“How to Make America Healthy: the Real Problems — and Best Fixes”

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H Pearson, Nature, 6/24/25: Partly Open Access! How to make America healthy: the real problems — and best fixes

An excerpt:

Since taking over as the top US health official in February, Robert F. Kennedy Jr has overseen radical changes that have alarmed many public-health experts…His mission, he says, is to ‘Make America Healthy Again’. “We are the sickest nation in the world,” he said in March, “and we have the highest rate of chronic disease.” His diagnosis holds some truth, say public-health specialists and analysts. Relative to other similarly wealthy nations, the United States has the shortest life expectancy despite spending the most on health care…And researchers agree that high rates of chronic disease, including heart disease and obesity, are key contributors to Americans’ higher death rates, as Kennedy emphasizes.

But researchers say that Kennedy — widely known as RFK Jr — has mostly ignored other leading causes of death and ill health, including car accidents, drug overdoses and gun violence…

Life expectancy in the United States was closer to the average for its peers around 1980 and gradually improved, according to KFF’s analyses. The gains were driven partly by a drop in smoking and increased use of cholesterol-lowering drugs known as statins…

Overall, chronic conditions — heart disease, cancer, stroke and respiratory disease — take up four out of five spots on the country’s list of biggest killers…One of the biggest drivers of those deadly conditions is obesity, say researchers. As of 2022, about 42% of adults were considered obese in the United States, compared with 27% in the United Kingdom and 5.5% in Japan. Obesity increases the risks of developing diabetes, heart disease, cancer and many other conditions. “The US has, particularly around diet, obesity and overweight, adopted unhealthier lifestyles at a higher rate than our country peers,” Bollyky says…

The problems caused by chronic disease are compounded by poor health care. Compared with a group of similar high-income countries, the United States is the only one that lacks universal health-insurance coverage… Lack of health insurance, high costs and other barriers prevent people from getting diagnoses and treatment early on…

The other big contributors to lower life expectancy in the United States — and what really sets the country apart, researchers say — are high death rates from substance misuse, car accidents, suicide and homicide (see ‘Varied causes’). These tend to kill people of working age…All told, the death rates in working-age people mean that one 5-year-old out of every 20 — or roughly one in every school class — will die before the age of 45, according to Angus’s calculations. The comparable figure is one in 50 in the United Kingdom and one in 100 in Switzerland…

Health spending in the United States was about US$13,000 per person in 2023, according to a KFF analysis. That compares to an average of about $7,000 per person in similar large, well-off countries…

Boosting rather than cutting spending on disease prevention is “where the big gains are
to be made on population health” [Reginald Williams, a health-policy specialist at the Commonwealth Fund says his] first priority would be to expand health coverage. In the United States, around 8% of people lack health insurance, compared with around 1% or less in similar high-income countries. The second, he says, would be to invest more in primary care — the physicians and other health professionals who are the first port of call for patients, and who deal with disease prevention and management…

Tackling the high death rates from overdoses and guns, meanwhile, would involve
addressing entrenched social and political issues such as gun ownership, poverty,
unemployment and inequality.

My take: Despite big promises from politicians, there are no quick fixes for improving our national health. Improving health care access would help but this does not address deaths due to firearms, drug overdoses and to car accidents.

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Infliximab for Autoimmune Hepatitis

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C Efe et al. Hepatology 2025; 81: 1660-1670. Efficacy and safety of infliximab in patients with autoimmune hepatitis

In this multicenter retrospective study, there were two groups of patients with autoimmune hepatitis (AIH) who received infliximab treatment:

  • Group 1 (n=20) had failed standard, second-line (mycophenolate mofetil and 6-mercaptopurine) or third-line (tacrolimus or cyclosporine) therapy.
  • Group 2 (n=22), infliximab was given for treatment of concomitant extrahepatic autoimmune diseases. Only 6 of these patients had active AIH at time of initiation of infliximab therapy

Key findings:

  • Overall, 65% (17/26) of the patients with active AIH achieved complete biochemical remission* (CR) on infliximab.  This included CR in 75% (6/8) of nonresponders to second-line and in 46% (6/13) of failing third-line therapy.
  • *CR defined as normalization of serum transaminases and IgG levels
  • Five patients developed anti-infliximab antibodies, 1 had an allergic reaction and 4 had a lack of control of a concurrent autoimmune disorder, prompting discontinuation of infliximab

My take: While a randomized controlled trial would be better, this study demonstrates that infliximab is an option for AIH, especially in those with concurrent immune-mediated disorders and in those not responding to standard therapy. It is worth noting that infliximab can paradoxically induce an autoimmune hepatitis and stopping infliximab therapy can be curative in these patients (we recently had such a case).

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Jump in Knowledge Regarding Gut-Brain Axis

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Eric Topol has summarized some of the recent advances in the understanding of the Gut-Brain Axis. Open Access Link: The Gut-Brain Axis Takes Center Stage (6/22/25)

Here’s a lengthy excerpt:

We’ve known about the gut-brain axis for decades but there has recently been an unprecedented jump in our knowledge base that has transformed our expectations for its preeminence.

There are 2 types of neural pathways, the “second brain” referring to the enteric (gut) nervous system from the cells that line the intestine and communicate to the vagus nerve to the brain (and in the opposite direction, too). There are also connections via the sympathetic, parasympathetic nervous system (autonomic nervous system, ANS) branches and spinal cord innervation to the gut primarily through the ANS.

Cells in the gut produce hormones (enteroendocrine cells) such as glucagon-like peptide (GLP-1), gastric inhibitory peptide (GIP), peptide YY, secretin, gherlin, gastrin, and many others. Some of these regulate pancreatic hormones such as insulin, glucagon and amylin, which can be considered as gut hormones but derived from pancreatic cells rather than intestinal lining cells. The hormonal interaction between gut and brain also goes through the hypothalamus-pituitary-adrenal (HPA) axis.

The abundant and diverse bacteria in the gut microbiome of tens of trillion of cells of more than 3,000 species. These gut bacteria and their metabolites have an outsized impact by producing or stimulating different neurotransmitters (5HT, GABA) and metabolites (e.g. short chain fatty acids, SCFAs) that communicate with the brain and the immune system. For example, see my previous Ground Truths on how a gut bacteria and its metabolites can drive sugar cravings.

The interaction with the immune system is critical to maintain integrity of the gut lining (avoiding “leaky gut syndrome”) and the blood-brain-barrier…

The precise way by which the gut can induce inflammation in the brain has remained unclear. In the journal Nature this week it was shown that inflamed gut-derived CD4+ T cells can infiltrate the brain, leading to neuroinflammation and neurological damage in the experimental model…bacteria derived proteins (antigens) looking like host derived proteins, inciting an immune response.

This was the second of 2 recent discoveries centered around gut-derived immune cells that get into the brain. Newly identified specialized CD4+ T cells from the gut and white adipose tissue establish residence in the brain’s subfornical organ and regulate feeding behavior…

It turns out the H. pylori can do good things too! As in blocking the formation of amyloid protein formation. This week in Science Advances it was demonstrated that H. pylori releases the protein CagA (cytotoxin-associated gene A) which potently inhibits pathogenic amyloid assemblies..for formation in Alzheimer’s disease, Parkinson’s disease and type 2 diabetes…

Several new gut hormone clinical trials, beyond the ones that are widely used—semaglutide (Ozempic) and tirzepatide (Zepbound, Mounjaro), were unveiled…Through randomized trials, their broad impact has been unequivocally proven for diabetes, obesity, and for treating related conditions of heart failure (with preserved ejection fraction), kidney disease, liver disease, sleep apnea, along with unexpected suppression of addiction to alcohol, cigarette smoking, nail biting and gambling. Add a surprising impact that we’re starting to see for autoimmune diseases. Even before there is weight loss with these drugs, there is evidence from experimental models of reduced systemic (body-wide) and brain inflammation. What is surprising is that drugs like semaglutide have little direct penetrance to the brain, but exert their effect chiefly through the gut-brain axis. New molecules in this class will have enhanced brain penetrance…

Will They Work For Alzheimer’s Disease?

[In a Liraglutide trial with 200 participants with Alzheimer’s,] after 1 year of treatment there was a reported 18% less cognitive decline and 50% reduced brain shrinkage compared to placebo…[There are also two studies] pending EVOKE and EVOKE Plus trials of daily oral semaglutide participants aged 55–85 years with mild cognitive impairment or mild dementia due to Alzheimer’s…About 12% of American adults are already taking GLP-1 drugs

U.S. Doctors Leaving For Canada

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B Kelman, NPR 5/29/25: American doctors look to relocate to Canada to avoid the Trump administration

An excerpt:

Earlier this year, as President Donald Trump was beginning to reshape the American government, Michael, an emergency room doctor who was born, raised, and trained in the United States, packed up his family and left the country…”Part of being a physician is being kind to people who are in their weakest place,” Michael said. “And I feel like our country is devolving to really step on people who are weak and vulnerable…”

The Medical Council of Canada said in an email statement that the number of American doctors creating accounts on physiciansapply.ca, which is “typically the first step” to being licensed in Canada, has increased more than 750% over the past seven months compared with the same time period last year — from 71 applicants to 615. Separately, medical licensing organizations in Canada’s most populous provinces reported a rise in Americans either applying for or receiving Canadian licenses, with at least some doctors disclosing they were moving specifically because of Trump…

 While it was once more difficult for American doctors to practice in Canada due to discrepancies in medical education standards, Canadian provinces have relaxed some licensing regulations in recent years, and some are expediting licensing for U.S.-trained physicians…

Michael, the physician who moved to Canada this year, said he had long been wary of what he describes as escalating right-wing political rhetoric and unchecked gun violence in the United States, the latter of which he witnessed firsthand during a decade working in American emergency rooms…

This desire to leave has also been striking to Hippocratic Adventures, a small business that helps American doctors practice medicine in other countries…

Alison Carleton, a family medicine doctor who moved from Iowa to Manitoba in 2017, said she left to escape the daily grind of America’s for-profit health care system and because she was appalled that Trump was elected the first time. Carleton said she now runs a small-town clinic with low stress, less paperwork, and no fear of burying her patients in medical debt.

My take: There are more than one million physicians in the U.S. per AAMC data; so the absolute numbers leaving are quite small. However, this uptick in physicians leaving is another indicator of U.S. physicians being unhappy with U.S. healthcare policy and the direction in which it is headed.

Related topic of physicians choosing alternative practice setting while staying in U.S.: YouTube: NEJM Interview: Zirui Song on the rise of concierge and direct primary care practices (13 minutes)

Related article: Z Song et al. N Engl J Med 2025;392:1977-1979. Primary Care — From Common Good to Free-Market Commodity

Throughout the United States, PCPs have been leaving traditional practices for concierge and direct primary care (DPC) practices, in which patients are offered personalized and more accessible primary care in exchange for membership or retainer fees… these models can offer physicians notable advantages over traditional primary care models, including greater clinical autonomy, more take-home pay, and improved work–life balance and job satisfaction.4,5 Less burdened by prior authorizations, insurance denials, billing and coding tasks, and other demands in traditional practices — including the need to adhere to regulatory requirements under alternative payment models — physicians often have more time for direct patient care...Yet trade-offs — in the form of decreased access for patients [without a concierge physician] and increased strain on PCPs in traditional primary care — are borne by the rest of society.

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Once-Weekly Mazdutide: Effective for Overweight and Obesity (GLORY-1 Study)

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L Ji et al. NEJM 2025; 392: 2215-2225. Once-Weekly Mazdutide in Chinese Adults with Obesity or Overweight

This study from China enrolled young participants (mean age 34 yrs) and lower BMI (mean 31.1) than in similar studies of other GLP1 RAs and GLP 1 RA/GIP dual agonists. However, there was a high prevalence of dyslipidemia (62.3%), MAFLD (48.9%), hyperuricemia (40.2%), and hypertension (22.8%).

Key findings:

  • At week 48, the mean percentage change in body weight from baseline was –11.00% in the 4-mg mazdutide group, –14.01% in the 6-mg mazdutide group, and 0.30% in the placebo group

My take: Mazdutide resulted in significant weight loss along with improvements in cardiometabolic measures. This study shows beneficial effects in a younger cohort with significant cardiometabolic disease. Improvements in younger populations is likely to result in more substantial effects on outcomes than improvement in older cohorts.

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Etrasimod for Eosinophilic Esophagitis?

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ES Dellon et al. Lancet Gastroenterol Hepatol 2025; 10: 622–33. Etrasimod as a treatment for eosinophilic oesophagitis (VOYAGE): a double-blind, placebo-controlled, randomised, phase 2 trial

Background: “Etrasimod is an oral, once-daily, selective S1P1,4,5 receptor
modulator for the treatment of moderately to severely active ulcerative colitis and in development for the treatment of other immune-mediated inflammatory diseases. Etrasimod prevents trafficking of lymphocytes to inflamed mucosal tissue and sites of primary disease
manifestation, offering a unique, promising mechanism for the treatment of eosinophilic oesophagitis.”

There were 108 participants in this study: 41 patients received etrasimod 2 mg, 39 received etrasimod 1 mg, and 28 received placebo.

Key findings:

  • Median percentage changes from baseline in peak eosinophil count (PEC) at week 16:6 were −58·4% for etrasimod 2 mg (p=0·010 vs placebo), −39·4% for etrasimod 1 mg (p=0·29 vs placebo) and −21·5% for placebo.
  • Significant reductions from baseline in oesophageal PEC were achieved with both etrasimod
    doses (n=27 for 2 mg n=28 for 1 mg) at week 24 versus placebo (n=19), with a numerically larger reduction seen with the 2 mg dose, which had a median placebo-adjusted difference of –103·9% from baseline in oesophageal PEC. Oesophageal PEC did not decrease further with longer etrasimod treatment during the extension period (to 52 weeks in a smaller subset)
  • Etrasimod 2 mg was associated with a significant improvement in DSQ score at week 24 versus placebo in patients with no history of dilation (LS mean −21·6 vs –9·6, p=0·031)
  • No serious treatment-emergent adverse events occurred.

My take (borrowed from the authors): “This [phase 2] study provides the first evidence
that targeting the S1P pathway can improve disease activity in eosinophilic oesophagitis. Given that current treatment options for eosinophilic oesophagitis have variable and incomplete response rates, etrasimod presents a promising option.” Larger studies are warranted.

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Wat Arun (Temple of Dawn), Bangkok

Sulfasalazine vs 5-ASA: Treatment Outcomes in Pediatric UC

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I Mansuri et al. J Pediatr Gastroenterol Nutr. 2025;80:988–997. Clinical outcomes of maintenance therapy with sulfasalazine compared to 5-aminosalicylates in children with ulcerative colitis

Methods: This was a retrospective review of children diagnosed with UC between June 1999 and December 2019 at Boston Children’s Hospital. 124 started on sulfasalazine (SZ) and 309 on 5-aminosalicylates (5-ASA). Most patients had mild to moderate disease based on PUCAI score; ~12% had severe disease.

Key findings:

  • At 1 year, 54%, 44.3%, and 36.6% of patients on SZ, 5-ASA, and those who switched, respectively, were in steroid-free remission (p = 0.13)
  • All medication switches due to adverse reactions (24) were from SZ to 5-ASA. No patient was switched from 5-ASA to SZ because of adverse reactions. The non-severe adverse reactions noted were nausea, vomiting, abdominal pain, non-severe skin rash, headache, mild leucopenia, and lymphadenitis. Three patients had serious skin reactions, and one had pancreatitis.
  • SZ tended to have more minor adverse reactions. Except for countering adverse reactions, switching between SZ and 5-ASA did not offer therapeutic benefits. Disease severity at diagnosis predicted early treatment escalation

Discussion Points:

  • SZ offers advantages such as lower cost and availability in suspension form; the suspension form is particularly beneficial for young children and those unable to swallow the solid form of medication.
  • 5-ASA formulations can be almost 10–50 times more expensive than SZ. For example, the wholesale acquisition cost of monthly generic SZ is $30 compared to $274 for generic Lialda, $1131 for generic Pentasa, and $1890 for generic Asacol HD

My take: About 20% of patients had to switch from Sz to 5-ASA due to adverse reactions; though, Sz had a mildly higher response rate (not statistically-significant). Switching between SZ and 5-ASA or vice versa is unlikely to provide much therapeutic benefit; patients who switched agents for medical reasons (rather than reactions) were more likely to require escalation to either a biologic or immune modulator.

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Chatttahoochee River (Sandy Springs)

Retrospective Study on Botulinum Toxin for Refractory Constipation in Children

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D Patel et al. J Pediatr Gastroenterol Nutr. 2025;80:956–962. Efficacy of anal botulinum toxin injection in children with functional constipation

Methods: This was a retrospective, multicenter study including pediatric patients (n=63) who received anal botulinum toxin (BTX) for functional constipation (FC) refractory to medical therapy.  Response to therapy was assessed based on improvement in weekly frequency of BM (bowel movements) to 3 or more per week and/or resolution of functional incontinence (FI)

Key findings:

  • There was a a response rate of 10% in group 1 (FC +FI), 50% in group 2 (only FC) and 14% in group 3 (only FI); the an overall symptom resolution in 21% of patients
  • Fecal incontinence was the most common side effect, reported in 11% of all patients 

My take: In this highly-selected refractory population, there was a poor response to BTX in those with fecal incontinence (groups 1 and 3). The results should be interpreted with caution due to the retrospective nature of the study and the a lack of a control group.

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Liver Transplantation for PSC: Long-term Outcomes and Complications

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M Mouchli et al. Liver Transplantation 2025; 31: 781-792. Long-term (15 y) complications and outcomes after liver transplantation for primary sclerosing cholangitis: Impact of donor and recipient factors

Methods: Using Mayo clinic prospectively maintained transplant database, 293 adult patients (>18 y, mean age 47 yrs) with PSC who underwent LT from 1984-2012 were identified. Patients with cholangiocarcinoma were excluded. One hundred and thirty-four patients received LT before 1995, and 159 were transplanted after 1995.

Key findings:

  • The 1-, 5-, 10-, and 15-year cumulative incidence of recurrent PSC was 1.0%, 8.0%, 23.5%, and 34.3%, respectively.
  • Vascular and biliary complications are frequent: hepatic artery thrombosis (N = 30), portal vein stenosis/thrombosis (N = 48), biliary leak (N = 47), biliary strictures (N = 87)
  • Graft failure occurred in 70 patients
  • Donor age >60 years was associated with an increased risk of recurrent PSC. 

My take: Overall, there was a good survival rate despite the increased frequency of vascular and biliary complications. Also, 2/3rds of patients did NOT have recurrent PSC. Older donor age was associated with higher graft failure in this cohort.

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RSV Vaccine and Treatment Lowered Hospitalizations in Infants

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Beth Mole, Ars Technica 5/08/25: New RSV vaccine, treatment linked to dramatic fall in baby hospitalizations

An excerpt:

RSV, or respiratory syncytial (sin-SISH-uhl) virus, is the leading cause of hospitalization for infants in the US. An estimated 58,000–80,000 children younger than 5 years old are hospitalized each year. Newborns—babies between 0 and 2 months—are the most at risk of being hospitalized with RSV…

But the 2024–2025 season was different—there were two new ways to protect against the infection. One is a maternal vaccine, Pfizer’s Abrysvo, which is given to pregnant people when their third trimester aligns with RSV season (generally September through January)…the other new protection against RSV is a long-acting monoclonal antibody treatment, nirsevimab, which is given to babies under 8 months old as they enter or are born into their first RSV season and may not be protected by maternal antibodies.

For the new study, CDC researchers looked at RSV hospitalization rates across two different RSV surveillance networks of hospitals and medical centers (called RSV-NET and NVSN)…

The analysis found that among newborns (0–2 months), RSV hospitalizations fell 52 percent in RSV-NET and 45 percent in NVSN compared with the rates from the 2018–2020 period.However, when the researcher excluded data from NVSN’s surveillance site in Houston—where the 2024–2035 RSV season started before the vaccine and treatment were rolled out—there was a 71 percent decline in hospitalizations in NVSN.

For a broader group of infants—0 to 7 months old—RSV-NET showed a 43 percent drop in hospitalizations in the 2024–2025 RSV season, and NVSN saw a 28 percent drop.Again, when Houston was excluded from the NVSN data, there was a 56 percent drop.

Lastly, the researchers looked at hospitalization rates for toddlers and children up to 5 years old, who wouldn’t have been protected by the new products. There, they saw RSV hospitalization rates were actually higher in the 2024–2025 season than in the pre-pandemic years.

Related CDC link: Healthcare Providers: RSV Immunization for Infants and Young Children

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