Category: 8. Health

Today, a new ESC Clinical Consensus Statement published in the European Heart Journal discusses the key role of vaccination in preventing cardiovascular events following various viral and bacterial infections.

We have known for many years that influenza can increase the risk of major adverse cardiovascular events such as heart attacks and can exacerbate heart failure. More recently, evidence suggests that other respiratory infections are also associated with increased cardiovascular morbidity and mortality. The new publication describes how vaccinations not only prevent infections but also reduce the risk of cardiovascular events, particularly in susceptible individuals.”

 Professor Thomas F. Lüscher, ESC President and senior author of the ESC Clinical Consensus Statement

The ESC Clinical Consensus Statement describes data on the risk of cardiovascular complications following infections such as pneumococcal pneumonia, influenza, SARS-CoV-2 and respiratory syncytial virus, among others, and describes the inflammatory mechanisms that may be responsible. Evidence is then summarised for the beneficial effects of vaccines in reducing cardiovascular events following various viral and bacterial infections, particularly in at-risk patient groups. Clinical practice guidelines from the ESC and from the American College of Cardiology (ACC)/American Heart Association (AHA) are presented, which advocate for vaccination against influenza and other widespread infections in patients with chronic coronary syndromes (including coronary artery disease) and in those with heart failure.

Serious adverse reactions to vaccinations are very rare. The consensus statement also discusses the risks of cardiovascular adverse events after vaccination, such as myocarditis, and describes appropriate management strategies. Then follows advice on which vaccines should be given to patients with cardiovascular diseases and how often. Vaccination of pregnant women and other vulnerable patient groups, such as those with congenital heart disease and heart transplantation, is considered.

Professor Lüscher concluded: “Prevention is crucial for reducing the considerable burden of cardiovascular disease. The totality of the evidence indicates that vaccinations should become a foundational pillar of preventive strategies alongside other established measures.”

Real-world study demonstrates next-gen EpiSwitch PSE blood test safely reduces unnecessary biopsies by up to 79% while accurately detecting prostate cancer.

A real-world study published high-impact journal Cancers demonstrates the transformative potential of a next-generation prostate cancer blood test developed in the UK to accurately detect more cases of early prostate cancer, while potentially drastically reducing the cost needed to implement a UK-wide screening program.

Prostate cancer is the most common cancer among men in the UK, yet there is no national screening program due to traditional testing relying on an initial prostate-specific antigen (PSA) test, which is not an accurate indicator of prostate cancer by itself.

Approximately 3 in 4 men with a high PSA level do not have cancer, according to Prostate Cancer Research. As a result, many healthy men undergo unnecessary medical scans, invasive procedures, and, in some cases, even overtreatment, leading to  significant anxiety and burden for patients, while also straining healthcare resources.

Dr. Garrett Pohlman, MD, Urologist at Kearney Urology Center and lead author of the study said: “The results we have seen by integrating EpiSwitch PSE have been transformative. These findings show that a routine blood test can enable us to safely avoid biopsies in up to a staggering 79% of patients with an elevated PSA without compromising diagnosis. This is a major advancement that helps our patients benefit from reduced anxiety and the avoidance of unnecessary, costly medical procedures.”

By integrating EpiSwitch PSE into clinical practice, the healthcare system could achieve significant savings. The study found that among 187 patients, the PSE test potentially avoided 97 unnecessary prostate biopsies and 95 MRIs in this group alone.

This translates into an estimated cost saving of over 170,000 GBP (230,000 USD), or almost 1,000 GBP per patient, accounting for reduced subsequent procedures, MRI scans, and occasional downstream complications due to risks from prostate biopsies. Fewer MRI scans also reduce the need for substantial government investment in additional imaging infrastructure.

When expanded to the national level, the health-economic impact of incorporating PSE into a screening workflow could be substantial according to the study. In the US, the authors estimates that PSE has the potential to conservatively help avoid up to 593,000 prostate biopsies per year, with the economic benefit approaching 2 billion USD annually.

Oliver Kemp, MBE, Chief Executive Officer of UK charity Prostate Cancer Research, said: “This study shows how smarter testing can save millions while improving care for patients. Reducing unnecessary biopsies and scans means less stress for men and more capacity in the system.”

The innovation behind EpiSwitch PSE originates from a British company, Oxford BioDynamics (OBD), in collaboration with leading researchers and clinicians at the Imperial NHS Trust, Imperial College London, and the University of East Anglia.

Dr. Alexandre Akoulitchev, MA, PhD, FRSM, Chief Scientific Officer at Oxford BioDynamics, said: “This study builds on our earlier robust clinical validation work which demonstrated the application of EpiSwitch PSE as a precise, minimally invasive test that empowers clinicians and patients with clarity, reduced patient risk, and improved outcomes, while easing the pressure on the diagnostic pathway.”

Given these health and economic outcomes, Oxford BioDynamics says that EpiSwitch PSE is poised to ‘set a new standard’ and streamline prostate cancer diagnosis and management strategies in the US, where it is routinely reimbursed by Medicare, and the UK, where it is currently widely available to private patients and reimbursed by Bupa Health Insurance.

Related

Washington State University researchers have discovered how the bacteria that cause anaplasmosis and Lyme disease hijack cellular processes in ticks to ensure their survival and spread to new hosts, including humans.

Based in the College of Veterinary Medicine, the team found that the bacteria can manipulate a protein known as ATF6, which helps cells detect and respond to infection, to support its own growth and survival inside the tick. The findings, published in the journal Proceedings of the National Academy of Sciences, could serve as a launching point for developing methods to eliminate the bacteria in ticks before they are transmitted to humans and other animals.

Most research has looked at how these bacteria interact with humans and animals and not how they survive and spread in ticks. What we have found could open the door to targeting these pathogens in ticks, before they are ever a threat to people.”

Kaylee Vosbigian, doctoral student and lead author on the study

Vosbigian and her advisor, Dana Shaw, the corresponding author of the study and an associate professor in the Department of Veterinary Microbiology and Pathology, focused their research on Ixodes scapularis, also known as the blacklegged tick, which is responsible for spreading both Anaplasma phagocytophilum and Borrelia burgdorferi, the causative agents of anaplasmosis and Lyme disease. Both diseases are becoming increasingly common and can cause serious illness in humans and animals.

The team discovered that when ATF6 is activated in tick cells, it triggers the production of stomatin, a protein that helps move cholesterol through cells as part of a normal cellular processes. The bacteria exploit this process against their tick hosts, using the cholesterol –which they need to grow and build their own cell membranes but cannot produce themselves – to support their own survival and success.

“Stomatin plays a variety of roles in the cell, but one of its key functions is helping shuttle cholesterol to different areas,” Vosbigian said. “The bacteria take advantage of this, essentially stealing the cholesterol they need to survive.”

When the researchers blocked the production of stomatin, restricting the availability of cholesterol, bacterial growth is significantly reduced. The researchers believe this shows targeting the ATF6-stomatin pathway could lead to new methods for interrupting the disease cycle in ticks before transmission occurs.

As part of the study, Vosbigian also developed a new research tool called ArthroQuest, a free, web-based platform hosted by WSU that allows scientists to search the genomes of ticks, mosquitoes, lice, sand flies, mites, fleas and other arthropod vectors for transcription factor binding sites – genetic switches like ATF6 that control gene activity.

“There aren’t many tools out there for studying gene regulation in arthropods,” Vosbigian said. “Most are built for humans or model species like fruit flies, which are genetically very different from ticks.”

Using ArthroQuest, the team found that ATF6-regulated control of stomatin appears to be prevalent in blood-feeding arthropods. Since the hijacking of cholesterol and other lipids is common among arthropod-borne pathogens, the researchers suspect many may also exploit ATF6.

“We know many other vector-borne pathogens, like Borrelia burgdorferi and the malaria-causing parasite Plasmodium, rely on cholesterol and other lipids from their hosts,” Shaw said. “So, the fact that this ATF6-stomatin pathway exists in other arthropods could be relevant to a wide range of disease systems.”

The research was supported in part by a National Institutes of Health R01 grant and a College of Veterinary Medicine intramural seed grant.

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.