Category: 8. Health

When ocrelizumab became the first FDA-approved treatment for early forms of multiple sclerosis (MS) in 2017, it offered patients immense hope. The long-awaited drug is a monoclonal antibody that depletes B cells—the immune cells that drive MS progression. Exactly how ocrelizumab does this, however, remains unclear.

In a new study published in The Journal of Clinical Investigation, Yale scientists begin to answer this question. By using single-cell RNA sequencing—a technique that provides a window into the gene expression in individual cells—the researchers laid out a detailed view of how ocrelizumab achieves its therapeutic effects.

“The surprise was that the drug doesn’t work at all the way we thought it was working,” says David A. Hafler, MD, William S. and Lois Stiles Edgerly Professor of Neurology at Yale School of Medicine, who led the study. “We knew what the end result was and that the drug was enormously effective in patients. But what’s driving the drug’s action is a type of white blood cell in the central nervous system. No one would ever hypothesize that.”

The roles of T cells and B cells in multiple sclerosis

B and T cells have closely intertwined roles in the immune system. B cells are critical cells that recognize foreign objects, bind them, and present them to T cells, which then signal other immune cells to take action. But this relationship goes awry in disease.

In MS, abnormally active B cells trigger T cells to attack the myelin sheath, the protective layer of nerve fibers, leading to neurological symptoms, such as loss of vision, muscle weakness, and cognitive impairment. More than two decades ago, Hafler and his team discovered this was due to defects in regulatory T cells, which normally put the brake on immune responses, but when defective, unleash immune cells that mistakenly target the body’s own tissues.

In the early stages of MS, both B and T cells are deemed to be the drivers of the disease. Once the disease progresses to a neurodegenerative stage, other inflammatory processes become more prominent.

“Once you enter the neurodegenerative phase of the disease, it is much more difficult to stop the process,” Hafler says. “What we’ve learned is that the earlier you treat the disease, the better the outcome.”

Ocrelizumab binds to the surface of B cells, leading to their destruction. And especially for people in the early stages of MS, it can be quite effective. “The drug works incredibly well,” Hafler says. But Hafler and his team found that ocrelizumab was doing far more than just controlling B cells.

In the new study, the researchers analyzed the blood and cerebrospinal fluid of 18 patients, all of whom had an early-onset form of multiple sclerosis in which patients cycle between periods of disease remission and relapse. The scientists measured the cell type-specific changes in protein expression before and after the patients received six months of ocrelizumab, in an effort to identify immune molecules that might change in response to the drug.

They discovered that the reduction in B cells driven by ocrelizumab led to an increase in the pro-inflammatory molecule TNF-α. This was unexpected because TNF-α has been shown to trigger the immune system and exacerbate inflammation in certain diseases. In fact, medications that block the activity of TNF-α are typically used for treating various autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease.

As they looked further, the researchers found that by inducing TNF-α, ocrelizumab led to an increase in a specific type of regulatory T cell. This, in turn, curbed the circulation of T cells that attack the myelin.

“This unpredicted increase in TNF-α shows that ocrelizumab works in a paradoxical way,” says Hafler.

Understanding the cause of multiple sclerosis

One of the current working models of MS suggests that the disease originates from the Epstein-Barr virus. “How the Epstein-Barr virus triggers the disease is a point that we don’t yet understand,” Hafler says. However, there is a strong body of evidence to show that the virus infects B cells. Therefore, understanding how a B cell-depleting drug affects T cell activity may lead to further explanations.

The current finding also explains why a fifth of the genes linked to MS risk involve the TNF pathway and why many of those genetic changes are protective in other diseases, such as inflammatory bowel diseases.

“This shows that biology has a richness to it,” Hafler says. “When these molecules are made, where they’re made, and what cell they’re working on have very different effects.”

Hafler suspects that ocrelizumab might be acting through other mechanisms as well, an inkling that motivates his lab to continue their investigation. “For something to work that well, there must be other things going on,” he says.

The team is now beginning to study the pathogenesis of MS in a large cohort of women who have at least one parent with the disease. By following the genetic evolution of the disease, the scientists are hoping to better understand how B cells change the immune landscape in real time.

“This study is only one piece of the puzzle,” Hafler says. “We’ll continue to look for other pieces.”

The research reported in this news article was supported by the National Institutes of Health (awards P01AI073748, U19AI089992, U24AI11867, R01AI22220, UM1HG009390, P01AI039671, P50CA121974, and R01CA227473) and Yale University. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was also supported by Race to Erase MS, the National MS Society, Genentech, and F. Hoffmann-La Roche.

Dementia poses a major health challenge with no safe, affordable treatments to slow its progression.

Researchers at Lawson Research Institute (Lawson), the research arm of St. Joseph’s Health Care London, are investigating whether Ambroxol – a cough medicine used safely for decades in Europe – can slow dementia in people with Parkinson’s disease.

Published today in the prestigious JAMA Neurology, this 12-month clinical trial involving 55 participants with Parkinson’s disease dementia (PDD) monitored memory, psychiatric symptoms and GFAP, a blood marker linked to brain damage. Parkinson’s disease dementia causes memory loss, confusion, hallucinations and mood changes. About half of those diagnosed with Parkinson’s develop dementia within 10 years, profoundly affecting patients, families and the health care system.

Led by Cognitive Neurologist Dr. Stephen Pasternak, the study gave one group daily Ambroxol while the other group received a placebo. “Our goal was to change the course of Parkinson’s dementia,” says Pasternak. “This early trial offers hope and provides a strong foundation for larger studies.”

Key findings from the clinical trial include:

• Ambroxol was safe, well-tolerated and reached therapeutic levels in the brain

• Psychiatric symptoms worsened in the placebo group but remained stable in those taking Ambroxol.

• Participants with high-risk GBA1 gene variants showed improved cognitive performance on Ambroxol

 • A marker of brain cell damage (GFAP) increased in the placebo group but stayed stable with Ambroxol, suggesting potential brain protection.

Although Ambroxol is approved in Europe for treating respiratory conditions and has a long-standing safety record – including use at high doses and during pregnancy – it is not approved for any use in Canada or the U.S.

Current therapies for Parkinson’s disease and dementia address symptoms but do not stop the underlying disease. These findings suggest Ambroxol may protect brain function, especially in those genetically at risk. It offers a promising new treatment avenue where few currently exist.”

Dr. Stephen Pasternak, Cognitive Neurologist 

Ambroxol supports a key enzyme called glucocerebrosidase (GCase), which is produced by the GBA1 gene. In people with Parkinson’s disease, GCase levels are often low. When this enzyme doesn’t work properly, waste builds up in brain cells, leading to damage. Pasternak learned about Ambroxol during a fellowship at The Hospital for Sick Children (SickKids) in Toronto, where it was identified as a treatment for Gaucher disease – a rare genetic disorder in children caused by a deficiency of GCase.

He is now applying that research to explore whether boosting GCase with Ambroxol could help protect the brain in Parkinson’s-related diseases. “This research is vital because Parkinson’s dementia profoundly affects patients and families,” says Pasternak. “If a drug like Ambroxol can help, it could offer real hope and improve lives.”

Funded by the Weston Foundation, this study is an important step toward developing new treatments for Parkinson’s disease and other cognitive disorders, including dementia with Lewy bodies. Pasternak and his team plan to start a follow-up clinical trial focused specifically on cognition later this year.

Odors from earwax may help distinguish individuals with Parkinson’s disease (PD) from those without the condition, a new study suggests.

Researchers found that four volatile organic compounds (VOCs) in ear canal secretions significantly differed between participants with and without PD.

The compounds — ethylbenzene, 4-ethyltoluene, pentanal, and 2-pentadecyl-1,3-dioxolane — may represent potential biomarkers. An artificial intelligence olfactory (AIO)-based screening model used in the study identified those with PD with 94% accuracy.

“The accuracy of the model really surprised us,” study investigator Hao Dong, Research Center for Frontier Fundamental Studies, Zhejiang Lab, Hangzhou, China, MD, told Medscape Medical News.

However, the study was a “small-scale, single-center experiment,” he noted in a press release.

“The next step is to conduct further research at different stages of the disease, in multiple research centers, and among multiple ethnic groups in order to determine whether this method has greater practical application value,” Dong said.

The findings were published online recently in Analytical Chemistry.

Unique Odor Profile

“Our team has long been engaged in the detection of [VOCs] secreted by the human body. By chance, we came across reports on the detection of sebum VOCs for Parkinson’s,” Dong said.

Sebum, the oily substance secreted by the skin, may carry a distinct scent in individuals with PD. In a 2019 study cited by Dong, researchers noninvasively collected sebum samples from the upper backs of 64 participants. The findings suggested that samples from those with PD contained compounds associated with a unique odor profile.

Dong and his team began with a confirmatory experiment using sebum samples collected from the upper back, as in the original study. However, they found that earwax was easier to collect and had a more stable chemical composition. These findings led them to focus on earwax in the current study.

Ear wax also contains sebum. But unlike sebum on the surface of the skin, which is exposed to various factors that can degrade it. In contrast, sebum on skin inside the ear canal is protected.

Dong’s study included 209 participants, 108 of whom had a diagnosis of PD. Ear canal secretions were collected from all participants using swabs and analyzed using gas chromatography-mass spectrometry.

Results showed that ear canal secretions from participants with PD contained 196 distinct VOCs compared with 168 VOCs in those without PD. Interestingly, no two participants had identical VOC profiles.

A Disease ‘Fingerprint’?

“In this case, VOC components could be used as a ‘fingerprint’ for disease identification,” the researchers wrote.

Adjusted analyses identified four VOCs that significantly differed between participants with and without PD: ethylbenzene, 4-ethyltoluene, pentanal, and 2-pentadecyl-1,3-dioxolane.

The investigators trained the AIO system using VOC data. By combining gas chromatography-surface acoustic wave sensors with a convolutional neural network (CNN) model, the AIO system achieved up to 94.4% accuracy in distinguishing participants with PD from those without.

In addition, the CNN model demonstrated a high level of performance with an area under the curve of 0.98, well above the 0.8 threshold considered strong by the researchers.

“Further enhancements to the diagnostic model could pave the way for a promising new PD diagnostic solution and the clinical use of a bedside PD diagnostic device,” the investigators wrote.

For now, Dong said the study’s takeaway message for clinicians is that “the potential of volatile organic compounds secreted by the skin as biomarkers for Parkinson’s disease has been further verified.”

The study was funded by the National Natural Science Foundation of China, “Pioneer” and “Leading Goose” R&D Program of Zhejiang Province, and the Fundamental Research Funds for the Central Universities. The investigators reported having no relevant financial relationships.

Our findings have contributed to a better understanding of the pathophysiology of this condition. We identified abnormalities in rectal sensitivity, anorectal pressure dynamics, and defecation-related anorectal dyscoordination in FARP. Additionally, We explored the psychological characteristics of patients with FARP and found that comorbid mood disorders are common in patients with FARP. Our findings provide a basis for the diagnosis and treatment of FARP.

Changes in the properties of the rectal wall and abnormalities in neural afferent pathways and central processing may all cause changes in rectal sensation. In terms of rectal sensory function, we found that when compared with controls, patients with FARP had significantly reduced sensation thresholds for desire to defecate, urgency to defecate and maximum tolerable sensation, indicating rectal hypersensitivity. Visceral hypersensitivity is a hallmark of IBS and manifests as reduced pain thresholds as a result of rectal distension and enhanced perception of bowel lumen distension, and studies have demonstrated a correlation between pain thresholds and the severity and frequency of pain symptoms [23]. FARP and irritable bowel syndrome are both centrally mediated FGIDs, and the mechanisms via pain that occur in these conditions may be similar. Several studies have shown that patients with IBS have lower initial sensation and initial pain thresholds and that visceral hypersensitivity to intestinal dilatation correlates with symptom severity [24,25,26]. Our findings suggest that visceral hypersensitivity is an important pathophysiological mechanism of FARP. Although the findings regarding first sensation were not statistically significant, patients with FARP showed an overall trend toward reduced sensation threshold, which might be related to the material in the expanded balloon used in our examination to assess rectal sensation. Rectal sensory thresholds are influenced by the stiffness of the rectal balloon. This balloon was mounted on a manometry catheter, and its tension might directly affect rectal compliance [27]. In future studies, we plan to investigate rectal sensory thresholds in patients with FARP further by using non-compliant polyethylene balloons and constant pressure or by means of electrical stimulation.

In this study, resting anal pressure and maximum anal squeeze pressure were significantly lower in the patients with FARP than in the controls, and the pelvic floor muscles were predominantly flaccid, which is consistent with previous findings [28]. Some investigators have focused on FARP associated with abnormal anorectal pressure. The correlation between abnormal anorectal pressure and anal pain is controversial, with few relevant reports in the literature. However, it is generally believed that anal levator ani syndrome is mostly caused by spasm of the pelvic floor muscles and elevated annal resting pressure and that an overactive anal sphincter muscle causes chronic pain. Grimaud et al. have suggested that chronic idiopathic anal pain may be caused by persistent abnormal contraction of the external anal sphincter and that this pain can be relieved by biofeedback treatment to relax the external anal sphincter and reduce muscle spasm and neuropsychological stress [23, 29]. We found that the anal resting pressure was lower in patients with FARP, which was the opposite of previous findings and might reflect the epidemiological characteristics of FARP. In our study, 72.14% of FARP patients were female, mainly perimenopausal patients, which is consistent with the characteristics of FARP patients in the study of Atkin GK et al. [30]. Most of these women had a history of pregnancy and childbirth, with obstetric damage to the anal sphincter and pubic nerves, damage to the tissues supporting the pelvic floor muscles, decreased muscle function, decreased hormone levels, and loss of elastin, manifesting as reduced pelvic floor muscle strength and decreased muscle tone [31, 32]. Weakness or spasm of the pelvic floor muscles is thought to be one of the pathophysiological bases for chronic pelvic pain [33].

During testing, we identified paroxysmal, transient, periodic sphincter spasms with elevated pressure in some patients with FARP, which might explain the spasm-related pain that occurs in these patients. Proctalgia fugax is short and episodic and is usually considered to be pain caused by abnormal smooth muscle contractions [34, 35, 36]. Some studies have shown that botulinum toxin injections relax the anal sphincter or levator ani muscle, but their therapeutic effect is inconsistent. The mechanism underlying anal sphincter or levator ani muscle tension in FARP remains unclear.

Some studies reported that the majority of patients with functional defecation disorders had anal levator muscle pressure pain and that their defecation disorders were improved with biofeedback treatment, suggesting that rectoanal incoordination of defecation is the pathophysiology of levator ani syndrome [37]. Interestingly, this hypothesis was consistent with our finding of paradoxical contraction of the anal sphincter during defecation in 76.92% of men with FARP. Defecation coordination disorders are manifested by insufficient rectal impulsion or abnormal anal canal relaxation during defecation. Chronic pain over time may cause the patient to fear defecation, which further increases pelvic floor muscle coordination disorders. Therefore, pelvic floor muscle dysfunction may be one of the causes of FARP.

Our findings indicate that anal resting pressure is positively correlated with sensory thresholds. The anal resting pressure mainly reflects the pressure of the internal anal sphincter (smooth muscle), so it is inferred that there may be a correlation between rectal sensitivity and smooth muscle pressure, but the mechanism of action needs to be investigated further. In contrast, the pathogenesis of FARP in patients with high anal resting pressure may be pain caused by smooth muscle spasms.

In our study, most patients with FARP exhibited symptoms of anxiety and depression. Although no significant gender differences were observed in anxiety and depression scores, female patients tended to report higher levels of these symptoms than males. Currently, Gut-brain interaction disorder is the most widely accepted theory regarding the pathogenesis of FGIDs. These disorders are often associated with psychiatric comorbidities, such as depression and anxiety, and these mood disorders cause gastrointestinal symptoms [38]. Anxiety states are widespread in patients with irritable bowel syndrome, and psychological factors may influence the persistence and perceived severity of these symptoms, which are significantly associated with pain levels and physical symptoms. Women’s anxiety, depression, and somatization are more obvious [39, 40]. Pain intensity is closely related to emotional symptoms. Pain has been shown to cause emotional disorders, and emotional disorders can exacerbate pain [41]. Whether pain is a somatic manifestation of psychological disorders and whether chronic pain is the main cause of emotional problems requires further research. Although our study did not find a correlation between mood and pain, it provides a basis for guidelines for the management of mood disorders in patients with FARP, which may include central neuromodulators, such as antidepressants, antipsychotics, and other central nervous system-targeted agents.

There were several imitations in our study. First, as a retrospective study, we were unable to obtain complete data on VAS scores, HAM-A scores, and HAM-D scores. A prospective study is needed to further investigate the anorectal physiological characteristics of FARP. Second, we did not assess the structure and function of the pelvic floor muscles in patients with FARP using a combination of pelvic floor ultrasound and defecography. Although HARM can aid in understanding the physiological features of the anus and rectum, it is better to be combined with other examinations to improve the diagnostic system for FARP, clarify its etiology and pathogenesis.

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Introduction

Elevated blood pressure (BP), particularly high systolic BP, is the most significant risk factor for premature death worldwide.¹ Data from Chinese national surveys among adults aged 35–75 years indicate low hypertension control rates, with fewer than one in twelve adults with hypertension achieving target BP levels.² The clinical complexity of hypertension is compounded by its frequent coexistence with comorbidities,³ resulting in the wide inclusion of hypertension in multimorbidity indices.⁴ These intersecting health burdens have been shown to reduce quality of life and functional capacity while exacerbating poor hypertension control and mortality risk.^5,6 The management of hypertension and its accompanying comorbidities in patients with duplicative and fragmented care often engenders treatment burden. This has been defined as the cumulative “work” of patienthood, encompassing attending medical appointments, undergoing diagnostic procedures, receiving therapeutic regimens, self-monitoring, and making lifestyle modifications, alongside their psychosocial impact on functioning and well-being.^7–9 These aspects of burden are often exacerbated by intensified treatment.⁹

Effective hypertension management necessitates sustained, multifaceted self-care, incorporating dietary changes, smoking cessation, moderation of alcohol consumption, physical activity, self-monitoring, and medication.^10–12 While robust evidence substantiates the effectiveness of self-care in achieving BP control,^13,14 the asymptomatic nature of hypertension may tend to undermine patients’ adherence to symptom-driven treatment strategies.^15,16 The reciprocal relationship between treatment burden and self-care has been posited, with empirical studies demonstrating that escalating treatment burdens often correlate with poorer compliance across pharmacological, exercise, and dietary domains.^17–20 Meanwhile, intensified self-care regimens may be conversely linked to a rise in perceived treatment burden.²¹ Nevertheless, evidence from population studies regarding the temporal relationship between treatment burden and self-care is largely scanty, with limited understanding of the extent to which such relationship may influence BP control.

The present study aimed to explore the temporal relationship between treatment burden and self-care through cross-lagged panel analysis, while further examining their longitudinal impact on systolic BP levels and hypertension control through mediation analysis.

Materials and Methods

Study Design and Participants

We conducted a prospective observational cohort study within a network of 33 community health centres (CHCs) managed by a tertiary-level hospital in Shenzhen, southern China. These CHCs function as primary care extensions of tertiary hospitals, delivering standardised, free-of-charge national basic public health (BPH) services in the community.^22,23 All hypertensive patients enrolled in the BPH programme from 2017 onwards were considered eligible for follow-up assessments. We employed a three-wave longitudinal design, ie, an initial enrolment assessment of treatment burden and self-care (T1), an interim follow-up evaluation of these measures after approximately 11 months (T2), and the final follow-up measurement of BP (T3; an approximate 14-month post-T2 observation) to capture any delayed clinical effects.

Measurement of Treatment Burden

Treatment burden was measured using the 15-item Treatment Burden Questionnaire (TBQ), an instrument originally developed in French.²⁴ The tool was subsequently translated into English and validated among patients with long-term conditions.²⁵ A Mandarin Chinese version of the TBQ instrument (TBQ_AU1.0_cmn-CN_RC) was developed by our team, commissioned by the Mapi Research Trust, following a standard forward and backward translation procedure. Our work adhered to the item structure of the English version without substantive modifications, additions, or omissions.²⁶ Linguistic validation was conducted by a review panel consisting of two senior general practice (GP) physicians and ten primary care patients with multimorbidity. Cultural differences in language usage were carefully examined, with minor adaptations made to optimise cultural relevance to the Chinese healthcare context while maintaining translation equivalence. Component matrix yielded from the factor analysis accounted for 71.3% of the total variance. Psychometric evaluation revealed excellent internal consistency, as evidenced by a Cronbach’s α coefficient of 0.884, complemented by strong test–retest reliability with intraclass correlation coefficients (ICC) ranging from 0.725 to 0.846 across all individual items.²⁶ These validation results substantiate the use of TBQ as a reliable and valid tool for measuring treatment burden in Chinese patients. Consistent with the original scoring interpretation of TBQ, a higher score reflects greater perceived treatment burden.

Measurement of Self-Care

The assessment of hypertension self-care encompassed 5 behavioural domains derived from the literature.^27,28 These domains included smoking, alcohol drinking, physical activity, daily diet, and medication adherence, each operationalised as a dichotomous variable (0=nonadherent vs 1=adherent) with equal weighting, in accordance with previously validated methodologies,^28,29 to reflect overall adherence. Current smoking was defined as smoking ≥1 cigarette daily for at least 6 months (0=smoking; 1=nonsmoking), while regular drinking was defined as alcohol drinking for an equivalent of >25 g/day (men) or >15 g/day (women) of alcohol consumption, or habitual drinking on ≥4 days per week (0=drinking; 1=nondrinking). Physical activity adherence required ≥30 minutes of moderate-intensity aerobic exercise (eg, brisk walking or cycling) on 5 or more days weekly on average (0=physical inactivity; 1=physical activity). A healthy diet was defined through self-reported adherence to principles of moderate flavouring and avoidance of excessive salty, sweety, or oily foods, alongside maintenance of balanced meat and vegetable consumption (0=unhealthy diet; 1=healthy diet). Medication adherence evaluation incorporated components of self-reported medication taking on time and following prescribed dosages, with participants reporting adherence to both components across seven consecutive days classified as adherent (1) [vs nonadherent (0)]. Patients who had missing or incomplete profiles on medication adherence during the study period were excluded to ensure the homogeneity of the study cohort in terms of self-care adherence measurements. A composite self-care score was derived through summation across all 5 domains (range: 0–5), with higher scores indicating better self-care adherence.

Assessment of Blood Pressure and Hypertension Control

The presence of hypertension and coexisting diabetes at enrolment was ascertained by the attending GP physician according to the clinical guidelines. Standardised BP measurement procedures were conducted using routinely validated automated sphygmomanometers with participants in a seated position. Measurements were obtained from the arm with higher BP values, with the mean of two readings taken at 1–2 minute intervals recorded. Patients who demonstrated a systolic BP ≥140 mmHg through repeated clinical measurements at the final follow-up assessment (T3) were classified as having suboptimal hypertension control.³⁰

Statistical Analysis

Generalised linear models using the analysis of covariance (ANCOVA) approach were used to assess sex-based differences in study variables among participants with and without coexisting diabetes. Reciprocal relationships between treatment burden and self-care across time were evaluated using cross-lagged panel models, in which spuriousness was tested by comparing cross-lagged correlations based on assumptions of synchronicity and stationarity.³¹ The paradigm of the cross-lagged correlations was depicted in Figure 1. The path coefficient β₁ represents the cross-lagged effects from self-care at enrolment (T1) on treatment burden at interim follow-up (T2), while path β₂ coefficient indicates the cross-lagged effects from treatment burden at T1 on self-care at T2. Pearson correlation coefficients were computed for standardised (z score transformed) treatment burden and self-care measures at T1 and T2, with covariate adjustment, yielding six pairwise associations. The cross-lagged path coefficients (β₁ and β₂) were estimated from the correlation matrix using maximum likelihood method. The model was fully saturated with two explicitly measured variables, allowing model fit evaluation to be omitted given its just-identified nature. Relationships between treatment burden and self-care examined using cross-lagged panel models (CLPM) were stratified by age (<60 vs ≥60 years) and presence of diabetes comorbidity (diabetics vs nondiabetics), with covariate adjustment. The between-group differences in path coefficients were assessed using Fisher’s z test.

Following the establishment of the temporal relationship between treatment burden at T1 and self-care at T2, a causal mediation model was constructed to examine whether self-care at T2 may mediate the association of treatment burden at T1 with systolic BP and hypertension control at T3. We specified treatment burden at T1 as the predictor variable (X), self-care at T2 as the mediator (M), and BP outcomes as dependent variables (Y). The mediation analysis was conducted via a four-stage sequential approach: (1) demonstrating the total effect of X on Y (β_Total), ie, X→Y association; (2) establishing the effect of X on M (β_MX), ie, X→M association; (3) determining the effect of M on Y (β_YM.X), ie, M→Y association while controlling for X; and (4) quantifying the mediation proportion by dividing the indirect effect (β_Indirect) by the total effect, ie, [(β_MX × β_YM.X)/β_Total] × 100%. CLPM analyses were performed using Mplus 8.3, while the mediation analyses were conducted using Stata 15.1 with adjustment for age, sex, and presence of coexisting diabetes. Statistical significance level was set at P<0.05.

In the sensitivity analysis, we applied a leave-one-out cross-validation approach in both CLPM and mediation models, in which self-care was restructured by systematically excluding each of the five original domains in turn, thereby creating modified composite scores comprising the sum of the remaining four domains (maximum score: 4 points). To illustrate, when leaving out the nonsmoking domain, the recalculated self-care score incorporated nondrinking, physical activity, healthy diet, and medication adherence. CLPM and mediation models were adjusted for age, sex, and the presence of coexisting diabetes, which maintained consistency with the primary analysis.

Results

The longitudinal cohort comprised 1718 hypertensive patients (54.4% male; mean age 54.6 ± 11.9 years), of whom 490 had coexisting diabetes. Table 1 summarises the mean levels of variables at T1, T2, and T3, stratified by sex and presence of diabetes comorbidity. After adjusting for age, women participants had significantly higher self-care scores at both T1 and T2 compared to men (P<0.001). Table 2 presents pair-wise Pearson’s correlations between T1 and T2 values for self-care and treatment burden in the total sample and across age groups and subjects with and without coexisting diabetes, with adjustment for covariates where appropriate. Most of the correlation coefficients were significant (P<0.05), except between T1 self-care and T2 treatment burden in the total sample, under 60s, and those without coexisting diabetes. We also observed no significant correlations between T2 treatment burden and T2 self-care in those aged less than 60 years and those with the absence of coexisting diabetes.

Table 1 Treatment Burden, Self-Care, Systolic Blood Pressure, and Hypertension Control Among Study Participants by Age and Presence of Diabetes Comorbidity

Table 2 Pearson’s Correlation Coefficients of Relationship Between Treatment Burden and Self-Care Among Study Participants

The CLPM analysis showed that path coefficients for treatment burden at T1 on subsequent self-care at T2 in the total sample (β₂ = −0.089, P<0.001), when adjusted for age, sex, and diabetes comorbidity, were significant and in the expected directions, suggesting that greater treatment burden was associated with poorer self-care adherence (Figure 1). This pattern persisted across age-stratified (β₂ = −0.083 for under 60s and β₂ = −0.113 for older participants; both P<0.001; Figure 2) and comorbidity-stratified (β₂ = −0.103 for patients with coexisting diabetes and β₂ = −0.085 for nondiabetic patients; both P<0.001; Figure 3) analyses. Notably, the path coefficients did not significantly differ by age (under 60s vs older participants: P=0.558) and presence of diabetes comorbidity (diabetics vs nondiabetics: P=0.733).

Figure 2 Cross-lagged panel model of treatment burden and self-care stratified by age. Notes: β1, β2 = cross-lagged path coefficients; r1 = synchronous correlations; r2, r3 = auto-correlations. Models adjusted for sex and presence of diabetes comorbidity. *P<0.001. aBetween-group difference in path coefficients (under 60 years: −0.083 vs ≥60 years: −0.113; P=0.558).

Figure 3 Cross-lagged panel model of treatment burden and self-care by presence of diabetes. Notes: β1, β2 = cross-lagged path coefficients; r1 = synchronous correlations; r2, r3 = auto-correlations. Models adjusted for age and sex. *P<0.001. aBetween-group difference in path coefficients (diabetics: −0.103 vs nondiabetics: −0.085; P=0.733).

Mediation analyses, controlling for age, sex, and diabetes comorbidity, revealed that self-care at T2 partially mediated (10.7%) the longitudinal association between treatment burden at T1 and systolic BP at T3 (β_Indirect = 0.024, P<0.001; β_Total = 0.226, P<0.001; Figure 4). This mediation operates through a negative association between treatment burden at T1 and self-care at T2 (β_MX = −0.010, P<0.001), coupled with a stronger inverse relationship between self-care at T2 and systolic BP at T3 (β_YM.X = −2.294, P<0.001). Similarly, self-care partially mediated (11.1%) the pathway between treatment burden at T1 and hypertension control at T3 (β_Indirect = −0.001, P<0.001; β_Total = −0.009, P<0.001; Figure 5), operating through a negative association between treatment burden at T1 and self-care at T2 (β_MX = −0.011, P<0.001), coupled with a stronger relationship between self-care at T2 and hypertension control at T3 (β_YM.X = 0.106, P<0.001).

Figure 4 Mediating effect of self-care on the relationship between treatment burden and systolic blood pressure. Note: *P<0.001.

Figure 5 Mediating effect of self-care on the relationship between treatment burden and hypertension control. Note: *P<0.001.

In the leave-one-out sensitivity analysis revealed stable path coefficients from treatment burden at T1 to self-care at T2 across all subgroups, indicating robust temporal relationships unaffected by self-care domain exclusion (Supplementary Table 1). Mediation analysis showed consistently modest effect magnitudes and significance levels, with self-care at T2 accounting for 7.0–8.9% of the total effect of treatment burden at T1 on systolic BP levels and hypertension control at T3 across subgroups, suggesting that no single behavioural domain exerts disproportionate influence within the self-care construct (Supplementary Tables 2 and 3).

Discussion

This longitudinal study elucidated the temporal associations between treatment burden and self-care in a sample of Chinese hypertensive patients using cross-lagged path analysis—a robust statistical approach for determining causal relationships. Results demonstrated that increased treatment burden significantly predicted reduced self-care levels. This pattern was consistent across age (<60/≥60 years) and diabetes comorbidity (diabetic/nondiabetic) subgroups. These patterns influenced systolic BP levels and hypertension control in the subsequent 14 months, with self-care accounting for 10.7% and 11.1% of the total effect of increased treatment burden on elevated systolic BP levels and reduced hypertension control (both P<0.001), respectively.

Treatment burden has been identified as a risk factor compromising self-care capacity among patients with chronic conditions. Evidence from American primary care settings suggests that both cumulative and task-specific treatment burdens predict poorer adherence to therapeutic regimens.²⁰ While such correlational findings are informative, they remain inadequate for establishing causal relationships. Our CLPM analysis advances these findings by establishing temporal precedence–higher treatment burden predicts later self-care decline.^20,32 It may be possible that when treatment benefits were not immediately apparent, patients may experience increasingly onerous burden, thereby diminishing one’s emotional engagement and undermining their long-term motivation to maintain health-monitoring routine. Notably, though between-group differences were non-significant, the association between treatment burden and self-care was marginally stronger in older adults and those with coexisting diabetes. In elderly populations, this likely reflects the compounding effects of age-related functional decline,³³ polypharmacy,³⁴ and multimorbidity-induced therapeutic complexity.³⁵ In those with concurrent diabetes, competing disease management priorities appear to exacerbate the challenges of maintaining hypertension self-care. These observations underscore the need for mixed-methods investigations to further understand the mechanisms driving these relationships in the process evaluation.³⁶

The mediation pathway identified in our study substantiates the Cumulative Complexity Model, demonstrating how intensified treatment burden worsens the workload-capacity imbalances, triggering breakdowns in self-care capacity and driving patient complexity.³⁷ Our secondary hypothesis suggests that excessive treatment burdens may exceed patients’ cognitive resources, impairing both self-care implementation and task prioritisation, ultimately compromising BP control. While self-care partially mediated these associations (9.3–11.1%), these modest effects warrant cautious clinical interpretation. The direct pathway established in our study revealed that each 1-unit decrease in treatment burden yielded a 0.20 mmHg systolic BP reduction (β_Direct = 0.202, P<0.001), implying that treatment burden alleviation that achieves a clinically meaningful BP reduction threshold (eg, a 10 mmHg reduction in systolic BP, corresponding to 20% fewer major cardiovascular events and 13% lower all-cause mortality³⁸) is likely to provide widely applicable health benefits. These findings collectively position treatment burden reduction as a viable intervention strategy for optimising BP management.

Empirical evidence confirms that enhanced self-care practices directly lower systolic BP.^39–41 This relationship is corroborated by our study findings and aligns with the Individual and Family Self-Management Theory,⁴² which emphasises that effective BP control depends on patients’ self-management capabilities and sustained engagement with treatment regimens that derive from positive reinforcement mechanisms and emotional responses.⁴³ Modifiable behavioural patterns have been estimated to account for up to 40% of premature deaths.⁴⁴ However, the pivotal role of self-care and health-promoting behaviours in hypertension management remains undervalued in daily practice. Significant barriers persist across multiple levels, encompassing individual psychological constraints (eg, low self-efficacy and outcome expectancy), familial interactions, boarder social determinants, and systemic healthcare challenges that collectively constrain self-care capacity.^12,45 This situation is exacerbated when clinical interventions are intensified without proper consideration of treatment burden, leading to unsustainable adherence as patients may inevitably prioritise among competing demands,³⁷ particularly in a multimorbidity context.⁴⁶

Implications for Theory and Practice

Our study provides empirical evidence supporting the Cumulative Complexity Model (CCM),³⁷ substantiating its theoretical framework through the identified “treatment burden → self-care → health outcomes” pathway. Our findings demonstrate that treatment burden detrimentally affects health outcomes both directly and indirectly through its deleterious impact on self-care capacity, thereby necessitating an expansion of the CCM to incorporate these parallel mechanistic routes. Therapeutic intensification, while clinically intended to improve outcomes, may inadvertently exacerbate treatment burden through increased workload demands, connecting the burdensome experience with erosion of patient capacity, which may subsequently worsen health outcomes.³⁷ The feedback loop may impose mounting pressures on healthcare systems through escalating service utilisation and resource expenditure.

The established mediation pathway (treatment burden → self-care → health outcomes) reveals treatment burden as a progressive determinant of self-care capacity erosion, thereby elevating BP through disruptions in self-management activities. These findings may call for a reorientation of strategies towards prioritising treatment burden mitigation, eg, through regimen simplification and use of organisational strategies, on top of the existing efforts to enhance an individual’s self-care competencies and adherence in medication management and lifestyle changes. Examples of implementation may include restructure of clinical services, patient-centred prescribing practices, and individualised treatment intensity calibration to better support chronic disease management. Incorporating burden-sensitive care assessment tools, eg, the TBQ,²⁵ into routine clinical metrics may enable identification of workload reduction opportunities while evaluating how care aligned with patient priorities ultimately influences health outcomes.⁴⁷

Strengths and Weaknesses

Our study has several strengths. To the best of our knowledge, this investigation represents the first population-level quantitative analysis to establish the temporal relationship between treatment burden and self-care while evaluating their combined impact on systolic BP and hypertension control. The research benefits from a relatively large primary care cohort of hypertensive patients and assessment of multiple aspects of self-care. The use of a valid and internationally recognised instrument ensured rigorous measurement of treatment burden. Result consistency across patient subgroups strengthened the robustness of study findings. This study has some limitations that warrant consideration. First, the reliance on self-reported measures of treatment burden and self-care behaviours may be susceptible to recall and socio desirability bias. Second, by excluding patients who discontinued medication from the analysis, the study may have biased the sample toward more engaged individuals. Third, our findings from a Chinese cohort may have limited generalisability to geographically diverse populations given cross-national variations in healthcare system structures and sociocultural contexts. Crucially, the characteristically strong family support in the Chinese society–encompassing filial piety, shared care-giving, intergenerational relationship, and emotional engagement–may disproportionately mitigate treatment burden relative to the Western populations wherein such support networks are often less institutionalised. Last but not least, the mediating effect of self-care on the treatment burden-BP linkage was modest, enunciating the need for further qualitative studies to uncover additional factors across the full adult life course.

Conclusions

In conclusion, our study demonstrated that elevated treatment burden preceded poor self-care behaviours in a longitudinal primary care cohort of Chinese hypertensive patients using cross-lagged path analysis. Self-care was identified as a significant mediator in the temporal pathway linking treatment burden to both systolic BP levels and hypertension control. These findings provide novel insights into the temporal relationships between treatment burden, self-care, and hypertension outcomes, which may be an important clue to optimise hypertension management strategies.

Data Sharing Statement

The datasets used and analysed during the current study are available from the last corresponding author (HHXW) upon reasonable request.

Ethics Statement

Ethics approval was granted from the School of Public Health Biomedical Research Ethics Review Committee at Sun Yat‐Sen University in accordance with the Declaration of Helsinki 2013.

Informed Consent Statement

All patients provided written consent. Data were anonymised in the dataset to protect patient privacy.

Acknowledgments

We wish to acknowledge the tremendous support of the Guangdong-provincial Primary Healthcare Association (GDPHA) for the liaison with all study sites. We also thank our research collaborators, frontline staff at primary care facilities and students from Guangzhou Medical University and Sun Yat‐Sen University who were involved in conducting fieldwork and data collection.

Funding

National Natural Science Foundation of China (grant 72061137002) and Health Commission of Guangdong Province (grant 202303281631424512). The funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Disclosure

The authors declare that there are no conflicts of interest in this work.

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Chinese researchers investigating Parkinson’s disease have made a curious discovery related to earwax that could improve the prospects of prevention and diagnosis.

A team based at Zhejiang University in Guangzhou has found that earwax tests could help with the early detection of the debilitating disease, which is difficult to treat and has no cure.

The researchers were following up on previous work showing that Parkinson’s sufferers’ sebum – an oily substance secreted through the skin – has a different odour than that of people without the disease.

Since earwax is largely made up of sebum, the team realised it would make for a potentially telling research target.

After screening samples taken from more than 200 people, the team found alterations in four volatile organic compounds – organic chemicals that easily evaporate into the air – in Parkinson’s patients’ earwax. These changes do not appear in the compounds in the sebum of those who do not have Parkinson’s.

WASHINGTON, July 1, 2025 /PRNewswire/ — Today, on World Bronchiectasis Day, the American Lung Association is launching a new campaign to support people living with bronchiectasis, which is a chronic and progressive lung condition that affects between 350,000 and 500,000 adults in the United States. The new campaign aims to educate people living with bronchiectasis about how to improve their disease management, help connect them with emotional support and ultimately improve their life.

Bronchiectasis is a chronic lung disease in which the airways (bronchi) become widened and scarred due to repeated inflammation and infection. This damage makes it difficult to clear mucus from the lungs, leading to persistent cough, shortness of breath, frequent infections and decreased lung function.

“While there is currently no cure for bronchiectasis, early diagnosis, effective management and a solid support system can help people with the disease lead heathy and active lives,” said Harold Wimmer, President and CEO of the American Lung Association. “Through education, support and empowering individuals to communicate effectively with their healthcare providers, we can help patients better manage their symptoms and prevent serious complications.”

The American Lung Association’s free bronchiectasis awareness campaign includes:

• Patient education on managing flare-ups, understanding disease progression, and exploring treatment options.
• Resources for newly diagnosed patients to help navigate the condition from the start.
• Support for emotional wellbeing, including access to the Lung HelpLine and guidance on coping with the psychological impact of chronic lung disease.
• Patient stories and insights to amplify the voices of those living with bronchiectasis.
• Use of social listening to identify community needs and shape future resources.

Bronchiectasis is more common in women and older adults, and in 40% of cases, the underlying cause is unknown. Treatment often includes airway clearance techniques, inhaled medications, antibiotics to manage infections, and in some cases, oxygen therapy. Though the disease shares some symptoms with COPD, it is a distinct condition and must be treated as such—especially for those living with both diseases.

To learn more about bronchiectasis and access educational materials, visit Lung.org/bronchiectasis.

Support for this awareness campaign is provided by Boehringer Ingelheim.

About the American Lung Association
The American Lung Association is the leading organization working to save lives by improving lung health and preventing lung disease through education, advocacy and research. The work of the American Lung Association is focused on four strategic imperatives: to defeat lung cancer; to champion clean air for all; to improve the quality of life for those with lung disease and their families; and to create a tobacco-free future. For more information about the American Lung Association, a holder of the coveted 4-star rating from Charity Navigator and a Platinum-Level GuideStar Member, or to support the work it does, call 1-800-LUNGUSA (1-800-586-4872) or visit: Lung.org.

CONTACT: Jill Dale | American Lung Association
               P: 312-940-7001 C: 720-438-8289 E: [email protected]

SOURCE American Lung Association

Compared with standard intensive speech and language therapy (iSLT) alone, right-sided cervical C7 neurotomy combined with iSLT significantly improved language function in patients with chronic aphasia after left hemisphere stroke in a randomized controlled trial conducted in China.

Compared with patients who received iSLT alone, patients who received the combined treatment showed statistically significant improvements across all measured outcomes, including naming ability, functional language scores, quality of life, and post-stroke depression, with no severe adverse events.

The results of the study, with first author Juntao Feng, MD, PhD, Fudan University, Shanghai, China, were published online on June 25 in The BMJ.

A Challenging Condition

Chronic aphasia affects more than 60% of stroke survivors beyond the first year, impairing communication and reducing independence. While iSLT remains the standard intervention, its effect is often modest and no adjunct treatment has consistently delivered sustained benefit.

Recent anecdotal findings from C7 nerve transfer surgeries for spastic arm paralysis have hinted at coincidental improvements in language, particularly naming, prompting exploration of targeted neurotomy for chronic aphasia treatment.

Feng and colleagues enrolled 50 patients, aged 40-65 years, with aphasia for more than 1 year after a stroke affecting the left side of the brain, which is responsible for language. Most of the patients also had coexisting spasticity of the right arm.

Half were randomized to right C7 neurotomy at the intervertebral foramen followed by 3 weeks of iSLT and half to iSLT alone.

The primary endpoint was change on the 60-item Boston Naming Test (BNT, scores 0-60, with higher scores indicating better naming ability). BNT assessments occurred at baseline, 3 days, 1 month, and 6 months.

At 1 month, the average increase in BNT score was 11.16 points in the neurotomy plus iSLT group vs 2.72 points in the iSLT-only group — a significant 8.51-point difference (P < .001).

The difference favoring neurotomy add-on remained robust at 6 months (8.26-point difference; P < .001).

Of note, improvement in naming deficits — which are among the most resistant to therapy — were detectable within 3 days after surgery, before iSLT started, suggesting an immediate neuromodulatory effect of the neurotomy itself, the researchers said.

“It could be speculated that neurotomy of the seventh cervical nerve triggered changes in plasticity of the brain regions responsible for language,” they wrote.

Neurotomy was also associated with significant improvement in aphasia severity (difference at 1 month of 7.06 points on the aphasia quotient; P < .001), as well as patient-reported activity of daily life and post-stroke depression.

No major complications or long-term adverse effects were reported. Adverse events that were related to C7 neurotomy included transient neuropathic pain, decreased sensory and motor function in the right upper limb, and minor blood pressure elevations occurred in some patients, but resolved within 2 months post-surgery. No adverse events were noted at 6-month follow-up.

The investigators noted that the study population was limited to relatively young Mandarin-speaking Chinese patients treated at four urban centers, raising questions about generalizability. Additionally, follow-up was limited to 6 months.

The study team plans to follow the participants for 5 years and explore applicability in broader, international cohorts.

Based on their results, they concluded that right C7 neurotomy at the intervertebral foramen plus iSLT is “superior” to iSLT alone for chronic post-stroke aphasia and “could be considered an evidence-based intervention for patients aged 40-65 years with aphasia for more than 1 year after stroke.”

‘Provocative’ Research

Commenting on the study for Medscape Medical News, Larry B. Goldstein, MD, chair of the Department of Neurology and codirector of the Kentucky Neuroscience Institute at the University of Kentucky, Lexington, Kentucky, called the study results “interesting and provocative.” 

“Caveats are that the participants were predominately men (80%), young (about 52 years; much younger than most stroke patients), and a high proportion had brain hemorrhages (about half; in general only 15% of strokes are from bleeding),” Goldstein noted.

“The participants’ primary language was Chinese, and there was no control for medications they might have been receiving that could affect brain function. Additionally, both the participants and the therapists were aware of the treatment group (although the assessors were unaware of group assignment),” Goldstein pointed out.

“With those limitations in mind, the reported data suggests the potential viability of the approach. It will need to be assessed in a more typical population of patients (ie, older, a higher proportion of women, a higher proportion of ischemic stroke), account for medication use, blind therapists to treatment group, and involve participants speaking other languages,” Goldstein told Medscape Medical News.

The author of a linked editorial said the study is “an interesting step forward with room to explore further.” 

“Although intensive SLT remains the cornerstone of aphasia treatment, C7 neurotomy could become a potential adjunctive option for carefully selected individuals in the future,” wrote Supattana Chatromyen, MD, with the Neurological Institute of Thailand, Bangkok, Thailand.

“This research should spark further scientific research and a critical re-evaluation of rehabilitation paradigms and policies for chronic stroke care, fostering a more optimistic and proactive approach to long-term recovery,” Chatromyen concluded.

This study had no commercial funding. Feng, Goldstein, and Chatromyen had no relevant conflicts of interest.

Study setting {9}

The investigation will be carried out by the department of anesthesiology at Suzhou Ninth People’s Hospital, an affiliated hospital of Soochow University. Our hospital’s anesthesiology department is recognized as a key clinical discipline in the region. With around 5000 laparoscopic surgery patients treated annually, the hospital will provide a sufficient patient population to ensure an adequate sample size for the study. Figure 1 illustrates the research workflow.

Eligibility criteria {10}

Inclusion criteria

1. 1.

   Participants aged 18 to 65 years old.

2. 2.

   American Society of Anesthesiologists (ASA) physical status I to III.

3. 3.

   Body mass index (BMI) between 18 and 30 kg/m².

4. 4.

   Scheduled to perform general anesthesia with endotracheal intubation for laparoscopic surgery, including appendectomy, laparoscopic cholecystectomy and laparoscopic hernia repair.

5. 5.

   Expected duration of surgery between 30 and 120 min.

Exclusion criteria

1. 1.

   Sick sinus syndrome or severe bradycardia (heart rate less than 50 beats per minute).

2. 2.

   History of hypertension or cardiac insufficiency.

3. 3.

   Second-degree or higher atrial block without a pacemaker.

4. 4.

   Left ventricular ejection fraction less than 40%.

5. 5.

   Diagnosed with coronary artery disease or history of myocardial infarction.

6. 6.

   Hepatic or renal insufficiency, Child–Pugh class C, or undergoing renal replacement therapy.

7. 7.

   Parkinson’s disease or Alzheimer’s disease.

8. 8.

   Seizures or epilepsy.

9. 9.

   Current pregnancy or lactation status.

10. 10.

    History of persistent pain or prior use of sedatives or analgesics.

11. 11.

    Known allergies to the drugs used in this study.

12. 12.

    Participation in another clinical trial within the past 30 days.

13. 13.

    History of substance abuse.

14. 14.

    Psychiatric illness or current use of antipsychotic medications.

15. 15.

    Communication disorders such as deafness or cognitive impairment.

16. 16.

    Anticipated difficult airway or history of difficult intubation.

Drop out criteria

Participants will not be excluded from the final analysis solely due to adverse events or other post-randomization occurrences. All randomized participants will be included in the intention-to-treat (ITT) analysis.

However, the following circumstances will be considered as dropouts, and the reasons will be recorded in detail:

1. 1.

   Withdrawal of informed consent for continued participation or data use.

2. 2.

   Loss to follow-up before the assessment of primary or secondary outcomes.

3. 3.

   Conversion from laparoscopic to open surgery.

4. 4.

   Use of non-permitted medications, including:

   • – Additional antiemetics not specified in the protocol.

   • – Perioperative corticosteroids.

   • – Sedatives or analgesics outside the study regimen.

5. 5.

   Non-collection of data.

In contrast, the following events will be considered protocol deviations and addressed in sensitivity analyses:

1. 1.

   Non-administration of the study drug.

2. 2.

   Unplanned additional surgical procedures.

3. 3.

   Minor violations of timing or dosage not affecting outcome measurement.

Screening failures (participants who do not meet eligibility criteria before randomization) will be recorded separately and excluded from all analyses. All dropout events and reasons will be meticulously documented in the case report forms (CRFs) and stored for auditing and future reference.

Consent or assent {26a, 26b}

Eligible patients will be approached by research team members, all of whom are licensed medical doctors, to be invited to participate in the study. Detailed instructions regarding the study protocol, procedures, and potential risks and benefits will be provided in clear language. Written informed consent will be obtained from each participant one day prior to surgery to ensure voluntary participation and adequate understanding of the research process.

Explanation for the choice of comparators {6b}

To provide a rigorous comparison, the comparator in this trial is the standard anesthetic regimen routinely used at our institution, consisting of intravenous induction with sufentanil and propofol, followed by maintenance with sevoflurane and a continuous remifentanil infusion. This approach is widely adopted in clinical practice and provides effective intraoperative analgesia with minimal postoperative sedation, making it particularly suitable for laparoscopic surgeries [11, 29]. The intervention group protocol is informed by the principles of OFA, where dexmedetomidine and esketamine are commonly utilized to achieve adequate analgesia and sedation while minimizing opioid exposure. The selected drug combination and administration strategy are based on published OFA studies and adapted for routine clinical application [13, 21, 25]. Given the established link between intraoperative opioid use and PONV, this study aims to determine whether an opioid-reducing approach incorporating these agents can improve PONV outcomes and postoperative recovery compared to the standard opioid-based regimen.

Interventions {11a, 11b, 11c, 11d}

Patients will be randomized into two groups using a computer-generated random number table at a 1:1 ratio, comprising the combination therapy group (dexmedetomidine and esketamine) and the control group. In the combination therapy group, anesthesia induction will involve intravenous infusion of dexmedetomidine (0.5 μg/kg over more than 10 min), followed by intravenous bolus administration of esketamine (0.3 mg/kg), sufentanil (0.2 μg/kg), and propofol (1.5–2.0 mg/kg). Anesthesia will be maintained with 2–3% sevoflurane. In the control group, anesthesia induction will consist of intravenous bolus administration of sufentanil (0.5 μg/kg) and propofol (1.5–2.0 mg/kg), while maintenance will include 2–3% sevoflurane inhalation and continuous intravenous infusion of remifentanil at 0.1 μg/kg/min. The selected remifentanil dose is within the low range and below thresholds typically associated with remifentanil-induced hyperalgesia, as supported by previous studies [30, 31].

All patients will receive 5 mg of dexamethasone intravenously after anesthesia induction, 4 mg of tropisetron at the end of surgery, and 50 mg of flurbiprofen axetil approximately 30 min before surgery completion to prevent PONV and manage postoperative pain. The intraoperative monitoring protocol includes ECG, SpO₂, non-invasive blood pressure, and end-tidal CO₂, with anesthesia depth maintained within a BIS range of 40–60. Vital signs will be continuously monitored using standard multi-parameter monitors. The dosages of anesthetic agents in both groups are derived from published literature and institutional protocols, with remifentanil and sufentanil dosing in the control group based on perioperative anesthesia studies [13, 32], and dexmedetomidine and esketamine dosing in the combination group adapted from opioid-free anesthesia protocols [13, 21].

Postoperative management will also be standardized. Pain and PONV assessments will be conducted at fixed time intervals: 0–6 h (PACU), 6–24 h, and 24–48 h after surgery. Pain intensity will be evaluated using the numerical rating scale (NRS) at 0, 6, 12, 24, and 48 h. Time to first PONV episode, time to first rescue medication use, and total dosage/frequency of rescue analgesics and antiemetics within 48 h will be recorded. Postoperative adverse events such as nightmares, drowsiness, bradycardia, length of hospital stay, and discharge condition will also be documented.

Rescue interventions are standardized. For pain (NRS ≥ 4), 5 mg of dezocine will be administered intravenously. Severe PONV, defined as ≥ 3 vomiting episodes or inability to perform daily activities, will be managed with 10 mg of azasetron; persistent vomiting post-treatment may lead to study withdrawal. Adverse reactions such as esketamine-related nightmares will be treated with 2 mg midazolam, while drowsiness will be managed with observation or opioid antagonists like naloxone in severe cases. Bradycardia (HR < 55 bpm) will be treated with 0.25 mg atropine or 2 μg isoproterenol and anesthetic dose adjustment.

To enhance adherence and consistency, interventions will be performed under general anesthesia, eliminating the need for patient cooperation during drug administration. Postoperative assessments will be carried out by trained personnel at predefined time points using standardized tools. Rescue medication criteria are clearly defined to minimize variability. Preoperative briefings for nursing and anesthesiology teams will ensure uniform postoperative care. The overall trial process, including patient enrollment, treatment, and data collection, will follow the SPIRIT guidelines as detailed in Table 2.

Outcomes {12}

Primary outcome

Postoperative pain and nausea severity will be assessed using the Numerical Rating Scale (NRS), an 11-point scale ranging from 0 (no symptom) to 10 (worst imaginable pain or nausea), based on patient self-report at predefined postoperative intervals. The incidence of nausea will be defined as any self-reported score ≥ 1, while vomiting will be defined as any observed or self-reported episode of forceful expulsion of gastric contents. Both nausea and vomiting episodes will be recorded separately by trained clinical staff through direct observation and/or patient reports. The primary outcome of this study is the incidence of PONV (including both nausea and vomiting) within 48 h after surgery. PONV will be assessed by trained clinical staff during three defined time intervals: 0–6 h, 6–24 h, and 24–48 h postoperatively. Both nausea and vomiting episodes will be recorded separately to allow for detailed analysis.

Secondary outcomes

Preoperatively, the Apfel simplified risk score will be used to evaluate each patient’s baseline risk of PONV, assigning one point for each of the following: female sex, non-smoking status, history of motion sickness or previous PONV, and anticipated postoperative opioid use (total score range: 0–4). The secondary outcomes include:

1. 1.

   Preoperative Apfel PONV risk score.

2. 2.

   NRS pain scores of the patients recorded at 0 h (in the PACU), 6 h, 12 h, 24 h, and 48 h after surgery.

3. 3.

   Time to first PONV episode and time to first rescue antiemetic administration.

4. 4.

   Time to first rescue analgesic administration.

5. 5.

   Total dosage and frequency of rescue analgesics and antiemetics within 48 h.

6. 6.

   Patient satisfaction score at discharge, rated on a 5-point Likert scale.

7. 7.

   Length of hospital stay (in days).

8. 8.

   Discharge condition score, assessed by the attending physician.

9. 9.

   Incidence and classification of AEs.

Participant timeline {13}

The timeline for participant involvement is illustrated in Table 2.

Sample size calculation {14}

In a recent investigation, OFA demonstrated a 65% reduction in the likelihood of PONV following laparoscopic gynecological surgery, decreasing the incidence from 42.5 to 15.0% (10). For the power analysis, we assume a baseline PONV incidence of 40% in laparoscopic surgery under traditional opioid anesthesia. With the hypothesis of a 50% average reduction in PONV, our combination therapy strategy is anticipated to lower the PONV incidence to 25%. To achieve a statistical power of 80% with a bilateral α level of 0.05, 64 patients per group will be deemed necessary to detect intergroup differences in PONV. Considering potential withdrawals, a planned recruitment of 140 patients will be intended, with 70 in each group. The sample size is determined using PASS software (V.11.0.7, NCSS, Kaysville, UT, USA).

Recruitment {15}

Patients participating in this study were enlisted from the anesthesia department. Our recruitment information was disseminated through the WeChat public platform. Additionally, soliciting recommendations from medical personnel constituted a significant aspect of our recruitment efforts. Furthermore, recruitment posters were prominently displayed in areas like the hospital outpatient and inpatient departments.

Allocation {16a, 16b, 16c}

In this study, randomization tables will be generated using IBM SPSS Statistics version 26.0 and maintained by independent statisticians overseeing the trial. Eligible participants will be randomly allocated to either the combination therapy group or the control group in a 1:1 ratio. To ensure allocation concealment, the randomization assignments will be enclosed in sealed, opaque envelopes and securely stored in a designated office. Neither the participants nor the investigators involved in clinical care or outcome assessment will be informed of group assignments, thereby maintaining the double-blind design. In cases of emergency or where clarification is required, only designated researchers will have access to the allocation list. Before surgery, coded study medications will be distributed to study personnel. The allocation sequence will remain confidential, accessible only to the principal investigator (PI) and an independent, unblinded researcher responsible for study drug preparation. The PI will assign participants to treatment groups according to the randomization list, while the unblinded researcher, who will not be involved in drug administration, anesthesia management, or outcome assessment, will prepare the corresponding study medications.

Blinding {17a, 17b}

To maintain double-blinding, each study syringe will be labeled solely with the participant’s unique identification number, without revealing the group allocation. The unblinded researcher, who is not involved in clinical care or outcome assessment, will prepare the study medication according to the randomization list and ensure that all other clinical staff and participants remain blinded throughout the trial. To ensure identical appearance and preserve blinding, both dexmedetomidine and esketamine (or their corresponding placebo components) will be diluted with 0.9% normal saline to a total volume of 20 ml. The final preparations, which are colorless and transparent, will be loaded into identical 20 ml syringes and handed over to the anesthesiologist immediately prior to anesthesia induction. All study personnel involved in clinical care, anesthesia management, outcome assessment, and data collection, as well as the participants themselves, will remain blinded to treatment allocation until data collection is completed and final analyses are conducted. In the event that unblinding is necessary due to medical emergencies or other justified reasons, access to allocation information will be strictly limited to designated personnel responsible for medication distribution.

Data collection methods {18a, 18b}

The subsequent data will be gathered as follows:

Preoperatively

1. 1.

   Patient’s general information (including height, weight, ASA classification, level of education, smoking habits, history of motion sickness, previous opioid use, allergies and surgical history).

2. 2.

   Apfel PONV risk score.

3. 3.

   Baseline NRS pain score.

4. 4.

   Results of laboratory tests.

Intraoperatively

1. 1.

   Hemodynamic parameters (such as NBP, HR, ECG and SpO₂).

2. 2.

   Surgical details (including duration of operation, anesthesia, pneumoperitoneum, dosage and concentration of anesthetic agents administered, blood loss, volume of fluid replacement, urine output, and body temperature).

Post-surgery

1. 1.

   Incidence of nausea and vomiting will be assessed at three intervals: 0–6 h (in the PACU), 6–24 h, and 24–48 h after surgery.

2. 2.

   NRS pain scores will be recorded at 0 h (PACU), 6 h, 12 h, 24 h, and 48 h postoperatively.

3. 3.

   Time to first PONV episode, time to first rescue antiemetic or analgesic administration, and the total dosage and frequency of rescue medications.

4. 4.

   Incidence of AEs.

5. 5.

   Postoperative laboratory results.

6. 6.

   Length of hospital stay and discharge condition.

All patient data will be meticulously recorded in a case report form by a designated independent researcher. These records will then be entered into an electronic database under the careful supervision of the PI. Oversight of data collection will be managed by a Data Monitoring Committee (DMC), with final analysis conducted by impartial statisticians.

To promote participant retention and ensure complete follow-up, investigators will provide a comprehensive explanation of the study protocol and expected outcomes during the preoperative assessment. Efforts will be made to maximize participants’ understanding of the study procedures through detailed instruction and clear guidance, thereby enhancing their compliance and engagement throughout the study period.

Data management {19}

Prior to commencing the study, members of our trial team will undergo training in the collection, management, storage and confidentiality of data to ensure comprehension and compliance with pertinent policies and regulations. Patient data will be securely stored in both paper and electronic formats. Coded paper records will be kept in designated, locked storage areas. Data entry for the study will be conducted using a password-protected Microsoft Access database by two trained team researchers employing a double-entry method, and the accuracy of entries will be verified against the electronic database. To minimize the risk of data loss, researchers will perform incremental backups on a daily basis.

Statistical analysis {20a, 20b, 20c}

The Shapiro–Wilk test will be employed to assess the normality of data distribution. Data will be presented as mean (standard deviation), median (interquartile range), or number (percentage), as appropriate. Descriptive statistics will be used primarily to summarize patient characteristics and baseline variables. Comparative analyses of perioperative variables and outcome measures will be performed using the Mann–Whitney rank sum test, chi-square test, or Fisher’s exact test, depending on data type and distribution. To evaluate the effect of combination therapy versus control, the median difference (MD) or odds ratio (OR) with corresponding 95% confidence intervals (CI) will be calculated.

Subgroup analyses of the primary outcome (PONV incidence) will be conducted based on gender, smoking status, and Apfel PONV risk score. No adjustments will be made for multiple testing in secondary outcome analyses, which will therefore be interpreted as exploratory. All statistical analyses will be conducted using IBM SPSS software (version 19.0; IBM SPSS, Chicago, IL, USA), with two-sided P-values < 0.05 considered statistically significant.

As the administration of study medications will be supervised by anesthesiologists, protocol adherence is expected to be high. Since outcome assessment is scheduled within 48 h postoperatively, the occurrence of missing primary outcome data is anticipated to be minimal. Any missing data will not be imputed.

Data monitoring {21a, 21b}

The data monitoring process for this study will be overseen by the monitoring manager, who is a member of the clinical trial management team at Suzhou Ninth Hospital Affiliated to Soochow University. This individual will be responsible for ensuring the proper preservation of informed consent documents, monitoring participant compliance, and verifying the validity and safety of the study data throughout the trial. Given the short duration of the study, the relatively small sample size, and the anticipated low incidence of serious adverse events (SAEs), no interim analysis is planned.

Harms {22}

All adverse events (AEs) will be closely monitored and documented throughout the perioperative period and until the patient is discharged from the hospital. Based on previous studies [27, 28], these include the following:

1. 1.

   Cardiovascular events: hypotension (systolic blood pressure < 90 mmHg), hypertension (systolic blood pressure > 180 mmHg), bradycardia (heart rate < 50 bpm), tachycardia (heart rate > 120 bpm), arrhythmias.

2. 2.

   Respiratory events: respiratory depression (respiratory rate < 8 breaths/min or SpO₂ < 90%), apnea, bronchospasm.

3. 3.

   Neurological and psychiatric events: emergence delirium or agitation, dizziness, headache, visual or auditory hallucinations, excessive sedation (BIS < 40 or unresponsiveness), seizures.

4. 4.

   Injection site reactions or hypersensitivity: rash, pruritus, swelling, or anaphylaxis.

Each AE will be classified by severity into mild, moderate, or severe according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0.

Severe adverse events (SAEs) are defined as unanticipated medical incidents that prolong hospitalization, result in persistent disability or dysfunction, pose a life-threatening risk, or cause death. If any SAE occurs, the infusion of dexmedetomidine and esketamine will be immediately discontinued, and the participant will be withdrawn from the study if necessary. All SAEs will be reported promptly to the Ethics Committee, and participants will be followed until the event resolves or stabilizes, or until hospital discharge, whichever comes later.

The attending anesthesiologists and trained research staff will be responsible for managing and recording all AEs and SAEs in the case report forms. An independent Data Monitoring Committee (DMC), composed of clinical experts not involved in the study, will review and categorize all AEs and SAEs according to predefined criteria. If a participant experiences more than three episodes of vomiting despite rescue treatment, or develops any SAE, the case will be considered for withdrawal from the study in accordance with the predefined discontinuation criteria.

Auditing {23}

There will be no plans for conducting formal trial audits.

Research ethics approval {24}

Ethical clearance for this investigation was granted by our hospital’s ethics committee on May 1, 2023 (2,023,067). Subsequently, the research protocol was registered with the China Clinical Trial Registry on June 14, 2023 (ChiCTR2300072455).

Protocol amendments {25}

Should there arise a need for protocol modifications, they will be duly registered at https://www.chictr.org.cn.

Confidentiality {27}

Confidentiality will be maintained for all potential and enrolled patients, with access restricted solely to the principal investigator. Anonymized patients will be assigned unique numerical identifiers (ID numbers) rather than names. Throughout the duration of the experiment, the DMC diligently oversees the database to enhance data integrity. Upon completion of the experiment, researchers will procure the results of statistical data analysis.