This study used transgenic, surgical, and pharmacological approaches to study the effects of intestinal epithelial serotonin reuptake transporter or serotonin on mood and gastrointestinal function, as well as relevant communication pathways.
Key findings:
Serotonin reuptake transporter ablation targeted to the intestinal epithelium promoted anxiolytic and antidepressive-like effects without causing adverse effects on the gastrointestinal tract or brain; conversely, epithelial serotonin synthesis inhibition increased anxiety and depression-like behaviors.
In utero SSRI exposure is a significant and specific risk factor for development of the DGBI, functional constipation, in the first year of life.
My take: While this lengthy article presents data mainly from mice studies, it further supports the likelihood that SSRI selective targeting of the gut epithelium may improve anxiety, depression and comorbid DGBI. Selective targeting of the GI tract would reduce adverse effects of these medications.
X Wang et al. N Engl J Med 2025;392:1334. Ménétrier’s Disease
History: 16-year-old girl was admitted to the hospital with a 2-month history of leg swelling and hypoalbuminemia. She had no gastrointestinal symptoms.
Treatment: She was placed on a high-protein diet and medications to eradicate a concurrent infection with Helicobacter pylori. At a 3-month follow-up visit, the patient’s edema and hypoalbuminemia had resolved.
Measles as of Friday May 2nd (per Caitlin Rivers): “According to CDC, a total of 935 confirmed measles cases have been reported by 30 jurisdictions. The previous high was 1,274 in 2019. So far this year, 121 cases (13%) have been hospitalized.”
“More U.S. children have died this flu season than at any time since the swine flu pandemic 15 years ago, according to a federal report released Friday…It’s a startlingly high number, given that the flu season is still going on. The final pediatric death tally for the 2023-2024 flu season wasn’t counted until autumn…There are likely several contributors to this season’s severity, but a big one is that fewer children are getting flu shots, added O’Leary, a University of Colorado pediatric infectious diseases specialist. The flu vaccination rate for U.S. children has plummeted from about 64% five years ago to 49% this season. Flu vaccinations may not prevent people from coming down with symptoms, but research shows they are highly effective at preventing hospitalizations and deaths, O’Leary said.”
Background: “GLP-2 is a specific, endogenous, intestinal, pro-adaptive factor that plays a key role in enhancing intestinal mucosal morphology, function, and integrity under normal and pathophysiological conditions. The introduction of GLP-2 analogue treatment has been a paradigm shift in the treatment of SBS, targeting the pathophysiology of SBS by aiming to reinforce the structural and functional integrity of the remaining intestine. Exogenous GLP-2 induces significant hyperplasia of the small intestinal mucosal epithelium via stimulation of stem cell proliferation in the crypts and via inhibition of apoptosis in the villi…
The short half-life of 5–7 minutes for circulating native GLP-232 is a significant practical limitation for its use in a therapeutic setting. This is improved for the currently marketed GLP-2 analogue teduglutide, which has a half-life in circulation of approximately 2 hours.33 However, treatment is time-consuming due to the requirement for daily drug product reconstitution and dosing…
Glepaglutide is a novel, long-acting GLP-2 analogue in a stable, aqueous formulation for subcutaneous administration to treat patients with SBS. The stability in aqueous solution allows for dosing of glepaglutide as a ready-to-use liquid formulation. The mean effective half-life is 88 hours,34 which enables extension of the dosing interval beyond daily dosing.”
Methods: In this placebo-controlled, randomized, parallel-group, double-blind, phase 3 trial, adult patients (n=106) with SBS with intestinal failure requiring PS ≥3 d/wk were randomized 1:1:1 to 24 weeks of glepaglutide 10 mg twice weekly or once weekly or placebo
Key findings:
Glepaglutide twice weekly significantly reduced weekly PS volumes from baseline to week 24 vs placebo (mean change, −5.13 vs −2.85 L/wk; P = .0039; primary end point).
The improvement with glepaglutide was more prominent in those without a colon in continuity.
Mean concentrations of citrulline (a biomarker for enterocyte mass) increase 47% and 19% from baseline in the TW and OW treatment groups vs 5% in the placebo group
Serious adverse events were more common in both glepaglutide groups (28.6% and 11.4% for TW and OW respectively) compared to 5.6% for placebo. Specific risks of the active treatment included injection site reactions (common). Stoma complications (swelling of stoma nipple) along with GI events (nausea, vomiting and pain) were reported in more than 10% of patients. One patient developed cholecystitis and one developed a generalized rash in the active treatment group.
61 of 70 patients (87%) treated with glepaglutide developed anti-drug antibodies. However, the authors found no apparent association with glepaglutide pharmacokinetics.
The improvement in parenteral support was more notable in those without the colon in continuityDifference compared to placebo: 14.1% more of patients receiving twice weekly dosing and 11.2% more of patients receiving once weekly dosing of glepaglutide achieved enteral autonomy.
My take: This study shows that glepaglutide, like its GLP-2 analogue predecessor teduglutide, reduces the volume of parenteral support for patients with SBS. Due to its longer half-life, less frequent dosing is an added benefit compared to teduglutide.
Drawbacks for this group of medications include the potential for long-term adverse effects, endoscopic monitoring (possibly both upper endoscopy and colonoscopy), substantial costs, and reversion of intestinal failure severity when the medications are stopped.
In this retrospective study from a high immigrant density community, patients aged 6–18 years old who had an fecal calprotectin (FC) level within 6 months prior to EGD and who were tested for HP infection were included in the study.
Key findings:
Of 129 patients, 37 (28.7%) tested positive for HP infection.
The mean FC level was significantly elevated in HP-positive patients (241.2) as compared with HP-negative patients (88.1) (p < 0.001)
HP-positive patients were also found to have small but notably higher elevations of CRP and ESR levels
My take: This study confirms what I have seen in my own practice. Patients with H pylori frequently have elevated calprotectin levels. Checking stool for H pylori may help avoid some colonoscopies. H pylori infection, however, can be present in patients with inflammatory bowel disease as well.
Methods: There were 405 cases included in this retrospective study (mean age = 9.6 years). TTG-IgA values were considered negative if <4 U/mL, equivocal between 4 and 10 U/mL inclusively, and positive if >10 U/mL. At the authors’ institution, TTG‐IgA ≥10× ULN corresponds to ≥100 U/mL.
Key findings:
Bulb-restricted CD was present in 7.4% of cases
TTG-IgA was negative or equivocal in 60.0% of bulb-restricted CD, compared to 5.3% of distal duodenal CD (odds ratio [OR] = 26.6
No bulb-restricted CD cases attained TTG-IgA ≥10× ULN, compared to 48.5% of distal duodenal CD
My take: This study confirms and quantitates what most clinicians have experienced. Isolated duodenal bulb pathology is associated with lower celiac titer abnormalities.
A Le-Nguyen. N Engl J Med 2025;392:1215. Meconium Ileus
An abdominal radiograph had shown dilated loops of small intestine (Panel A). Owing to concern for intestinal malrotation with midgut volvulus, an urgent laparotomy was performed. Considerable distention of the small bowel by thick meconium — rather than midgut volvulus — was identified. An enterotomy for evacuation of meconium was performed (Panel B). On postoperative genetic testing, the baby was found to be homozygous for a mutation in CFTR, the gene encoding cystic fibrosis transmembrane conductance regulator… The condition is associated with a very high risk of cystic fibrosis, so genetic testing is warranted in all cases. Uncomplicated cases are typically managed with serial enemas.
It’s been shown that reactivation of the chickenpox virus can lead to the accumulation of aberrant proteins associated with Alzheimer’s…
The new research, published Wednesday in Nature, analyzed data from more than 280,000 older adults in Wales and found that people who received the original shingles live virus vaccine were 20% less likely to develop dementia of any type than those who were not vaccinated...
The new study was possible because of an unusual public health policy in Wales that provided a “natural experiment” to explore the potential impact of the vaccine on dementia risk. With the rollout of the vaccine on Sept. 1, 2013, in Wales, shots were offered to people who were 79 on that date but not given to people who had turned 80.That allowed the German and Stanford University researchers to compare two groups of people with similar health characteristics who differed only by one week in age...
Bolstering the case for the shingles vaccine protecting against dementia were the findings from a study published in Nature Medicine in 2024 that analyzed medical records from more than 100,000 patients. That analysis suggested the newer shingles vaccine was associated with even better protection against dementia.
Two recent commentaries discuss some of the problems for aspiring physicians:
RP Walensky, LD Walensky. NEJM 2025; 392: 1251-1254. Application Overload — A Call to Reduce the Burden of Applying to Medical School
DB Holt, EA Elster. NEJM 2025; 392: 1249-1251. Rethinking Shadowing for Aspiring Physicians
In the first article, the authors detail the burden associated with the common-place high-volume applications to medical schools.
“The cost is approximately $150 per school for application fees, plus $345 for taking the MCAT and having the score distributed through AMCAS. These fees are waived for qualifying low-income applicants (as primarily defined by household income below 400% of the national poverty level) who apply to the AAMC Fee Assistance Program and provide the required financial documentation.2 After submitting the primary application, applicants face a flood of secondary applications, some requiring up to eight additional essays. Even when the essay prompts are similar to those from other schools, the instructions often specify different lengths. One premedical student posted on social media the findings of his review of 54 medical schools’ secondary applications: he identified 222 different prompts, which he provided to help applicants get a jumpstart on their frenzied essay writing.3..
Between 2013 and 2023, … the total number of applications and the average number of applications per student increased dramatically — by 40% (from 690,281 to 966,947) and 28% (from 14.4 to 18.4), respectively. Despite the disproportionate escalation in applications submitted, the success rate (matriculants divided by applicants) remained flat (range, 36 to 44%).”
The authors recommend limiting applications to 10 to 12 medical school applications per applicant. This would benefit students as well as faculty burdens.
“The secondary-application process also needs to be reined in. Medical schools could adopt standardized secondary essays… Under this model, a student applying to 10 schools would complete a maximum of 13 secondary essays — 3 standardized and 1 customized essay per school — rather than the current norm of 60 to 80 essays (e.g., 20 secondary applications with 3 to 4 distinct essays each).”
My take: In Charlie and the Chocolate Factory, there are only five golden tickets. If everyone buys twice as many Wonka bars, it is a lot more expensive and perhaps more time-consuming. For medical school applicants, applying to 20 or more programs does not help if almost everyone is doing this. It does disadvantage the minority who do not have the financial means or available time to complete this arduous task.
In the second commentary, the article details the problems with shadowing experiences.
“Medical school admission in the United States remains intensely competitive. In 2024, according to the Association of American Medical Colleges (AAMC), prospective students submitted an average of 18 applications apiece…Many medical school admissions committees consider shadowing a physician to be an essential clinical experience for professional identity formation, so nearly all applicants now do some shadowing: 95% of respondents to the 2024 AAMC Matriculating Student Questionnaire (MSQ) said they’d spent time observing a physician at work.1…
Premedical students are spending more time shadowing — sometimes hundreds to thousands of hours, which often necessitate taking a “gap year” between college and medical school at a financial cost…Three quarters of medical school applicants report taking time off before medical school, 50% taking 1 to 2 years and 25% taking 3 or more years...
These additional years delay entry into the workforce and result in higher levels of debt than moving more quickly toward potential earnings as a physician; one lost year of a physician’s salary (an average of $265,000) would result in an estimated net loss of $2 million by retirement if the money were invested at a 7% return…
Although medical schools consider clinical experiences other than shadowing, a review of our own data suggests that applicants who have shadowed physicians for more than 50 hours are more likely than their peers to be admitted — and more likely to come from higher-income families.“
The authors point out that unstructured observation is of unclear benefit. A course from Stanford, that far fewer hours (11-20 hrs) was sufficient for more than 90% of students “to decide whether medicine was the right career for them….The current emphasis on shadowing not only contributes to a longer and more expensive medical education pathway but also discourages nontraditional applicants and pursuit of genuine interests in other areas that make for well-rounded physicians.”
My take: The pathway to medical school has become more time-consuming and expensive. At the same time, it is doubtful that lengthy shadowing experiences or extensive numbers of applications are benefiting aspiring students.
gutsandgrowth 