Category: 8. Health

Introduction

Inflammatory bowel disease is a group of chronic nonspecific intestinal diseases, including ulcerative colitis (UC) and Crohn’s disease (CD), characterized by remission and relapse. The current incidence of IBD in Asia is 1.4 cases per 100,000.¹ Among the Asia Pacific Crohn’s and Colitis Epidemiologic Study countries, the incidence of IBD in India is 9.3 per 100,000 person-years and in China is 3.3 per 100,000.¹ Gut microbiota, immune response, external environment and individual genetic susceptibility are closely related to the occurrence and development of IBD.^2,3 IBD is currently incurable and has a tendency to recur and exacerbate. Effective monitoring and evaluation of the disease is required, which helps physicians to adjust treatment plans in a timely manner based on disease activity, lesion severity, complications, and patient response to drugs. Endoscopic assessment is considered to be the “gold standard” for evaluating intestinal lesions and plays a very important role. However, endoscopy is an invasive procedure with certain risks, which often makes patients feel uncomfortable and is expensive. Frequent endoscopy is painful for patients. In clinical practice, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are the most commonly used biomarkers for monitoring IBD activity. However, the two are easily affected by various factors in the body, and are also elevated in infection, cancer, and cardiovascular disease.⁴ Fecal calprotectin (FC) has begun to be used in the assessment of intestinal inflammation in some regions. However, due to the fact that there is no uniform standard for its cut-off value, and the technical conditions of detection FC are limited, it is still not widely used in medical institutions. Therefore, we need to find a more widely applicable and easily detectable biomarker to monitor the activity of the disease.

Studies have shown that inflammation and lipid metabolism interact with each other.^5,6 Inflammation can lead to the accumulation of intracellular lipids and the loss of the function of lipoproteins. Conversely, the imbalance of lipid metabolism can also cause inflammatory responses and the release of inflammatory factors. Dyslipidemia has been demonstrated in some chronic inflammatory diseases, such as systemic lupus erythematosus (SLE), which has a particular pattern of dyslipoproteinemia characterized by low HDL levels and increased triglycerides in flares aggravated.⁷ Atherosclerosis is considered a chronic inflammatory process, and dyslipidemia is a major risk factor for coronary artery disease. Diets high in saturated fatty acids and processed meats have been found to exacerbate the risk of IBD.⁸ In contrast, a high-fiber diet was associated with a 40% reduction in CD risk.⁹ This may be attributed to the production of short-chain fatty acids with anti-inflammatory properties by colonic bacteria during digestion of dietary fiber.¹⁰ It has been reported that six lipid species and seven metabolites were significantly altered in IBD patients, with the majority belonging to glycerophospholipid, linoleic acid, and sphingolipid metabolisms.¹¹ Compared to CD, five lipid species and only one metabolite were significantly increased in UC. It is suggested that serum lipid and metabolite profiles may be used as monitoring indicators for IBD and to distinguish CD from UC.¹¹ In the treatment of IBD, delivery systems using a variety of materials such as polymers, silica, chitosan (CS), liposomes and cell membranes have been successfully developed. Cell membrane nanomaterials composed of phospholipids and glycoproteins have been used for drug delivery in inflammatory bowel disease.¹²

There are geographical differences in the incidence and clinical manifestations of IBD. At present, there are inconsistent conclusions about serum lipid levels in IBD patients, and there is a lack of research on the correlation between IBD disease activity and serum lipid levels. The aim of this study was to describe the LDL and HDL levels of Chinese IBD patients, to explore their correlation with IBD disease activity and their value in disease activity assessment.

Methods

Study Design and Patient

In this retrospective study, electronic medical charts of patients with IBD were collected from Wuhan Union Hospital and Tongji Hospital, which are top tertiary referral centres and IBD centres in China. Between December 2015 and December 2022, data on patient demographic information, clinical symptoms, comorbidities, complications, treatments, laboratory test, imaging examination, endoscopy findings and pathology reports were collected. The diagnosis of IBD was confirmed after review of admission notes, laboratory, radiological, endoscopic and histological reports. Lipid measurements were obtained for each patient only on the second day of admission. Inclusion criteria were as follows: a) age from 18 to 65 years; b) all patients underwent endoscopy and the clinical data were complete. Exclusion criteria were as follows: a) combined with other autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, etc; b) a history of hyperlipidemia, liver cirrhosis, asthma, malignancy; c) currently experiencing bacterial or viral infection; d) a history of taking lipid-lowering drugs or were taking lipid-lowering drugs. Healthy subjects were included as the control group.

Assessment of Disease Activity

The Montreal classification was used to classify the location and behavior of the disease.¹³ Clinical disease activity was measured by the Harvey–Bradshaw Index (HBI)¹⁴ for CD and the modified Mayo clinical score for UC.¹⁵ Clinical activity was defined as HBI >4 for CD or Mayo clinical score >2 for UC. Crohn’s Disease Endoscopic Index of Severity (CDEIS) score was used for endoscopically active of CD patients, CDEIS ≤ 3 suggested inactive.^16,17 The Ulcerative Colitis Endoscopic Index of Severity (UCEIS) served for endoscopic scoring and a UCEIS = 0 indicated remission.¹⁸ All patients underwent endoscopy by experienced physicians.

Statistical Analysis

Continuous variables were described as medians and interquartile ranges (IQRs), and categorical variables were expressed as counts and percentages. We adopted the Mann–Whitney U-test or Kruskal–Wallis test to analyze continuous variables. Spearman’s rank correlation (r) served as exploring associations between two variables. Receiver operator characteristic (ROC) curves were plotted to estimate the thresholds for LDL, HDL, CRP and ESR in assessing moderate-severe disease activity. Comparing the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the thresholds. All of the data were analyzed in SPSS version 22.0 and MedCalc 19.5.6. P < 0.05 was considered statistically significant.

Results

A total of 490 patients with IBD (280 CD and 210 UC) and 200 healthy controls were enrolled in this study (Table 1). In CD patients, the median age was 28 years (IQR, 23–38), and 202 (72.1%) cases were male. There were 62.9% of male in UC and the median age was 45 years (IQR, 33–53). Ileocolon (L3) was the most common disease location in CD and left-sided colitis disease extent in UC.

Table 1 Demographic and Clinical Characteristics of the Study Population

Serum Biomarkers Levels and Lipid Profile in Patients with IBD

The median LDL level was 2.11 mmol/L in CD and 2.25 mmol/L in UC, both lower than 2.64 mmol/L (p<0.001) in healthy control. And the median HDL level of IBD patients was also lower than that of healthy controls (CD, 1.03 mmol/L vs 1.23 mmol/L, p<0.001; UC, 1.08 mmol/L vs 1.23 mmol/L, p<0.001). Compared with healthy controls, the levels of CRP (p<0.001) and ESR (p<0.001) were significantly higher in IBD patients (Table 2).

Table 2 Laboratory Findings of IBD Patients and Healthy Controls

In CD, there were no statistically significant differences in LDL levels between different disease activity groups (66 remission; 98 mild disease activity; 73 moderate disease activity; 43 severe disease activity) (p=0.5). On the contrary, there were statistically significant differences in HDL, CRP, ESR, PLT, albumin, and BMI levels (p<0.001). In CD patients with severe disease activity, the levels of HDL and albumin were lowest, conversely, both were highest in CD remission patients (Table 3). In UC, there were statistically significant differences in LDL, HDL, CRP, ESR, PLT, and albumin levels between different disease activity groups (16 remission; 63 mild disease activity; 105 moderate disease activity; 26 severe disease activity) (p<0.001). The levels of LDL, HDL and albumin were lowest in patients with severe disease activity, while they were highest in UC remission patients (Table 4).

Table 3 Comparison Between Indicators Classified According to Different Activity Groups of CD

Table 4 Comparison Between Indicators Classified According to Different Activity Groups of UC

Serum LDL and HDL Levels with IBD Disease Activity

LDL levels were not correlated with HBI, CDEIS, CRP levels, and ESR levels in patients with CD, however, there was a negative correlation between HDL and HBI (rs= −0.0341, p<0.001, CDEIS (rs= −0.304, p<0.001), CRP (rs= −0.557, p<0.001) and ESR (rs= −0.484 p<0.001), respectively. In UC patients, both LDL levels and HDL levels were negatively correlated with Mayo clinical scores, UCEIS, CRP levels and ESR levels respectively. The correlation of HDL and Mayo clinical scores was stronger than that of LDL and Mayo clinical scores. Besides, the correlation of HDL and UCEIS was stronger than that of LDL and UCEIS. The relationships between LDL, HDL and inflammatory markers were similar to those described above (Table 5, Figures 1 and 2).

Table 5 Correlation Between LDL, HDL and IBD Disease Activity

Figure 1 The correlation between LDL, HDL and disease activity in CD patients.

Figure 2 The correlation between LDL, HDL and disease activity in UC patients.

The Value of LDL and HDL in the Evaluation of Moderate-Severe IBD Activity

Patients with CD and UC were divided into remission-mild activity and moderate-severe activity, respectively. In CD, the accuracy of HDL in evaluating moderate-severe disease activity was similar to that of CRP and ESR (AUC=0.617 vs AUC=0.671, and AUC=0.691, respectively), and, the specificity of HDL (65.85%) was higher than CRP (52.44%) and ESR (60.98%). In this study, LDL (p=0.6099) could not be used to distinguish between remission-mild and moderate-severe CD activity (Table 6 and Figure 3).

Table 6 Receiver‐operating Characteristic Analysis of LDL and HDL in Evaluating Moderate- Severe Activity in IBD Patients

Figure 3 Receiver‐operating characteristic analysis of LDL and HDL in evaluating moderate- severe activity in CD patients.

In UC, both LDL and HDL could be used to evaluate whether the disease was moderate-severe activity. The sensitivity of LDL was slightly higher than that of CRP (65.65% vs 60.31%, p=0.0390). The specificity and sensitivity of HDL in evaluating moderate-severe disease activity were 87.34% and 46.56%, respectively (Table 6 and Figure 4).

Figure 4 Receiver‐operating characteristic analysis of LDL and HDL in evaluating moderate- severe activity in UC patients.

Discussion

In this study, we evaluated the correlation of LDL and HDL with inflammatory bowel disease activity and their value as potential biomarkers of IBD. We found that LDL levels and HDL levels in IBD patients were significantly lower than those in healthy subjects. Both were correlated with disease activity, and this correlation was more significant in UC patients. In addition to being involved in cholesterol transport, LDL and HDL were also associated with inflammation and sepsis recovery,¹⁹ and some studies had found the changes of lipid profile in IBD patients. In 1996, Becker et al found that CD patients who underwent ileal resection had low cholesterol and high triglyceride (TG) levels.²⁰ Later, Romanato et al reported significantly lower LDL and HDL levels in patients with CD recurrence than in remission.²¹ In a prospective study that followed 701 IBD patients, it was found that compared with the general population, IBD patients had lower levels of total cholesterol (TC), LDL and HDL, higher TG levels, and this lipid pattern was more significant in CD patients than in UC patients.²² However, a study by Sappati Biyyani et al showed that compared with the control group, IBD patients had lower TC and HDL-C levels but higher LDL-C and TG levels, which was inconsistent with the above studies.²³ Our results showed that Chinese IBD patients have low LDL and HDL levels. LDL demonstrates higher sensitivity than CRP in assessing patients with moderate-to-severe UC, which helps to better assess these individuals. HDL has a higher specificity than CRP and ESR in CD and UC. Detection of HDL might help assess moderate to severe IBD patients, and detection of LDL might help identify moderate to severe UC patients. In clinical practice, adding these indicators can help improve the accuracy of the assessment.

Inflammation and lipid metabolism interact. SLE had a particular pattern of dyslipoproteinemia characterized by elevated levels of very low-density lipoproteins and triglycerides and lower HDL-C, called the “lupus pattern”.²⁴ Multiple mechanisms can induce an altered lipoprotein metabolism in SLE, such as the production of autoantibodies against lipoprotein lipase. Also, the presence of inflammatory cytokines such as tumor necrosis factor (TNF), interleukin-6 (IL-6) and interferon-gmay downregulate lipolytic enzyme activity, resulting in dyslipidemia.²³ IL-6 and acute phase protein participated in lipid metabolism, inhibit LPL activity of adipocytes and thus interfered with serum lipoprotein metabolism. TNF-α can mediate some of the effects of IL-6, as well as induce lipolysis and triglyceride synthesis.^25,26 It has been found that Infliximab induction therapy is associated with a significant increase in abdominal fat tissue in CD patients.²⁷ HDL-IgG antibody can be detected in SLE and RA, which was considered to be closely related to HDL dysfunction.^28,29 The highest anti-HDL levels were found in systemic autoimmune rheumatic conditions (MCTD, pSS, and AAV) as well as in IBD, whereas increased anti-HDL levels were not observed in organ-specific autoimmune diseases.³⁰ A remarkable finding was the difference in anti HDL levels among different immune-driven diseases. An increased CVD risk has been documented in IBD, especially during disease flares, suggesting the involvement of immune-driven mechanisms and blood lipid outcomes were effected by anti-HDL.³⁰

The exact mechanism of HDL decrease in inflammation was not clear and may involve multiple pathways. It is demonstrated that human acute inflammation can induce selective remodelling of HDL with induction of specific HDL lipases, suppression of CETP and LCAT activity, HDL enrichment with SAA, loss of specific small-medium sized HDL particles, and reduction in selective HDL cholesterol efflux functions.³¹ In acute inflammation, the synthesis of apo A-1 in liver decreased, and a large amount of serum amyloid A protein (SAA) was produced. SAA replaces apo A-1 to combine with HDL, which accelerated the clearance of HDL.^31,32 But over-expression of SAA in non-acute inflammatory stage does not lead to the decrease of HDL level.³³ The inflammatory reaction reduced the lecithin cholesterol acyltransferase (LCAT), led to the decrease of cholesteryl ester formation, and affected the synthesis of HDL. Cytokines can induce the increase of enzymes that metabolize key components of HDL, such as secretory phospholipase A2 (sPLA2) and endothelial lipase, leading to change the stability and metabolism of HDL.³²

IBD patients display dyslipidemia with significantly lower HDL cholesterol. The intestine was the second most important site of HDL production, low HDL cholesterol has traditionally been interpreted to be the consequence of IBD.³⁴ However, research shows that in addition to its role in reverse cholesterol transport, HDL had anti-inflammatory, antithrombotic and cytoprotective effects.³⁵ Gerster et al found that HDL and apoA-I suppress intestinal inflammation, both in vitro and in vivo.³⁴ In an in vivo model of intestinal inflammation, colonoscopy and histology showed increased mucosal damage and inflammation in apoA-I knockout mice, which lack HDL. In contrast, transgenic mice overexpressing human apoA-I, which has very high plasma levels of HDL, were protected from intestinal inflammation.³⁴ A prospective study of approximately 10 million individuals found a association between serum lipid profiles and the incidence of IBD.³⁶ In individuals without concomitant use or history of statin, low level of TC, LDL‐C, HDL‐C were associated with developing CD, and low serum TG levels were related to development of UC.³⁶ The use of certain medications, such as long-term antibiotics, birth control pills, and statins, has been associated with an increased risk for inflammatory bowel disease.¹² Such findings may implicate pre-clinical inflammation with increased catabolism or increased retention of lipids rather than decreased production. HDL also decreased cholesterol levels in lipid rafts of cell membranes by promoting a removal of cholesterol from peripheral cells, leading to decreased number of major histocompatibility complex class II molecules and impaired T-cell activation.³⁷

In the latest therapeutic strategy for IBD, the use of activated immune cell membrane (eg, macrophage membrane, neutrophil membrane) to encapsulate nanoparticles or drugs can form an excellent delivery system.^12,38 This immune cell membrane encapsulation has the effect of immune escape, extending the circulation time of drugs in the blood, and achieving precise targeting of inflammation.¹² This strategy provides a new idea for improving the efficacy of clinical targeted therapy for IBD. In another study, Escherichia coli Nissle 1917 (EcN) was prepared as EcN ghosts for drug delivery.³⁹ It demonstrated excellent safety and effectiveness.

Intestinal microbiota stability is an important factor affecting nutrient absorption, metabolism, immune regulation, and resistance to pathogen infection.⁴⁰ Encapsulation of drugs with unique cell membranes, such as probiotic outer membranes, fungal cell membranes, can minimize the influence of the GI environment, target inflammatory sites in the gut, and improve the efficacy and safety of probiotics and drugs.^12,41

Patients with IBD had slightly lower levels of total cholesterol and low-density lipoprotein cholesterol, but the risk of cardiovascular diseases was increased. It may be linked to chronic systemic inflammation rather than to traditional cardiovascular risk factors.⁴² Ridker et al found that reducing inflammation reduced the risk of cardiovascular events without affecting lipid levels in a non-IBD population.⁴³ Decrease in LDL and HDL may indicate impaired intestinal absorption, as CD may involve the whole GI tract, including the small bowel. Subclinical stage of the disease may hinder the absorption of dietary intake in the small bowel. The distal ileum was the main site of bile acid absorption and a common lesion site in IBD, especially in CD. Intestinal malabsorption caused the loss of bile acids and cholesterol through the stool, leading to low lipoprotein levels. A prospective study of CD patients undergoing intestinal surgery showed that TC, HDL-C, and LDL-C levels were significantly increased in patients in remission compared that in recurrent activity.^21,44 Our study showed that LDL was not associated with CD activity, which may be related to intestinal malabsorption due to CD may involve the whole digestive tract.

This study had some limitations. Firstly, this was a retrospective study in a single center, which was a tertiary referral center treating complex IBD cases. The results may be influenced by selection bias and memory bias, and the effect of lipid profile on IBD incidence could not be assessed. Second, our study did not assess lipid profiles in IBD patients who were not 18 to 65 years old, and the correlation between lipid profile and disease activity in these individuals was not clear. Furthermore, this study did not evaluate the relationship between lipoproteins and FC, which was considered as a marker reflecting endoscopic lesions in IBD, and only included inflammatory markers CRP and ESR. Finally, given that our study is retrospective, further mechanistic studies and large-scale prospective studies are warranted to validate our findings.

Conclusion

In conclusion, our study demonstrated that the serum levels of LDL and HDL in IBD patients were lower than those in healthy subjects. LDL was negatively correlated with disease activity in UC, and HDL was negatively correlated with that in both CD and UC. HDL was more specific than traditional inflammatory markers CRP and ESR in distinguishing between moderate to severe and non-moderate to severe disease activity. We propose LDL and HDL as potential biomarkers for assessing IBD activity with further research, LDL and HDL may be used in the assessment of disease activity in clinical practice.

Ethics Statement

The study was carried out according to the Declaration of Helsinki and approved by the Ethics Commission of Tongji Medical College. All data were anonymized to maintain participants’ privacy. This study was observational and met all the following criteria: a) the risk to the subjects of this study was minimal; b) waiving informed consent will not affect the rights and health of the subjects; c) due to the long time span of case collection and the loss of contact information of some patients, it was impossible to contact them; d) a commitment was made to inform the subjects of the relevant information at an appropriate time after the end of the study; e) the study could not be conducted effectively without waiver of informed consent. So, the requirement of informed consent was waived.

Author Contributions

All authors made substantial contributions to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation; took part in drafting, revising or critically reviewing for important intellectual content; have agreed on the journal to which the article will be submitted; gave final approval of the version to be published; agree to take responsibility and be accountable for the contents of the article.

Funding

This work was supported by National Natural Science Foundation of China [grant number [82270559, 82070572, 81770554, 82273321, 81974383, 81772607].

Disclosure

The authors report no conflicts of interest in this work.

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Breast cancer remains a major health concern, with cases rising among younger women under 50. Research shows an increase in estrogen-receptor positive tumours, which grow in response to estrogen, highlighting the importance of understanding hormone-driven cancers. Awareness of breast cancer risk influences health monitoring and preventive behaviours, including regular screening and self-examination. Recognising common symptoms such as lumps, nipple changes, and skin dimpling, along with understanding causes and risk factors like genetics, hormones, lifestyle, and environmental exposures, is crucial. Practising early detection and adopting healthy habits are essential strategies for effectively managing breast cancer in younger women.

Understanding risk perception and health monitoring in younger women at risk of breast cancer

A study published in the Journal of the National Cancer Institute Monographs examined younger women at increased risk of breast cancer. It explored how their perception of risk affected psychological well-being and health monitoring behaviours. The research found that heightened awareness of personal risk influenced both mental health and the likelihood of performing regular breast checks. These findings underscore the importance of addressing both emotional and behavioural aspects of breast cancer risk to support younger women in early detection and preventive care.

Breast cancer and its common symptoms

Breast cancer occurs when cells in the breast grow uncontrollably, forming a tumour. It can originate in different parts of the breast, such as the ducts (ductal carcinoma) or lobules (lobular carcinoma). Some tumours are hormone-sensitive, meaning they grow in response to hormones like estrogen or progesterone.Early detection is critical, as treatment is most effective when cancer is identified at an initial stage.Common symptoms of breast cancerRecognising symptoms early can save lives. Common signs include:

Not all lumps are cancerous, but any unusual changes should be evaluated by a healthcare professional promptly.

Estrogen-receptor positive tumours on the rise

Younger women at increased risk for breast cancer are showing a higher prevalence of estrogen-receptor positive tumours, which grow in response to estrogen, a hormone in the body. In simple terms, these tumours have receptors that “feed” on estrogen, making the hormone a key factor in their growth. In contrast, estrogen-receptor negative tumours do not rely on estrogen and are becoming less common. The study also highlighted that awareness of personal risk influences women’s health monitoring behaviours, emphasising the need for early detection, education, and targeted preventive strategies to manage hormone-driven cancers effectively.Estrogen-receptor positive tumours grow in response to estrogen.Estrogen-receptor negative tumours are decreasing.Risk awareness affects monitoring and health behaviours.

Causes and risk factors of breast cancer

Several factors may contribute to the rising trend of breast cancer in younger women:

Prevention and early detection

Early detection and preventive strategies can significantly reduce risk:

Disclaimer: This article is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional before making any changes to your health routine or treatment.

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Although the material damage from 2012’s Hurricane Sandy may have been repaired, the storm left a lasting impact on cardiovascular health, according to new findings from Weill Cornell Medicine and New York University researchers.

The study, published Sept. 3 in JAMA Network Open, found that older adults living in flood-hit areas in New Jersey faced a 5% higher risk of heart disease for up to five years after Sandy’s landfall. This is one of the first studies to rigorously quantify long-term cardiovascular risks associated with flooding in older adults. Most studies focus on the immediate consequences of severe weather events.

“Climate-amplified hurricanes and hurricane-related floods are expected to increase into the future,” said Dr. Arnab Ghosh, assistant professor of medicine at Weill Cornell Medicine and an internist at NewYork-Presbyterian/Weill Cornell Medical Center, who led the research. “So, it’s essential to understand the long-term health effects on those most vulnerable.”

Natural Controlled Experiment

The researchers analyzed Medicare data from over 120,000 people aged 65 and older living in New Jersey, New York City, and Connecticut in the five years after the storm.

They compared ZIP code areas that were flooded during the hurricane to nearby ZIP code areas that weren’t, matching the communities in terms of age, income, race and health status before the storm. Using advanced statistical models, the team tracked heart-related health events like heart attacks, strokes and heart failure in people who did not relocate after the hurricane.

“Capitalizing on such a large, diverse and stable patient population as Medicare recipients, allowed our team to see broader population trends while controlling for many of the threats to validity, whether socio-economic factors or the prevalence of co-morbidities,” said senior author Dr. David Abramson, clinical professor of social and behavioral sciences in the School of Global Public Health at New York University. The researchers concluded that heart failure rates were higher in flooded areas, especially in New Jersey, and that the risk persisted for four to five years—not just weeks or months—after the storm.

They hypothesize that more people in New Jersey were directly affected by the storm’s physical and emotional stressors. Flooded zip codes in New Jersey had lower median incomes and higher area deprivation index scores, which are indicators of social and economic disadvantage. These factors are linked to worse health outcomes and lower access to care, especially after a disaster. The residents also faced lingering difficult environmental and psychological circumstances and reduced community support.

In a related study published last month in Frontiers in Public Health, Dr. Ghosh and his colleagues found that the rate of death in elderly individuals living in areas flooded after Sandy was 9% higher on average five years later compared to those in less affected neighborhoods. The magnitude of this effect varied by region. While New York City saw an 8% increase in mortality, Connecticut had a 19% increase. However, the rest of coastal New York, including Long Island, and New Jersey seemed to escape this effect.

“The regional differences that we noted may highlight how local environments differ and need further examination,” Dr. Ghosh said. “New York City, for example, is heavily urbanized, while impacted parts of Connecticut and New Jersey are suburban with different infrastructure and more single-family homes.”

Taking a Longer-Term View

The study suggests that disaster preparedness and recovery frameworks should integrate chronic disease management and long-term health monitoring, not just short-term emergency care. The findings are particularly relevant for climate resilience planning, especially in regions with aging populations and increasing hurricane exposure.

“We are starting to appreciate that disasters are happening more frequently. But our policies and support systems for vulnerable groups after severe weather has struck haven’t been well developed,” Dr. Ghosh said.

Given the regional variation in health outcomes, localized health system preparedness is essential, added the researchers. This includes resource allocation, training and infrastructure to manage chronic disease burdens in the aftermath of disasters.

“With this work, we lay the groundwork to show that hurricanes can have long-term impacts on health,” said Dr. Ghosh. Building on these results, the researchers are now planning to conduct larger-scale analyses on the health consequences of other events such as wildfires and tornadoes. Another aspect they plan to study involves how increased health risks related to weather affect Medicare, Medicaid and the health care system financially.

This work was supported with funding from the National Heart, Lung, and Blood Institute and the National Center for Advancing Clinical Translational Science, both part of the National Institutes of Health, through grant numbers  R03TR004976 and K08HL163329.

On August 6, the Science of Skin and Scalp Studio opened its doors at Home Studios in New York City for a 1-day immersive event focused on awareness, education, and authentic conversations around chronic skin and scalp conditions. Building on 5 years of the Science of Skin initiative, the Studio was designed to spark dialogue between dermatologists, beauty experts, and patient influencers living with inflammatory diseases.¹ Attendees moved through interactive experiences such as The Derm Desk, The Scalp Lab, and The Beauty Bar, each tackling unique aspects of skin and scalp health.

At The Derm Desk, Heather Woolery-Lloyd, MD, FAAD, dermatologist and director of the Skin of Color Division at the University of Miami, led a myth-busting discussion on the challenges faced by patients with skin of color. In an interview with Dermatology Times following the event, Woolery-Lloyd expanded on these themes, offering clinical insights into misconceptions, disease presentation, and strategies to improve culturally sensitive care.

Misconceptions in Patient and Clinician Perspectives

One of the most significant patient misconceptions, Woolery-Lloyd explained, is the delay in seeking dermatologic care for scalp and hair conditions. She noted, “I definitely think there’s this misconception that when you have hair loss, you see your hair stylist, you ask your friend, your aunt, anyone else, and really you should really be making a beeline straight to the dermatologist for scalp conditions.”

From a clinician’s standpoint, she added that treatment recommendations have not always accounted for textured hair practices. “People might say, ‘Oh, you need to wash your hair every single day with a medicated shampoo.’ And we know in women with textured hair that’s not realistic. It’s never going to happen because the hair styling process can take hours.”

Woolery-Lloyd emphasized the importance of offering patients choices that fit their hair type and styling routine. “Some people might like oil formulation. Depending on their hair type or texture or hairstyle, some might prefer a solution. So I don’t assume anything for my patients when it comes to the topical treatment of scalp conditions. I explain to my patients there are many different vehicles available — which would you prefer? You might want an ointment, you might want an oil, you might want a foam. You might want a liquid solution. I don’t make the decision. I tell the patient what’s available and kind of help them decide what works best for the hairstyle.”

Differences in Disease Presentation

Clinicians must also be vigilant in recognizing how inflammatory conditions manifest differently across skin tones. Speaking on eczema, Woolery-Lloyd explained, “Erythema is might not be as visible, and might look different instead of being bright pink or red, and might look red brown, violaceous or more purple. It might even just look like hyperpigmentation.”

She added that in some patients of African descent, eczema is more likely to present with a papular morphology. “They will have eczema that presents more papular, so more likely to have tiny little bumps and versus patches and plaques.” Distribution may also vary: “Its more likely to present on the extensor surfaces, so this part of the arm versus the inner arm.”

Psoriasis follows similar patterns, with redness less apparent and post-inflammatory hyperpigmentation (PIH) often persisting after plaques resolve.² As Woolery-Lloyd noted, “Although there’s no more inflammation, no more scale, you still have these dark brown plaques all over the body, and visually it’s the same to the patient.”

The Importance of Early Intervention

Whether managing alopecia, eczema, or psoriasis, early diagnosis is central to outcomes. Woolery-Lloyd highlighted this particularly in the context of hair loss: “Definitely with inflammatory scalp conditions, and specifically with alopecia, early intervention is really important, especially for scarring alopecia, is where the inflammation can lead to scarring of the hair follicles.”

She stressed that patients often delay seeking medical care, trying at-home or community remedies first. “People sometimes will get a little patch of hair loss or a little something, and see their hairstylist, ask friends, ask family members, look online. Do an at home treatment. Try all of these things before they get to the dermatologist.”

Building Trust Through Listening and Cultural Sensitivity

Beyond medical management, Woolery-Lloyd underscored the critical role of communication. “I would say the best thing is just to listen. It’s hard, because we’re in busy practices, and we only have a certain period of time to see our patients beginning to end. But especially in a first patient visit, that might be a time to kind of pause, ask open ended questions and listen. Make the patient know that they’re being heard and seen.”

Leveraging Resources and Patient Advocacy

For both patients and clinicians, Woolery-Lloyd recommends established, credible resources. She highlighted organizations such as the Skin of Color Society, National Psoriasis Foundation, and the American Academy of Dermatology’s provider search tools. These resources help patients identify physicians with a specific interest in skin of color and inflammatory skin conditions.

She also emphasized the value of community. “Patient support groups can be very, very helpful. Someone will say, ‘I really love this product, I use it for when I’m going to be sweating a lot outside because it doesn’t budge in the sweat’…Those subtle things that only like it’s patient to patient.”

Key Takeaways

The Science of Skin & Scalp Studio spotlighted the intersection of science, culture, and lived experience. Woolery-Lloyd’s contributions reinforced the importance of early dermatologic care, culturally sensitive treatment planning, and truly listening to patients.

Her message to clinicians is clear: ask questions, listen carefully, and adapt treatments to align with patient needs and cultural practices. For patients, the advice is equally actionable—seek dermatologic care early, connect with knowledgeable providers, and leverage peer support networks for practical insights. In doing so, dermatology can move closer to equitable, personalized care that improves outcomes and patient quality of life across diverse populations.

References

1. The Science of Skin. AbbVie. Accessed September 2, 2025. https://view.ceros.com/abbvie/science-of-skin/p/1
2. Gkini MA, Nakamura M, Alexis AF, et al. Psoriasis in people with skin of color: An evidence-based update. Int J Dermatol. 2025;64(4):667-677. doi:10.1111/ijd.17651

Early diagnosis of ovarian cancer is critical because it significantly improves patient prognosis and survival rates. Currently, about 75% of patients are diagnosed at an advanced stage (stage III or IV), where survival rates drop to 40-50%. In contrast, Stage I diagnosis boasts an 80 to 90% survival rate. The main challenge lies in the difficulty of early detection, similar to pancreatic cancer, as conventional methods like imaging and CA125 lack sufficient sensitivity and specificity for early-stage disease.

Researchers, including Jesús Gonzalez Bosquet, MD, PhD, are exploring the use of DNA methylation patterns as markers for early diagnosis of ovarian cancer, detectable through a liquid biopsy from blood. This method aims to identify specific methylation changes in cell-free DNA (cfDNA) circulating in the blood, which could indicate the presence of cancer at an earlier stage.

“We did preliminary analysis in methylation in ovarian cancer. It turns out that there’s DNA floating in the blood that can be analyzed, and some of them is methylated. So potentially, methylation patterns in DNA could be a good marker for diagnosis of ovarian cancer,” explained Gonzalez Bosquet, who is an associate professor of obstetrics and gynecology and gynecologic oncology at the University of Iowa.

The researchers utilized a methylation chip analysis, specifically an Illumina Infinium MethylationEPIC BeadChip Array, which probes over 850,000 different methylation sites in the genome. They analyzed DNA collected from ovarian tumor samples and normal controls. To manage the vast number of variables, they employed machine learning and deep learning methodologies, including MethylNet for initial reduction, followed by univariate ANOVA analyses and multivariate lasso regression. This rigorous process allowed them to narrow down the most informative probes from over 850,000 to a highly predictive set of 9 probes.

“The difficult part is trying to reduce the numbers of variables,” said Gonzalez Bosquet. “So, we used some machine learning and deep learning methodology.”

This was a pilot case-control study that included 99 high-grade serous cancer (HGSC) tissue samples and 12 normal fallopian tube samples as controls from the University of Iowa’s Gynecologic Oncology Bank. The initial prediction models using MethylNet were highly accurate, achieving an area under the curve (AUC) of 100%. After optimization through variable reduction using ANOVA and lasso regression, a model with only 9 methylated probes also achieved an AUC of 100% in predicting HGSC.

Using a small number of probes, such as the 9 identified in this study, is advantageous for developing a practical diagnostic test. A model with fewer variables is less complex, more easily validated, and more feasible for clinical implementation. The initial methylation chip provided over 850,000 data points, which is impractical for a diagnostic test. By reducing this to 9 highly informative probes while maintaining high accuracy (AUC of 100% in the initial dataset), the researchers made significant progress towards a clinically usable test.

The predictive model was rigorously validated using several methods. First, it was validated in an independent dataset (GSE65820) from a different geographical location (Australia) with similar patient ancestry. The 11,167-probe model showed an excellent AUC of 98%, and the simplified 9-probe model achieved a very good AUC of 84% in this external validation. Additionally, the models were re-trained, validated, and tested using an independent machine learning analytic platform, TensorFlow, which also showed excellent performance.

Strengths of the study include the use of a well-annotated single-institution biobank, focusing on a homogeneous phenotype of high-grade serous cancer, and validating the model in an independent dataset from a different geographical location. The use of advanced AI and machine learning techniques for probe selection is also a notable strength.

Limitations include the relatively small and imbalanced sample size (99 cases vs 12 controls in the initial set, and even more imbalanced in the validation set), and the fact that the initial study used tissue samples rather than blood.

“One of the problems with ovarian cancer always have seen the false positives,” said Gonzalez Bosquet. “We need to now go to population study, try to identify this in blood first, then if we can then put it in a in a prospective trial to see if it’s if it’s valid in a prospective way.”

The “black box” effect of some deep-learning tools like MethylNet in variable selection was also noted by researchers, though mitigated by downstream analyses. The generalizability of the model might also be limited as it was tested in populations with similar backgrounds, suggesting a need for testing in more diverse populations.

The ultimate goal of this research is to develop a method that can be used for early detection of ovarian cancer using cfDNA from blood samples, ideally for population-level screening.

The next crucial steps involve transitioning from tissue analysis to population studies to identify these methylation markers in blood samples, conducting a prospective trial to validate the findings in a real-world setting, and optimizing the model’s performance in blood, with a diverse population of patients across all stages.

“It needs validation in real life to have really impact. As we know, with this environment, it is difficult to get funding. [But] we still insist on trying to get this further, because I think it’s a potential good mechanism for detection,” Gonzalez Bosquet said.

REFERENCE:

Bosquet JG, Wagner VM, Russo D, et al. Identifying ovarian cancer with machine learning DNA methylation pattern analysis. Sci Rep. 2025 Jul 1;15(1):20910. doi: 10.1038/s41598-025-05460-9.

Robert F Kennedy Jr, the US secretary of health and human services, defended his response to the largest measles outbreak in the US in 33 years in a new editorial, calling it an example of “what a focused” Centers for Disease Control and Prevention (CDC) “can achieve”.

Kennedy did so in a Wall Street Journal editorial published on Tuesday, which coincides with extreme tumult at the CDC and strong claims from a former employee that the secretary wasn’t even briefed on the measles outbreak.

In the piece, Kennedy praises his agency’s handling of the outbreak in west Texas, which hospitalized nearly 100 people and killed two children earlier this year.

He argued that the outbreak “ended quickly, proving the CDC can act swiftly with precision when guided by science and freed from ideology”, described the CDC’s response as “effective” and said that “effectiveness – not politics – will be the watchword of our leadership.”

The outbreak, which affected several states, was officially declared over by local officials on 18 August. Throughout the crisis, Kennedy faced criticism from some health experts who described his messaging as inconsistent. They pointed out that while he acknowledged the importance of the measles, mumps and rubella (MMR) vaccine, he also framed vaccination as a “personal choice” and promoted and endorsed alternative treatments such as vitamins and cod liver oil.

The editorial arrives amid growing calls for his resignation, triggered by a disastrous few weeks at the CDC. Last week, the White House abruptly fired CDC director, Dr Susan Monarez, claiming that she did not “align” with Donald Trump’s agenda. She also reportedly clashed with Kennedy over vaccine policy.

Her ousting triggered the resignations of several other senior CDC officials, including Dr Demetre Daskalakis, the former head of the National Center for Immunization and Respiratory Diseases at the CDC.

In a recent interview, Daskalakis even said that Kennedy has never been briefed by CDC experts on several health issues including measles, Covid-19 or the flu.

“No one from my center has ever briefed him on any of those topics,” Daskalakis told CNN. “Perhaps he has alternate experts that he may trust more than the experts at CDC that the rest of the world regards as the best scientists in the areas.

“He’s getting information from somewhere, but that information is not coming from CDC experts who really are the world’s experts in this area … and he’s not taking us up on several offers to brief him on these very important topics,” Daskalakis added.

On Wednesday morning, more than 1,000 current and former HHS employees signed a public letter demanding Kennedy’s resignation.

The letter accused Kennedy of putting US public health at risk and criticized his role in firing Monarez. It also blasts him for “appointing political ideologues” to influential vaccine policy positions, “refusing to be briefed by well-regarded CDC experts on vaccine-preventable diseases” and of “rescinding the FDA’s emergency use authorizations for Covid-19 vaccines”..

Earlier this week, nine former CDC officials penned a guest essay in the New York Times in which they called Kennedy’s leadership “unlike anything our country has ever experienced” and “unacceptable.”

They warned that his leadership “should alarm every American, regardless of political leanings” and said that “amid the largest measles outbreak in a generation, he’s focused on unproven treatments while downplaying vaccines”.

Last month, more than 750 current and former HHS staffers sent a separate letter to Kennedy, in the wake of the 8 August shooting at the CDC headquarters that killed a police officer. In that letter, the staffers accused him of fueling harassment and violence directed at government healthcare staff.

Despite the mounting pressure, Kennedy did not address Monarez’s firing, the subsequent resignations or the growing calls for his resignation in his editorial this week.

Instead, Kennedy defended the Trump administration’s role in what he described as “restoring public trust” in the CDC which he argued had been “corroded” in recent years by “bureaucratic inertia, politicized science and mission creep”.

Kennedy, who previously founded an anti-vaccine group, also criticized the CDC’s handling of the Covid-19 pandemic, calling it a “failure” and blasted policies such as social distancing, mask mandates, lockdowns, and “the suppression of low-cost therapeutics in favor of experimental and ineffective drugs”.

Kennedy is scheduled to testify before the Senate finance committee on Thursday for a hearing on Trump’s healthcare agenda, according to the committee website.

Investigators have identified the presence of at least 1 modifiable risk factor for birth defects in two-thirds of reproductive-aged women, publishing their findings in the American Journal of Preventive Medicine.¹

These findings included low red blood cell (RBC) folate concentrations in 1 in 5 women, diabetes in nearly 5%, obesity in 1 in 3, and tobacco exposure in nearly 1 in 5. Investigators stated that this data can be used to identify and challenge modifiable risk factors to reduce the risk of birth defects.¹

“The most significant finding—that two-thirds of women of reproductive age had at least one modifiable risk factor—highlights how common these changeable risk factors are. The good news is that they can be lowered,” said Arick Wang, PhD, epidemiologist at the CDC.¹

Assessing risk factors

Data from a US sample was obtained through household interviews and in-person health examinations.² Investigators also conducted 2 dietary-intake 24-hour recall interviews for each participant to complete. The collected data was categorized into 5 cycles of 2 years and 1 pre-pandemic cycle of 3.2 years, all from 2007 to March 2020.

Women of reproductive age (WRA) status was determined through self-reported sex and age, with reproductive age defined as 12 to 49 years. Patients with a positive pregnancy test or self-reporting pregnancy or lactation were excluded from the analysis.²

There were 5,374 nonpregnant, nonlactating WRA included in the final analysis, 66.4% of whom presented with at least 1 known risk factor of birth defects and 10.4% with 3 or more based on the all-risks profile. When assessing risks with the nonfolate risk profile, these rates were 59.1% and 6.3%, respectively.²

Nutritional supplement use and folate intake

Of WRA, 6.7% had very low food security, while consumption of FA-containing supplements was reported in approximately 28% and both FA- and B12-containing supplements in 27.2% Consumption of supplements with at least 400 µg/day of FA was reported in only 12.6%.²

When excluding supplement use, 98.7% of patients had FA intakes under 400 µg/day. RBC folate concentrations under 748 nmol/L were reported in 19.5%, obesity in 33.8%, diabetes in 4.8%, and prediabetes in 28.9%.²

An increasing trend of women with at least 1 known risk factor was observed over time, from 65.3% between 2007 and 2010 to 69.5% between 2015 and 2020. Rates of women with at least 1 nonfolate risk also rose from 55.3% to 64%, while the prevalence of RBC folate concentrations 748 nmol/L declined from 23.4% to 17.9%.²

Trends over time

Rates of very low food security, total FA intake under 400 µg/day, obesity, diabetes, and prediabetes increased over time, while rates of active tobacco use and daily FA intake over 400 µg/day decreased. A correlation was reported between age and presenting with at least 1 risk factor.²

Non-Hispanic Black and Hispanic patients were significantly more likely to present with at least 1 risk factor vs White patients, with rates of 80.4%, 70%, and 62.2%, respectively. For the nonfolate risk profile, these rates were 70.3%, 62.8%, and 56.2%, respectively.²

These results indicated a high prevalence of modifiable risk factors for birth defects among US women. Investigators concluded women should visit their physician before pregnancy to prevent adverse outcomes.²

“Every growing family hopes for a healthy pregnancy and healthy baby. Understanding modifiable risk factors for birth defects helps families, health care providers, and public health professionals make data-informed decisions that can lead to healthier pregnancies and babies,” said Wang.¹

References

1. Two thirds of reproductive-aged women have at least one modifiable risk factor for birth defects, study reveals. Elsevier. August 26, 2025. Accessed September 3, 2025. https://www.eurekalert.org/news-releases/1095031.
2. Wang A, Zauche LH, Crider KS. Trends and prevalence of modifiable risk factors for birth defects among US women of reproductive age: National Health and Nutrition Examination Survey 2007 to March 2020. American Journal of Preventive Medicine. 2025. doi:10.1016/j.amepre.2025.107947

Introduction

Sevoflurane is the most frequently administered inhaled anesthetic in pediatric patients owing to its hemodynamic stability, absence of airway irritation, and rapid induction and emergence.¹ Nevertheless, a significant limitation of sevoflurane anesthesia in this population is its association with emergence agitation and delirium, which has been reported to occur with an incidence ranging from 10% to 80%.² Pediatric emergence delirium (ED) is a complex psychomotor disturbance that commonly manifests during the early post-anesthesia period. It is defined by symptoms such as inconsolable crying, involuntary motor activity, restlessness, and disorientation.³ Although ED is typically transient and self-limiting, its occurrence may precipitate a range of postoperative complications, including self-injurious behavior, surgical wound dehiscence or hemorrhage, and the removal of indwelling catheters. Furthermore, ED substantially increases the length of stay in the post-anesthesia care unit (PACU), thereby creating significant challenges for medical staff and diminishing parental satisfaction.^4,5

The precise pathogenesis of ED remains elusive. Nevertheless, a variety of pharmacological interventions have been explored for the prevention or management of pediatric emergence delirium, including α2-adrenergic receptor agonists,⁶ sedatives,⁷ opioids,^8,9 and non-opioid analgesics. Nevertheless, the use of these drugs may result in adverse effects such as bradycardia, respiratory depression, postoperative nausea and vomiting (PONV), and delayed recovery. Given these concerns, it is highly valuable to investigate more suitable alternatives for the prevention of pediatric ED.

Remimazolam, a novel water-soluble ultra-short-acting benzodiazepine, has been safely utilized for sedation in pediatric procedures and for the induction and maintenance of general anesthesia.^10,11 Due to the activity of non-specific tissue esterases, it is subsequently rapidly hydrolyzed into a pharmacologically inactive carboxylic acid metabolite (CNS 7054). This characteristic confers the advantages of rapid onset and offset of sedation, as well as a predictable duration of action.¹² When utilized for anesthesia, remimazolam exhibits a mild inhibitory effect on respiration and circulation, and its sedative effects can be effectively reversed by flumazenil.¹³ Remimazolam exhibits a high clearance rate and a short context-sensitive half-life in pediatric patients. After normalization by body weight, its pharmacokinetic properties are comparable to those observed in adults, enabling the development of target-controlled infusion protocols.¹⁴

A study conducted by Yang et al demonstrates that administering 0.2 mg/kg of remimazolam at the conclusion of adenotonsillectomy under sevoflurane anesthesia can significantly reduce the incidence of ED.¹⁵ Additionally, the research by Cai et al indicates that either a continuous intraoperative infusion of remimazolam at 1 mg/kg/h or a single intravenous bolus dose of 0.2 mg/kg administered at the end of surgery can effectively decrease the incidence of ED in pediatric patients following laparoscopic surgery.¹⁶ Although remimazolam demonstrates considerable potential and advantages, its efficacy and role in preventing pediatric ED remain underexplored, particularly regarding the determination of the optimal dosage and administration protocol. Therefore, we aimed to determine the 90% effective dose (ED90) of remimazolam when continuously infused during surgery for preventing ED in children undergoing adenoidectomy or adenotonsillectomy under sevoflurane general anesthesia.

Methods

Study Design

This is a prospective, double-blind, sequential allocation dose-finding study. This study received approval from the Medical Ethics Committee of The Affiliated Women and Children’s Hospital of Ningbo University, China (Approval Number: EC2024-163; Approval Date: December 11, 2024). Prior to the enrollment of patients, we registered the clinical trial at the Chinese Clinical Trial Registry (Registration Number: ChiCTR2400094727; Principal Investigator: Zhongsai Yang; https://www.chictr.org.cn/showproj.html?proj=254654; Registration Date: December 26, 2024). Written informed consent was obtained from the parents or legal guardians of the children prior to their enrollment. This study was conducted in strict compliance with the principles outlined in the Declaration of Helsinki and clinical trial CONSORT.

Patients and Setting

We prospectively recruited patients aged 3–7 years with American Society of Anesthesiologists (ASA) Physical Status I or II who underwent adenoidectomy or adenotonsillectomy under general anesthesia at The Affiliated Women and Children’s Hospital of Ningbo University, located in Zhejiang Province, China, between January 2025 and February 2025. The exclusion criteria were as follows: preoperative respiratory tract infection; incidents in the recovery room (eg, airway spasm, wound bleeding, etc.); allergy to remimazolam; abnormal liver or kidney function; abnormal cardiac function; bradycardia (heart rate less than 60 beats per minute); neurological or psychiatric disorders, including patients with a history of epilepsy, developmental delay, or autism; a history of three or more surgeries; use of anticonvulsant, sedative, or analgesic drugs within two weeks; severe obstructive sleep apnea (apnea-hypopnea index ≥5.0); and declined to participate in.

Study Protocol

All patients were required to fast from solid food for 6 hours and clear liquids for 2 hours prior to surgery. A 22 gauge peripheral vein catheter was inserted in the preoperative preparation room. Upon entering the operating room, standard monitoring was initiated, comprising electrocardiogram (ECG), non-invasive blood pressure monitoring, pulse oximetry, and bispectral index (BIS) monitoring. Prior to anesthesia induction, atropine was administered at a dose of 0.01 mg/kg to inhibit airway secretions. For postoperative analgesia, flurbiprofen axetil was given at a dose of 1 mg/kg (with a maximum dose of 50 mg). To prevent postoperative nausea and vomiting, dexamethasone was administered at a dose of 0.1 mg/kg (maximum dose 5 mg), along with tropisetron at a dose of 0.1 mg/kg (maximum dose 5 mg). The anesthesia induction protocol consisted of propofol at 3 mg/kg, fentanyl at 3 μg/kg, and cisatracurium besilate at 0.1 mg/kg.

Following the successful induction of anesthesia, and once the child was fully muscle-relaxed and unconscious, an endotracheal tube was inserted. Remifentanil was administered via continuous infusion at a rate of 10 to 20 μg/kg/h, the concentration of sevoflurane was titrated within the range of 1% to 3%, and the target BIS value was maintained between 40 and 60. During the operation, vital signs were maintained within 20% of their baseline values through meticulous monitoring and timely interventions with adjustments in the dose of remifentanil and sevoflurane. The end-tidal carbon dioxide pressure (PetCO2) was maintained within the range of 35 to 45 mmHg by finely adjusting the respiratory rate and tidal volume of mechanical ventilation.

Atropine was administered to the patient when the heart rate (HR) decreased to less than 60 bpm. If the mean arterial pressure (MAP) dropped by more than 20% from the baseline value, the dosage of maintenance anesthetic drugs was adjusted accordingly. Additionally, norepinephrine or epinephrine was administered as needed to stabilize the patient’s condition based on the anesthesiologist’s discretion. When the MAP increased by more than 30% of the baseline value, clinicians implemented clinical intervention measures based on their professional experience to ensure the safe and successful completion of both anesthesia and surgery.

Upon completion of the surgery, the administration of maintenance anesthetic drugs was discontinued, and the child, with the endotracheal tube still in place, was transferred to the PACU.

In the PACU, once the child’s spontaneous respiration was fully recovered, neostigmine at a dose of 0.02 mg/kg and atropine at a dose of 0.01 mg/kg were administered as needed to antagonize any residual muscle relaxation. The endotracheal tube was extubated upon fulfillment of predefined criteria, specifically when the tidal volume was adequate (≥6 mL/kg) and the respiratory rate was at least 15 breaths per minute. Then, the child underwent close monitoring and evaluation in the PACU. Upon achieving an Aldrete score of 9 or higher, the child was transferred back to the ward under supervision.

Administration Management of Remimazolam Infusion and the Biased Coin Design Up-and-Down, Sequential Method (BCD-UDM)

Remimazolam was continuously infused from the initiation of anesthesia induction until 5 minutes before the conclusion of surgery, at which point the infusion was terminated. Based on the existing literature¹⁶ and the results of the preliminary experiment, the predetermined infusion rate of remimazolam for the first patient was set at 0.8 mg/kg/h, with a dose increment or decrement gradient of 0.1 mg/kg/h. Dose for next patient was based on the response of the previous patient using the BCD-UDM.¹⁷ In brief, if the dose administered to the previous patient is considered ineffective (defined as the dose that failed to prevent the patient from experiencing ED), the dose for the next patient will be increased by 0.1 mg/kg/h. Conversely, if the dose administered to the preceding patient is determined to be effective (defined as the dose that successfully prevented the occurrence of ED), the dose for the subsequent patient is established via randomization using the BCD-UDM method with the statistical software R (Γ=0.9). For the next patient, there is an 11% probability [b=(1-Γ)/Γ=0.11] that the remimazolam dose will be decreased by 0.1 mg/kg/h, while there is an 89% probability (1-b=0.89) that it will remain unchanged.

In accordance with the requirements specified in the remimazolam drug instruction manual, the upper limit of the dose for this study was determined to be 3 mg/kg/h. The study drug was prepared by a research assistant who was not involved in either the clinical management or the study. An anesthesiologist in the recovery room is responsible for ED assessment and management. This anesthesiologist, along with the patients and their guardians, was kept unaware of the dose of remimazolam administered.

Diagnosis and Management of Emergence Delirium During the Recovery Period

In the PACU, following extubation of the child’s endotracheal tube, a trained anesthesiologist evaluated the presence and severity of ED during the period from extubation until the child was transferred to the ward. The anesthesiologist systematically documented the corresponding data. If any signs of delirium or restlessness were observed during this period, the Pediatric Anesthesia Emergence Delirium (PAED) scale (Table S1) would be promptly employed for evaluation. A score of ≥10 points on the PAED scale indicates emergence delirium (ED), while a score of ≥15 points suggests severe ED.¹⁸ Additionally, the Face, Legs, Activity, Cry, Consolability (FLACC) scale (Table S2) would also be used to assess pediatric pain behavior. On the FLACC scale, a score of 0 indicates no pain and comfort, 1–3 points indicate mild pain, 4–6 points indicate moderate pain, and 7–10 points indicate severe pain.¹⁹

Diagnostic process for delirium: postoperative delirium is diagnosed when the PAED score is ≥10 and the FLACC score <4. When the PAED score is ≥10 and the FLACC score is ≥4, indicating moderate to severe pain in the patient, an intravenous injection of 0.1 μg/kg sufentanil is administered. Then, the PAED score is reassessed 5 minutes later. If the reassessed PAED score remains ≥10, ED is diagnosed, irrespective of the FLACC score. Additionally, if a child exhibits ED with a PAED score of ≥15 and the episode duration is ≥2 minutes, it is classified as severe ED.²⁰ If the child does not exhibit ED but the FLACC score is ≥4, rescue analgesics (0.1 μg/kg of sufentanil) are administered. If the patient is asleep, pain assessment is not performed. Patients diagnosed with delirium receive initial comfort measures. Should these measures prove ineffective, an intravenous injection of 1 mg/kg of propofol were administered for treatment and were repeated as necessary. The administration of rescue boluses of propofol and sufentanil was documented.

Data Collection and Outcome Assessment

The primary outcome was the effective or ineffective dose of remimazolam for preventing ED. Secondary outcomes were as follows: PAED scale, time of occurrence and interventions in patients with ED; FLACC scale and dose of rescued sufentanil; patients extubation time (defined as the time interval from the discontinuation of anesthetics to extubation), post-anesthesia recovery time (defined as the time from the discontinuation of anesthetics until the child reaches a fully conscious state, characterized by spontaneous eye opening, normal responses to questions, and compliance with movement instructions), as well as the duration of stay in the PACU (defined as the time interval from transfer to the PACU until departure from the PACU), as well as delayed recovery, which is defined as a length of stay in the PACU exceeding 120 minutes; the incidence of adverse effects during the intraoperative and postoperative recovery periods, such as hypotension, and bradycardia. In addition, the level of preoperative anxiety assessed by the Modified Yale Preoperative Anxiety Scale,²¹ the anesthesia duration, surgical procedure duration, volume of infused fluids, and concentration of sevoflurane were recorded. The demographic characteristics of patients, including gender, age, weight, height, and BMI, as well as the ASA score, type of surgery, and baseline blood pressure and heart rate, were also systematically recorded.

Statistical Analysis

In a dose-finding study employing the biased coin up-and-down design, the data distribution exhibits both non-independence and an unknown structure. Simulation analyses demonstrate that enrolling a minimum of 20 to 40 patients typically provides robust and reliable estimates of the target dose across the majority of scenarios. To account for potential dropouts and achieve a sufficiently narrow 95% confidence interval (95% CI), this study approximately determined a sample size of 52 pediatric patients.

Continuous data were assessed for normality using the Shapiro–Wilk test. Measurement data conforming to the normal distribution were expressed as mean ± standard deviation (Mean ± SD), and measurement data not conforming to the normal distribution were expressed as median (M) and interquartile range (IQR). Enumeration data were expressed as the number and percentage (%). The ED90 and 95% confidence interval of remimazolam were calculated via the isotonic regression method, which was used as the primary estimate. And Probit regression was also used as a backup estimate in this study. The Pearson χ2 goodness-of-fit test was used to evaluate the satisfaction of the probit model fitting the data. The GraphPad prism software (ver. 10.4.0) was used for graphing. The data processing and statistical analysis of this study were carried out using the SPSS software (ver. 29.0), and the BCD random sequence was generated using the R for Windows software (ver. 4.3.2).

Results

The patient recruitment and follow-up period extended from January 1, 2025, to February 28, 2025 (Figure 1). A total of 58 patients were assessed for eligibility. Among the participants, one patient had a neurological or psychiatric disorder (specifically, autism), two patients had upper respiratory tract infections with a fever exceeding 38 degrees Celsius, and three patients declined to participate in the study. Finally, a total of 52 patients were involved in the study, and all of them successfully completed the final analysis. The demographic and baseline characteristics of the patients are presented in Table 1.

Table 1 Demographic and Baseline Characteristics of the Patients

Figure 1 Study recruitment diagram.

The sequence of allocation, as well as the response to the administration of remimazolam, is illustrated in Figure 2. The estimated ED90 and 95% confidence interval [95% CI] of remimazolam for preventing ED in pediatric patients undergoing adenoidectomy or adenotonsillectomy under sevoflurane general anesthesia was 1.08 mg/kg/h (1.03–1.97 mg/kg/h) with the isotonic regression method and was 1.07 mg/kg/h (1.02–1.26 mg/kg/h) with Probit probability regression. The results of the Pearson goodness-of-fit χ2 test indicated that the probit model exhibited an adequate fit (P = 0.38).

Figure 2 Data of the sequential up-and-down responses of remimazolam for the prevention of ED. The starting dose is 0.80 mg/kg/h, and the dose increment is 0.10 mg/kg/h. Solid dots represent successful prevention of ED, while hollow dots represent failure of preventing ED.

Secondary results are shown in Table 2. The mean extubation time for the patients was 29.94 ± 6.53 minutes, the post-anesthesia recovery time was 45.96 ± 10.53 minutes, and the duration of stay in the PACU was 52.58 ± 9.82 minutes. During the study period, sufentanil rescue was administered in 3 patients (5.8%); hypotension was observed in 4 patients (7.7%) during the anesthesia process; there were no cases of nausea and vomiting, delayed recovery, bradycardia, or hypoxemia during post-anesthesia recovery time.

Table 2 Postoperative Outcomes and Complications

For patients who experienced ED, the infusion dose of remimazolam, PAED scores, the timing of ED occurrence, and the interventions administered to patients with ED were summarized in Table 3. A total of eight patients developed delirium, as indicated by a PAED score of ≥10. Among them, one child experienced severe delirium (PAED score ≥16), and four patients received propofol treatment for the management of delirium symptoms.

Table 3 Failure of Remimazolam in Preventing ED

Discussion

The main finding of this study is that the optimal dose of remimazolam for preventing ED in pediatric patients undergoing adenoidectomy or adenotonsillectomy under sevoflurane inhalation anesthesia is 1.08 mg/kg/h (95% CI: 1.03–1.97 mg/kg/h). Furthermore, no severe adverse effects were observed during remimazolam infusion within the dose range of 0.8–1.2 mg/kg/h in pediatric patients. To the best of our knowledge, this is the first time to explore the dose-response study of remimazolam in preventing ED in pediatric patients.

Currently, the precise pathophysiological mechanisms underlying post-anesthetic delirium in pediatric patients remain incompletely understood. Recognized high-risk factors include the use of sevoflurane inhalation, preoperative anxiety, unstable anesthetic induction, male sex, preschool age, parental anxiety, and certain types of surgeries (eg, craniofacial surgeries).²² In this study, we enrolled preschool pediatric patients aged 3 to 7 years who underwent adenoidectomy or adenotonsillectomy under sevoflurane anesthesia. Our results indicate that in 90% of this kind of population who did not experience ED, the infusion dose of remimazolam was 1.08 mg/kg/h. In addition, our results indicated that 4 out of 18 patients (22%, Figure 2) experienced ED at an infusion dose of 1.0 mg/kg/h, which is obviously higher than that reported by Cai et al¹⁶ in whose study the incidence of ED was 5% with remimazolam infusion dose at 1.0 mg/kg/h for pediatric patients who underwent laparoscopic inguinal hernia repair. Carefully comparing the protocols of the two studies, we acknowledged that the different types of surgeries might account for this discrepancy.

The results of current study suggest higher 1.1–1.2 mg/kg/h of remimazolam infusion dose produces less incidence of ED. Given that the pediatric patients in the current study were associated with several high-risk factors for the occurrence of ED during the anesthesia recovery period, we propose that selecting a more appropriate dose of remimazolam (approaching or a little higher than ED90) is particularly critical. This approach can effectively reduce the incidence of ED, alleviate the postoperative management burden on clinical anesthesiologists, and enhance the quality of postoperative recovery for pediatric patients. Additionally, we did not find any undesirable adverse adverse effect associated with high dose infusion in the current study. Therefore, our results suggest the dose of 1.1 and 1.2 mg/kg/h of remimazolam infusion are an effective and safety dose for the study population in the current study.

The precise mechanism by which remimazolam decreases the incidence of ED remains to be further elucidated. Prior investigations indicate that its potential protective effects may be attributed to a variety of factors, including sedative properties, agonistic effects on γ-aminobutyric acid (GABA) receptors, anti-inflammatory capabilities, vasodilatory actions, and antioxidant activities.²³ Nevertheless, the continuous administration of remimazolam during BIS-guided anesthesia can effectively reduce the requirement for sevoflurane, thereby decreasing the incidence of ED. However, this hypothesis needs to be further validated, despite the findings of a recent cohort study suggesting that the dose of sevoflurane was not associated with the severity or occurrence of delirium.²⁴ However, it should be noted that opioids, such as remifentanil, are frequently utilized in clinical anesthesia. Although the dosage in the current study is typically determined based on body weight, it remains unclear whether they interact with remimazolam or whether their combined use influences the risk of ED. Further investigation into this area is warranted.

In this study, our protocol specifies that the specific antagonist flumazenil was not used to reverse the effects of remimazolam for rapid awakening in children. The extubation time was 29.94 ± 6.53 min, and the recovery time was 45.96 ± 10.53 min, and no patients experienced delayed recovery, which is similar to prior studies¹⁶ indicating that infusion of remimazolam at the study dose does not affect the metabolic profiles and leads to delayed recovery.

A large number of studies have investigated the effects of remimazolam on the prevention and treatment of postoperative delirium across diverse populations, utilizing various protocols, doses, and delivery strategies. These studies recommend a broad infusion dose range of 0.1 to 3.0 mg/kg/h.^{15,16,25–30} In this study, we possess a distinct advantage in providing dose-response information for the prevention of ED within specific high-incidence populations. Although the ED90 was determined in this study, further investigations into the minimal effective dose for this population using the traditional up-and-down method could provide valuable insights for clinical reference.

When concerns regarding the safety of remimazolam in pediatric use were raised, a study conducted by Fang et al demonstrated that remimazolam exhibited good tolerability for inducing and maintaining general anesthesia in preschool-age children. It was also found to be non-inferior to propofol, with a lower incidence of adverse effects.¹⁰ Similar to prior findings, no other severe adverse events were observed in the current study, which reinforces the safety of remimazolam infusion in pediatric patients. However, caution should be paid when large doses are used in specific population.³¹

This study has several limitations. First, while this study determined the ED90 of remimazolam for preventing ED in preschool age children undergoing adenoidectomy or adenotonsillectomy, it was unable to account for potential confounding effects from other variables that might influence the results. Therefore, further studies are warranted to address various scenarios in clinical practice. Second, variations in anesthesia management protocols, particularly in postoperative pain management, might influence the ED90 results of remimazolam for preventing ED, thereby limiting the generalizability of these findings. Third, despite the integration of the FLACC score and the utilization of the PAED assessment scale for diagnosing delirium—both evaluated by a trained professional physician—the scoring system remains inherently subjective. Consequently, clearly differentiating between delirium and postoperative pain in the PACU poses a significant challenge, which may subsequently affect the results despite measures taken, such as pain management strictly adhering to the study protocol and the ED being reassessed via PAED assessment scale 5 minutes after a FLACC score of ≥4. Fourth, it should be noted that our study enrolled pediatric patients without specifically considering factors such as sex, surgical duration or preoperative anxiety, which may influence ED incidence and dose-response relationships. Further studies investigating the impact of these variables on the dose requirements of remimazolam for preventing ED may be warranted. Finally, the 95% CI of the ED90 lies outside the range of doses examined in this study, and therefore, this value was not directly observed. As a result, clinical application of this dose should be approached with caution. Further studies focusing on relatively higher doses in this area are warranted.

In preschool age children undergoing adenoidectomy or adenotonsillectomy under general anesthesia with sevoflurane, the ED90 of remimazolam for preventing emergence delirium during intraoperative continuous infusion was 1.08 mg/kg/h (1.03–1.97 mg/kg/h). However, cautions should be paid as the 95% CI of the ED90 lies outside the range of doses examined in this study.

Abbreviations

ED, emergence delirium; ASA, American Society of Anesthesiologists; PACU, post-anesthesia care unit; BMI, Body mass index; BIS, Bispectral index; PONV, postoperative nausea and vomiting.

Data Sharing Statement

The datasets generated during and/or analyzed during the current study are not publicly available due to the privacy policy but are available from the corresponding authors on reasonable requests.

Acknowledgment

The authors sincerely express their gratitude to the colleagues and faculty members from the Department of Anesthesiology, Affiliated Women and Children’s Hospital of Ningbo University, Ningbo, China, for their valuable contributions and support throughout the study.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

There is no funding to report.

Disclosure

The authors declare that they have no competing interests.

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