17 [95% CI, 0.00–0.93] vs 0.40 [95% CI, 0.16–0.83])
Major cardiovascular events were rare with 2 in placebo group 0.34 and 2 in the ustekinumab group 0.12

More key findings:

No cases of progressive multifocal leukoencephalopathy or reversible posterior leukoencephalopathy
Antibodies to ustekinumab were identified in 3.6% of patients

My take: This study showed similar safety between ustekinumab and placebo, but is limited by short followup. The authors note that 5-year data from ustekinumab’s use with psoriasis has found no safety signals for malignancy.

Related blog posts:

Why I Didn’t Like a Study on Resilience Plus One

Posted on July 20, 2021 by gutsandgrowth

P Sehgal et al. Inflamm Bowel Dis 2021; 27: 791-796. High Levels of Psychological Resilience Associated With Less Disease Activity, Better Quality of Life, and Fewer Surgeries in Inflammatory Bowel Disease

This cross-sectional study with 229 patients examined the relationship between inflammatory bowel disease (IBD) activity and resilience based on the Connor-Davidson Resilience Scale questionnaire (high resilience score ≥ 35).

Key findings:

High resilience was noted in 27% of patients with UC and 21.5% of patients with CD.
Among patients with UC, those with high resilience had a mean Mayo score of 1.54, and those with low resilience had a mean Mayo score of 4.31, P < 0.001.
Among patients with CD, those with high resilience had a mean HBI of 2.31, and those with low resilience had a mean HBI of 3.95, P = 0.035.
In multivariable analysis, high resilience was independently associated with lower disease activity in both UC (P < 0.001) and CD (P = 0.037) and with higher QoL (P = 0.016).
High resilience was also associated with fewer surgeries (P = 0.001) among patients with CD.

Reading this study, made me think of Galen’s assertion about a different treatment, circa 100 AD: “All who drink of this remedy recover in a short time except those whom it does not help, who all die. It is obvious, therefore, that it fails only in incurable cases.” In the case of this study, the remedy is resiliency.

This study is intriguing and adds to the literature that mental health and IBD may be a two-way street: mental health may affect IBD and IBD activity may affect mental health. However, it is difficult to prove causation in a cross-sectional study. Reverse causation is possible; that is higher disease burden may result in lower resilience.

Also, it is not clear to me that resilience is a particularly modifiable factor. Some may interpret this study in a ‘blame the victim’ mode. I think a lot of individuals would think they are resilient but most do not know until they face a difficult situation. Perhaps, Mike Tyson’s assertion is more apt: “Everyone has a plan until they get punched in the mouth.”

My take: This study does not prove that resilience helps prevent IBD activity, though being resilient is nice if you have it.

Plus one: JR Rosh et al. J Crohns Colitis. 2021 May 26; jjab089. doi: 10.1093/ecco-jcc/jjab089. (EPUB). Ustekinumab in Pediatric Patients with Moderately to Severely Active Crohn’s Disease Pharmacokinetics, Safety, and Efficacy Results from UniStar, a Phase 1 Study This was a “multicentre, 16-week, double-blind induction dose-ranging study (NCT02968108), patients aged 2-<18 years; patients were randomized (1:1) to one of 2 weight range-based intravenous induction doses: 130mg vs 390mg in patients ≥40kg and 3mg/kg vs 9mg/kg in patients <40kg. At week 8, all patients received a single subcutaneous ustekinumab maintenance dose of 90mg in patients ≥40kg or 2mg/kg in patients <40kg..” (Kudos to my partner, Stanley Cohen, one of the authors)

Key finding: Pharmacokinetics were similar to those in adults with Crohn’s disease. However, serum ustekinumab concentrations were lower among those with body weight <40kg…These results suggest a different dosing regimen may be required for patients <40kg

Related blog posts:

Image below from Anne’s Beach (Lower Matecumbe Key, Florida)

Oral Treatment of Celiac Disease & Research Optimist

Posted on July 19, 2021 by gutsandgrowth

A long time ago I heard a joke from a mentor about how can you tell if a person is an optimist. An optimist is a person who finds a pile of manure under the tree on Christmas morning and declares: ‘Oh boy, I’m getting a pony.’

Researchers who are trying to identify oral treatments for celiac disease are probably true optimists. Yet, despite my skepticism, a recent study (D Schuppan et al. NEJM 2021; 385: 35-45. A Randomized Trial of a Transglutaminase 2 Inhibitor for Celiac Disease) provides the best proof yet that an oral treatment may be helpful.

In this 6-week randomized, double-blind, placebo-controlled study with 159 participants, treatment with ZED1227, a selective oral transglutaminiase 2 inhibitor reduced histologic injury compared to placebo; all patients were receiving a diet with 3 grams of daily gluten. Key findings:

Treatment with ZED1227 at all three dose levels attenuated gluten-induced duodenal mucosal injury. The estimated difference from placebo in the change in the mean ratio of villus height to crypt depth from baseline to week 6 was 0.44 (95% confidence interval [CI], 0.15 to 0.73) in the 10-mg group (P=0.001), 0.49 (95% CI, 0.20 to 0.77) in the 50-mg group (P<0.001), and 0.48 (95% CI, 0.20 to 0.77) in the 100-mg group (P<0.001)
The estimated differences from placebo in the change in intraepithelial lymphocyte density were −2.7 cells per 100 epithelial cells (95% CI, −7.6 to 2.2) in the 10-mg group, −4.2 cells per 100 epithelial cells (95% CI, −8.9 to 0.6) in the 50-mg group, and −9.6 cells per 100 epithelial cells (95% CI, −14.4 to −4.8) in the 100-mg group
Adverse events were similar to placebo; 3 (8%) patients in the 100 mg group developed a rash

The need for a treatment besides a gluten-free diet is significant; among adults, 40-50% do not achieve mucosal healing/recovery despite GFD institution; in addition, the diet is difficult and costly.

My take: I think it is still a long journey to find an effective & safe oral treatment for celiac disease.

Related blog posts:

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

Posted on July 18, 2021 by gutsandgrowth

Briefly noted:

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.
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.
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.