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Beyond Diabetes Care, Sodium-Glucose Co-transporter-2 (SGLT2) Inhibitors in Cardiovascular and Renal Health: Evidence and Implementation

DOI: 10.31038/EDMJ.2025924

Abstract

Multiple studies have established the benefits of sodium-glucose co-transporter-2 (SGLT2) inhibitors in heart failure and chronic kidney disease (CKD) in patients with type 2 diabetes. Following these studies, additional large randomized controlled trials were conducted to assess their efficacy across various stages of heart failure and CKD and demonstrated benefit in patients regardless of diabetes status. While the data supporting the use of SGLT2 inhibitors is robust and national guidelines now recommend their use, the adoption of these treatments in clinical practice remains suboptimal. To improve patient outcomes, leveraging a multidisciplinary team-based approach can help accelerate widespread adoption.

Review of the Evidence in Heart Failure

Numerous randomized controlled trials in patients with type 2 diabetes have demonstrated the benefits of SGLT2 inhibitors in managing cardiovascular disease and chronic kidney disease [1-7]. In the initial SGLT2 inhibitor trials, these therapies significantly reduced heart failure hospitalizations compared to placebo in patients with established cardiovascular disease or those at high risk, a benefit that is primarily attributed to the prevention of incident symptomatic heart failure. Another placebo-controlled study found that initiating a combined SGLT1/2 inhibitor (sotagliflozin) either before or shortly after discharge in patients with diabetes and recent worsening heart failure led to a significant reduction in cardiovascular mortality as well as the number of hospitalizations and urgent visits for heart failure [8]. SGLT2 inhibitors have similarly been shown to slow the progression of kidney disease and reduce the incidence of renal events when added to standard care. The mechanisms underlying these benefits are believed to extend beyond glucose, weight, and blood pressure reduction; they are hypothesized to be driven by reductions in plasma volume, decreased cardiac preload and afterload, alterations in cardiac metabolism, and tubuloglomerular feedback which in turn lowers intraglomerular pressure [9,10].

Given the benefit seen in patients with type 2 diabetes, several landmark large clinical trials were conducted to analyze the benefits of these medications for these indications in patients with or without diabetes. These trials investigated the benefit of SGLT inhibitors in patients with heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, and chronic kidney disease. A summary of these trials and their findings are presented in Table 1.

Table 1: Summary of randomized controlled trials for non-diabetes indications.

Heart Failure with Reduced Ejection Fraction
Trial	Intervention	Key Patient Characteristics	Results
DAPA-HF¹¹	Dapagliflozin 10 mg once daily (n=2373) or placebo (n=2371)	· NYHA Class II 67.7% (dapa); 67.4% (placebo) · Systolic blood pressure (mmHg) 122.0 + 16.3 (dapa); 121.6 + 16.3 (placebo) · Mean LVEF (%) 31.2 + 6.7 (dapa); 30.9 + 6.9 (placebo) · Mean eGFR (mL/min/1.73m²) 66.0 + 19.6 (dapa); 65.5 + 19.3 (placebo) o eGFR < 60 40.6% (dapa); 40.7% (placebo) · Background therapy with ACE/ARB/ARNI 95% (dapa); 93.7% (placebo)	Primary composite outcome of worsening heart failure (hospitalization or an urgent visit resulting in IV therapy for heart failure) or death from cardiovascular causes: 16.3% dapa vs 21.2% placebo (HR 0.74 [0.65-0.85]; p<0.001)
EMPEROR-Reduced¹²	Empagliflozin 10 mg once daily (n=1863) or placebo (n=1867)	· NYHA Class II 75.1% (empa); 75.0% (placebo) · Systolic blood pressure (mmHg) 122.6 ± 15.9 (empa); 121.4 ± 15.4 (placebo) · Mean LVEF (%) 27.7 ± 6.0 (empa); 27.2 ± 6.1 (placebo) o LVEF < 30% 71.8% (empa); 74.6% (placebo) · Mean eGFR (mL/min/1.73m²) 61.8 ± 21.7 (empa); 62.2 ± 21.5 (placebo) o eGFR < 60 48.0% (empa); 48.6% (placebo) · Background therapy with ACE/ARB/ARNI 88.8% (empa); 89.6% (placebo)	Primary composite outcome of death from cardiovascular causes or hospitalization for heart failure: 19.4% empa vs 24.7% placebo (HR 0.75 [0.65-0.86]; p<0.001)
Heart Failure with Preserved Ejection Fraction
Trial	Intervention	Patient Characteristics	Results
EMPEROR-Preserved¹⁴	Empagliflozin 10 mg once daily (n=2997) or placebo (n=2991)	· NYHA Class II 81.1% (empa); 81.9% (placebo) · Systolic blood pressure (mmHg) 131.8 ± 15.6 (empa); 131.9 ± 15.7 (placebo) · Mean LVEF (%) 54.3 ± 8.8 (empa; placebo) · Mean eGFR (mL/min/1.73m²) 60.6 ± 19.8 (empa); 60.6 ± 19.9 (placebo) o eGFR < 60 50.2% (empa); 49.6% (placebo)	Primary composite outcome of death from cardiovascular causes or hospitalization for heart failure: 13.8% empa vs 17.1% placebo (HR 0.79 [0.69-0.90]; p<0.001)
DELIVER¹⁵	Dapagliflozin 10 mg once daily (n=3131) or placebo (n=3132)	· NYHA Class II 73.9% (dapa); 76.6% (placebo) · Mean LVEF (%) 54.0 ± 8.6 (dapa); 54.3 ± 8.9 (placebo) · Mean eGFR (mL/min/1.73m²) 61.0 ± 19.0 (dapa; placebo)	Primary composite outcome of worsening heart failure (hospitalization or urgent visit for heart failure) or death from cardiovascular causes: 16.4% dapa vs 19.5% placebo (HR 0.82 [0.73-0.92]; p<0.001)
Chronic Kidney Disease
Trial	Intervention	Patient Characteristics	Results
DAPA-CKD²⁰	Dapagliflozin 10 mg once daily (n=2152) or placebo (n=2152)	· Systolic blood pressure (mmHg) 136.7 ± 17.5 (dapa); 137.4 ± 17.3 (placebo) · Mean eGFR (mL/min/1.73m²) 43.2 ± 12.3 (dapa; 43.0 ± 12.4 (placebo) o eGFR 30-45 45.5% (dapa); 42.7% (placebo) · Median urinary albumin-to-creatinine ratio(IQR) 965 (472-1903; dapa); 934 (482-1868; placebo) · Serum potassium (mEq/L) 4.6 ± 0.5 (dapa); 4.6 ± 0.6 (placebo) · Background therapy with ACE/ARB 98.4% (dapa); 97.9% (placebo)	Primary composite outcome of sustained decline in the eGFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes: 9.2% dapa vs 14.5% placebo (HR 0.61 [0.51-0.72]; p<0.001)
EMPA-KIDNEY²¹	Empagliflozin 10 mg once daily (n=3304) or placebo (n=3305)	· Systolic blood pressure (mmHg) 136.4 ± 18.1 (empa); 136.7 ± 18.4 (placebo) · Mean eGFR (mL/min/1.73m²) 37.4 ± 14.5 (empa); 37.3 ± 14.4 (placebo) o eGFR 30-45 44.4% (empa); 44.2% (placebo) · Median urinary albumin-to-creatinine ratio(IQR) 331 (46-1061; empa); 327 (54-1074; placebo) · Background therapy with ACE/ARB 85.7% (empa); 84.6% (placebo)	Primary composite outcome of progression of kidney disease or death from cardiovascular causes: 13.1% empa vs 16.9% placebo (HR 0.72 [0.64-0.82]; p<0.001)

The Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction (DAPA-HF) and Empagliflozin in Heart Failure with a Reduced Ejection Fraction (EMPEROR-Reduced) trials were the two earliest trials to evaluate the benefit of SGLT2 inhibitors in patients with heart failure and reduced ejection fraction (HFrEF) independent of diabetes status [11,12]. These studies compared dapagliflozin and empagliflozin, respectively, with placebo. Participants in both trials were predominantly male with a mean age of approximately 65 years, and less than half had a history of type 2 diabetes. Most patients presented with New York Heart Association (NYHA) class II symptoms and were on background therapy with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or angiotensin receptor-neprilysin inhibitors (ARNIs). In both studies, the use of an SGLT2 inhibitor resulted in significant improvements in the primary composite outcomes including heart failure-related hospitalizations and cardiovascular mortality. These benefits were consistent across various subgroups, though the effects were particularly pronounced in patients with NYHA class II symptoms and an LVEF of less than 30%. Additionally, no significant differences were observed in the incidence of side effects including volume depletion, renal adverse events, or major hypoglycemia in either trial.

With the clear benefits of SGLT inhibitors established in the HFrEF patient population, the question remained whether this benefit persists across the spectrum of heart failure. Left ventricular ejection fraction (LVEF) has historically been used for trial inclusion and exclusion criteria, creating a body of evidence that is therefore subcategorized based on ejection fraction, when the reality is that heart failure is a clinical syndrome that exists along a spectrum of ejection fraction. There is broad agreement on the definitions of HFrEF (LVEF ≤ 40%) and HFpEF (LVEF ≥ 50%) while much ambiguity remains for those with LVEF between 40% and 50% as well as those who previously qualified as HFrEF with subsequent improvement in LVEF to ≥ 40% [13].

The Empagliflozin in Heart Failure with a Preserved Ejection Fraction (EMPEROR-Preserved) and Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction (DELIVER) trials sought to assess the potential benefits of SGLT2 inhibitors in patients with heart failure and LVEF > 40%; importantly, DELIVER allowed enrollment of patients with prior LVEF ≤ 40% provided their LVEF was > 40% at the time of study enrollment (a group that has been labeled heart failure with “improved” EF according to the Universal Definition of heart failure) while EMPEROR-Preserved did not [13-15]. These trials involved a slightly older population with a mean age of approximately 72 years, and nearly half of the participants were female. Like EMPEROR-Reduced and DAPA-HF, about half of the patients had a history of type 2 diabetes, although approximately 90% participants enrolled in EMPEROR-Preserved and DELIVER had a history of hypertension. In both trials, patients were evenly distributed across the spectrum of eligible LVEF. The use of SGLT2 inhibitors in both studies resulted in significant improvements in primary composite outcomes including heart failure-related hospitalizations and cardiovascular mortality. These benefits were consistent across subgroups; however, the EMPEROR-Preserved trial showed a signal towards greater benefit in patients with lower-range LVEF, while the DELIVER trial suggested more pronounced benefits in those with higher-range LVEF. These differences may be attributed to variations in primary outcomes (such as the addition of urgent HF visits to the composite endpoint in DELIVER), patient inclusion criteria (such as the inclusion of patients with heart failure with recovered ejection fraction in DELIVER), and the duration of heart failure symptoms prior to enrollment. While there is likely a class effect of SGLT2 inhibitors in heart failure and there is evidence that canagliflozin can improve activity and patient-reported outcomes compared with placebo, there are currently only three FDA approved SGLT2 inhibitors for broad heart failure use with varying approved eGFR cutoffs based on study inclusion criteria: sotagliflozin (eGFR > 30 ml/min/1.73 m²), empagliflozin (eGFR > 20 ml/min/1.73 m² ), and dapagliflozin (eGFR > 25 ml/min/1.73 m²) [16-19].

Review of the Evidence in Chronic Kidney Disease

Another key patient population hypothesized to benefit from SGLT2 inhibitors is those with chronic kidney disease. The DAPA-CKD and EMPA-KIDNEY trials therefore sought to evaluate the potential benefits of SGLT2 inhibitors in patients with chronic kidney disease independent of diabetes status, though the characteristics of participants enrolled in these studies differed in a few key ways [20,21]. The DAPA-CKD trial enrolled a higher proportion of patients with a history of cardiovascular disease and diabetes, while the EMPA-KIDNEY trial included a greater percentage of patients with an eGFR < 30 and a broader range of baseline urinary albumin-to-creatinine ratios (UACR). Both trials demonstrated that SGLT2 inhibitors (dapagliflozin and empagliflozin, respectively) provide significant benefits in slowing CKD progression and reducing cardiovascular risk regardless of diabetes status and across a wide spectrum of renal function. However, in EMPA-KIDNEY, subgroup analysis revealed that the benefits may be more pronounced in patients with lower baseline UACR levels (Table 1).

Guideline Recommendations

As a result of these trial findings, national guidelines for heart failure, chronic kidney disease, and diabetes now recommend initiating SGLT2 inhibitor therapy in eligible patients (Table 2).

Table 2: Summary of guideline recommendations.

National Guideline	Class of Recommendation/Level of Evidence	Recommendation
2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines²²	1/A	Initiate SGLT2 inhibitor for patients with type 2 diabetes and CVD or high risk for CVD
	1/A	In patients with symptomatic chronic HFrEF, SGLT2 inhibitors are recommended to reduce hospitalization for HF and cardiovascular mortality, irrespective of the presence of type 2 diabetes
	2/A	SGLT2 inhibitor use recommended in patients with HF with mildly reduced ejection fraction (HFmrEF; LVEF 41-49%)
	2/A	SGLT2 inhibitor use recommended in patients with HF with preserved ejection fraction (HFpEF; LVEF > 50%)
KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease²³	1/A	Recommend treating patients with type 2 diabetes, CKD, and an eGFR > 20 ml/ min per 1.73 m² with an SGLT2 inhibitor
	1/A	Recommend treating adults with CKD with an SGLT2 inhibitor for the following: · eGFR > 20 ml/min per 1.73 m2 with urine ACR > 200 mg/g (> 20 mg/mmol) · Heart failure, irrespective of level of albuminuria
	2/B	Treat adults with eGFR 20 to 45 ml/min per 1.73 m2 with urine ACR < 200 mg/g (< 20 mg/mmol) with SGLT2 inhibitor
American Diabetes Association Standards of Care in Diabetes – 2025²⁴	A	In adults with type 2 diabetes and established or high risk of atherosclerotic cardiovascular disease, the treatment plan should include medications with demonstrated benefits to reduce cardiovascular events (e.g., GLP-1 and/or SGLT2 inhibitor) for glycemic management and comprehensive cardiovascular risk reduction (irrespective of A1c)
	A	In adults with type 2 diabetes who have heart failure with either preserved or reduced ejection fraction, an SGLT2 inhibitor is recommended for both glycemic management and prevent of HF hospitalizations (irrespective of A1c)
	A	In adults with type 2 diabetes who have CKD (with confirmed eGFR 20-60 mL/min/1.73 m² and/or albuminuria), and SGLT2 inhibitor or GLP-1 RA with demonstrated benefit in this population should be used for both glycemic management (irrespective of A1c) and for slowing progression of CKD and reduction in cardiovascular events. The glycemic benefits of SGLT2 inhibitors are reduced at eGFR < 45 mL/min/1.73 m²

Important Considerations for Safe Use and Adverse Events

Many patients do not carry only a single indication for treatment with an SGLT2 inhibitor. In fact, a 2018 study of 530,747 patients with type 2 diabetes found that over 90% had concomitant cardiovascular or kidney disease [25]. Given the interconnectedness of metabolic syndrome, cardiovascular disease, and chronic kidney disease, it is crucial for clinicians managing patients with these conditions to consider initiating SGLT2 inhibitors in eligible individuals from multiple vantage points. Clinicians should be mindful of dual disease purposes and screen appropriately for benefit using UACR and NT-proBNP for CKD and heart failure, respectively.

According to the KDIGO guidelines, once an SGLT2 inhibitor is initiated, it is generally appropriate to continue the therapy even if the eGFR drops below 20 mL/min/1.73m², unless the medication is poorly tolerated or kidney replacement therapy (KRT) is require [26 ]. Additionally, starting or continuing SGLT2 inhibitors does not necessitate a change in the frequency of CKD monitoring. There is often a reversible decrease in eGFR observed at the start of therapy that is typically not a reason to discontinue treatment. It is important to note that while glycemic control may be less effective when eGFR falls below 45 mL/min/1.73m², the cardiovascular and renal benefits of SGLT2 inhibitors remain, and therefore these agents should still be initiated as long as the eGFR prior to initiation is >20 mL/min/1.73m².²³ In the HFrEF and CKD trials previously described, most patients were already on background therapy with ACE inhibitors, ARBs, or ARNI, suggesting that SGLT2 inhibitors can safely and effectively be added to these guideline-directed medical therapies with few adverse effects. However, due to the generally favorable hemodynamic and laboratory tolerability of SGLT2 inhibitors, clinicians may consider initiating them before other classes of guideline-directed therapies based on individual patient factors. However, special consideration should be made for management of diuretics, anti-hypertensive regimens, and anti-hyperglycemic regimens to reduce risk of side effects and simplify complex medication regimens.

Specifically, because hyperkalemia often limits the use of combination therapy with renin-angiotensin system inhibitors (RASi) and/or mineralocorticoid receptor antagonists (MRAs), the hypokalemic side effect of SGLT2 inhibitors may help balance potassium levels in patients on combination therapy. Indeed, there is evidence that SGLT2 inhibitors reduce hyperkalemic events in patients with and without diabetes making early initiation of this therapy enabling of combination GDMT [27]. With recently published evidence for the non-steroidal MRA finerenone showing clinical benefit in reducing heart failure morbidity, but with higher than expected hyperkalemic events, upfront initiation of SGLT2 inhibitors with MRAs in patients with heart failure and/or CKD indication(s) is an attractive strategy that may improve tolerability [28].

Though not the focus of this review, combination therapy in treating cardiovascular, kidney, and metabolic disease has gained traction over the prior several years. The pathophysiology of both CKD and heart failure are complex with multiple targetable pathways of injury including the renin-angiotensin system, inflammation and fibrosis, and metabolic derangement; as such, a single therapy is highly unlikely to modulate all involved pathways. In addition, cardiovascular disease (including heart failure, stroke, and myocardial infarction [MI]) is a significant cause of morbidity and mortality among patients with metabolic syndrome and those with CKD. However, each of these cardiac comorbidities is affected differently by each class of CKD therapy: SGLT2 inhibitors and ns-MRAs appear to most modulate heart failure outcomes, while RASi more significantly reduce blood pressure and GLP-1 receptor antagonists modulate metabolic syndrome, reduce ASCVD risk, and modify CDK outcomes. Additionally, though efficacy of empagliflozin in HFrEF and HFpEF has been demonstrated, inhibition of these pathway did not demonstrate meaningful impact in patients with MI with regards to first hospitalization for HF or death when compared to placebo.²⁹ Subsequent post hoc analyses revealed a decreased risk of heart failure (HF) in patients with left ventricular dysfunction or congestion following acute MI, as well as a reduction in both first and total HF hospitalizations among individuals with type 2 diabetes [29-31]. We believe that aggressive and early combination therapy in treating the distinct but interrelated conditions of metabolic, kidney and cardiovascular disease should become the norm moving forward.

Although the benefits of SGLT2 inhibitors extend across multiple physiological pathways, this medication class is not without adverse effects. SGLT2 inhibitors have been linked to an elevated risk of genitourinary infections, hypovolemia, and diabetic ketoacidosis (DKA). The increased risk of genitourinary infections is primarily attributed to the glucosuric effects of these medications, a relationship highlighted in previous meta-analyses [32]. The use of canagliflozin, dapagliflozin, and empagliflozin in patients with diabetes is particularly linked to a higher risk of genitourinary tract infections, especially in women, with this risk further heightened in those with a history of urinary tract infections (UTIs) and obesity [33]. Among these patients, there have been reports of Fournier’s gangrene; however, the connection between SGLT2 inhibitor therapy and this severe perineal infection remains weak, as patients with diabetes already have a higher baseline risk for such infections. Across all heart failure and CKD trials reviewed, although SGLT2 inhibitor groups exhibited a higher rate of genitourinary tract infections, there were no reported cases of Fournier’s gangrene in either the placebo or intervention arms.

Volume depletion has been consistently observed in multiple randomized controlled trials, including those focused on heart failure and CKD, due to osmotic diuresis induced by SGLT2 inhibitors, which may lead to symptomatic hypotension. The induction of DKA by this medication class has been postulated to occur due to different mechanisms, including impairment in ketone clearance. While the overall incidence of DKA remains rare across trials included in this review (<0.1%), the risk may be higher in patients hospitalized on SGLT2 inhibitor therapy, particularly when additional risk factors such as dehydration, infection, or changes in medication regimens including insulin or other glucose-altering agents are present. Due to these concerns, perioperative discontinuation and avoidance of this therapy on sick days has been advocated [34].

Furthermore, earlier concerns regarding potential associations between SGLT2 inhibitors and bone fractures, amputations, or malignancies have not been substantiated by more recent data, with variations in findings depending on the specific medication within the class.

SGLT2 inhibitors have been widely used and an effective therapeutic option for managing diabetes for several years. As our understanding of the potential side effects of this medication class evolves, especially in patients with multiple comorbidities, the benefits of SGLT2 inhibitors remain well-established and significant. These benefits are most pronounced when used in appropriately selected patients, with close monitoring by the multidisciplinary care team.

Translating Evidence to Implementation

A decision-analytic modeling study of heart failure patients in the United States estimated that optimal implementation of SGLT2 inhibitors over three years could prevent or delay approximately 630,000 worsening heart failure events across the entire LVEF spectrum. Of these, roughly 230,000 to 280,000 events would be prevented or postponed in patients with heart failure and LVEF greater than 40% [35]. Population health initiatives focused on managing chronic kidney disease, diabetes, and cardiovascular disease aim to prevent, manage, and reduce the impact of these conditions across diverse populations. These initiatives typically emphasize disease detection, improved access to therapeutics, patient and provider education, and initiation/titration of medical therapy.

Particularly in a value-based care context, wherein there are existing resources targeting better chronic disease management that are sustainable and not simply being used for demonstration projects, access to regularly updated patient, prescribing, and provider data is paramount [36 ]. Health system data can be leveraged to target therapeutic gaps, reduce practice variation and idiosyncratic use of evidence-based therapy, address disparities in care, and, ultimately improve health outcomes at scale. Furthermore, multiple strategies can be tested and iteratively improved. As outlined in national guidelines for these diseases, care delivery models at the local level that engage multidisciplinary teams, provide targeted interventions and education, and focus on improving outcomes are essential for achieving these goals (Figure 1). Telehealth strategies may be incorporated to increase utilization of remote monitoring, improve education delivery, and incorporate more frequent touch points to provide care.^22-24

Figure 1: Multidisciplinary Management Strategy to Optimize Guideline-Directed Medical Therapy in Patients with Heart Failure.

For example, through daily electronic health record (EHR) identification of inpatients with heart failure patients with suboptimal GDMT, the IMPLEMENT-HF trial demonstrated that the integration of pharmacist consultative services into inpatient workflows can improve medication access to novel GDMT. Through streamlined prior authorization and use of patient assistance programs (PAPs), pharmacists and heart failure specialists in collaboration facilitated the safe initiation and titration of heart failure GDMT through targeted recommendations to rounding generalist physicians [37].

In the outpatient setting, PROMPT-HF was a pragmatic, EHR-based trial in which 100 healthcare providers treating patients with HFrEF were randomly assigned to receive either an alert or usual care [38]. The alert provided individualized, guideline-directed medical therapy recommendations along with patient-specific details. As a result, the alert group demonstrated significantly higher rates of guideline-directed medical therapy use at 30 days compared to those receiving usual care. The authors emphasized that this low-cost intervention could be quickly integrated into clinical practice, promoting faster adoption of high-value therapies in heart failure.

Another example of an ambulatory study that utilized EHR-identification of patients with GDMT gaps was the DRIVE study that enrolled 200 patients with indications for, but not currently on, an SGLT2 inhibitor or GLP1 receptor agonist [39]. This trial used a remote, team-based education and medication management program either simultaneously with a navigator/pharmacist outreach effort with or prior to navigator/pharmacist outreach effort; patients were randomized in a blinded fashion to one of these strategies. After 6 months, 64% of patients received a new prescription for either SGLT2 inhibitor or GLP1 agonist. These trials highlight how EHRs, telehealth models, and remote multidisciplinary interventions can be leveraged to improve patient care; one example of how to leverage the patient messaging portal to prompt uptake of SGLT2 inhibitor prescription can be seen in Figure 2. Importantly, once patients are in front of clinicians with knowledge and expertise to initiate GDMT, there is a high degree of success. Unfortunately, even with dedicated navigation resources, the ability to identify and connect patients with these expert providers remains a significant challenge. In the aforementioned DRIVE study, 1289 eligible patients were contacted: 771 were unreachable, 288 declined participation, and ultimately 200 patients were enrolled. Though these results show the value of dedicated pharmacists as a strategy to improve GDMT prescription, they also highlight the challenges in activating the pipeline of eligible patients into the pharmacist visit.

Figure 2: Educational Outreach Embedded In Direct Patient Messaging to Facilitate Uptake of SGLT2 Inhibitors in the Outpatient Setting.

Conclusion

While SGLT2 inhibitors began as antihyperglycemic therapy for type 2 diabetes, the indications and benefits of this class of medications have expanded rapidly over the past decade. Despite the broad body of literature supporting their benefits across the spectrums of both heart failure and chronic kidney disease, there remains significant work to be done to improve national adherence to guideline recommendations and increase prescribing of these medications especially as most patients carry at least two indications for treatment with SGLT2 inhibitors. A multidisciplinary, team-based approach to treatment of patients with type 2 diabetes, heart failure, and chronic kidney disease is therefore crucial in the care for these patients. With increasing sophistication in both the ability to identify patients at risk and to provide personalized clinical decision support, remote patient data coupled to multidisciplinary teams can iteratively improve care delivery [40,41].

Disclosures

Dr. Bhatt has received research grant support to his institution from National Institutes of Health/National Heart, Lung, and Blood Institute, National Institutes of Health/National Institute on Aging, American College of Cardiology Foundation, and the Centers for Disease Control and Prevention and consulting fees from Heart Health Leaders, Sanofi Pasteur, Merck, Amgen, AstraZeneca, and Novo Nordisk. Dr. Martyn serves as an advisor or receives consulting fees from, Fire1, Prolaio, Boehringer Ingelheim/Eli Lilly, Dyania Health, Novo Nordisk, AstraZeneca, Cleveland Clinic/American Well Joint Venture, BridgeBio, Pfizer, Apricity Robotics, and Kilele health and receives grant support from Ionis Therapeutics, AstraZeneca and the Heart Failure Society of America (HFSA). All other authors report no relevant disclosures.

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Halimi S, Verges B (2014) Adverse effects and safety of SGLT-2 inhibitors. Diabetes Metab. [crossref].
Stollberger C, Finsterer J, Schneider B (2023) Adverse events and drug-drug interactions of SGLT2 inhibitors in heart failure. Expert Rev Cardiovasc Ther.
Talha KM, Butler J, Greene SJ, et al. (2023) Population-level implications of SGLT2 inhibitors. JAMA Cardiol.
Ahmad T, Desai NR (2022) Reimagining evidence generation for heart failure. Circ Cardiovasc Qual Outcomes.
Bhatt AS, Varshney AS, Moscone A, et al. (2023) Virtual care team guided management. J Am Coll Cardiol.
Ghazi L, Yamamoto Y, Riello RJ, et al. (2022) Electronic alerts to improve therapy. J Am Coll Cardiol.
Blood AJ, Chang L-S, Hassan S, et al. (2024) Remote management program. Circulation.
Epping-Jordan J, Pruitt S, Bengoa R, et al. (2004) Improving quality of care. BMJ Qual Saf.
Desai AS, Maclean T, Blood AJ, et al. (2020) Remote optimization of therapy. JAMA Cardiol.

Patient Education in Primary Health Care by Advanced Practice Nurses (APN) in Germany

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DOI: 10.31038/IJNM.2025614

Experiences of Advanced Practice Nurses in the FAMOUS Research Project

Examples from practice experiences of advanced practice nurses (APNs) in Germany are shown in this article by illustrating various approaches to patient education in primary healthcare.

Advanced Practice Nurses in Germany

The academization of nursing is still in its very first steps in Germany. Bachelor’s degree programs in nursing were first introduced in 2006. Advanced practice nursing has not yet been established in primary health care in Germany and legal requirements for this role still do not exist [1]. Nevertheless, many efforts within nursing practice and research aim to promote the use of APNs. One such effort was the FAMOUS (effects of care of multimorbid patients in general practices by advanced practice nurses) research project [2].

FAMOUS

The purpose of this controlled nonrandomized mixed methods study was to evaluate the care for multimorbid patients by APNs deployed in general practices in rural areas in Germany. Every patient in the FAMOUS project had at least three or more chronic diseases. The objective of FAMOUS was to stabilize the homecare situation of these patients through the involvement of APNs. The intervention took place from October 2021 to March 2024. Each patient in the intervention group (N=859) received evidence-based and person- centred care by an APN for 12 months. The control group (N=1700) received standard care. For evaluation, routine data from health insurance companies for the control group was used [2,3].

Patient Education and Person-centred Care

Patient education played a significant role in the care for multimorbid patients by APNs in the FAMOUS project, with person- centred care being a requirement for successful education. Person- centred care is about engaging with patients’ life contexts based on a mutual valued relationship. Recognizing and respecting individual values, attitudes, and needs builds the basis for the shared decision- making process, a core element of person-centred care. Family members and relevant healthcare providers are also included in the person-centred care process [4]. The following case examples are a selection of the varied educational situations that the APNs encountered. They intend to provide an insight into the complex care and education needs of multimorbid patients in primary health care and show how the APNs managed to meet them.

Complex Education for Complex Needs

The APN visits Ms A. a few weeks after her discharge from hospital, where treatment for her newly diagnosed type 2 diabetes mellitus was initiated. In addition to grade 1 obesity, she has a mild intellectual impairment and urinary incontinence. Ms. A. is 62 years old and lives by herself. She is illiterate. A domestic help, funded through her care insurance relief allowance, supports her with household tasks and shopping. A home care service handles blood glucose monitoring, medication management, and insulin administration. Due to her illiteracy, Ms. A. has never participated in a diabetes education program. She hardly ever leaves the house because of her incontinence. The lack of exercise increases her obesity. As a result of the in-depth medical history assessment, the APN identifies a lack of knowledge in Ms. A. regarding diabetes management and healthy lifestyle. Together they discuss the goals that Ms. A. would like to achieve. Ms. A. wants to feel confident when choosing suitable foods for a healthy diabetes diet. She would also like to go for more walks outside again despite her incontinence. During the next home visit, the APN provides individualized nutrition education using visual materials like a food pyramid to explain food choices and the importance of exercise. The APN repeats key points and uses comprehension questions to assess the gain of knowledge. Discovering that Ms. A. enjoys drawing, the APN encourages her to draw a picture of the food pyramid and to use it on the next shopping trip. The APN involves the domestic help for the practical part of the training. At the supermarket, Ms. A. and the domestic help compare groceries with the hand-drawn food pyramid to choose appropriate items. Later, Ms. A. reports feeling more confident selecting suitable foods. The involvement of the domestic help contributes to a long-lasting effect of this education. On the next visit the APN discusses methods to promote continence with Ms. A. At the patient’s request, the APN instructs her on bladder training to increase the intervals between visits to the toilet. Furthermore, Ms. A. receives a prescription for pelvic floor exercises with the Maria Gerz (2025) Patient Education in Primary Health Care by Advanced Practice Nurses (APN) in Germany physiotherapist and sanitary pads. After a few weeks, the incontinence has improved to such an extent that Ms. A. can go for outdoor walks again. The regular exercise also led to an improvement in her blood sugar levels and body weight.

App-supported Medication Adherence

Mr. M., aged 78, lives by himself and was recently diagnosed with heart failure, requiring regular medication. However, he frequently lacks to follow his medication, leading to several urgent house calls from his physician due to dyspnea and leg edema. To address this, the APN visits Mr. M. and discusses his medication habits. He admits that he often forgets his medications and is unaware about the importance of adherence. The APN explains the nature of heart failure and the necessity of regular medication. Further evaluation reveals that Mr. M.’s lack of daily routines contributes to his forgetfulness. Since he regularly uses a smartphone, the APN suggests a medication reminder app. Together, they set up the free app, which will alert him with audio signals when it is time for his medication. The APN informs his general practitioner, ensuring that any future medication adjustments are reflected in the app. This approach uses technology effectively to address Mr. M.’s adherence challenges.

Acute Intervention Needs

Mrs. L. suffers from dementia, and her husband, Mr. L., uses a wheelchair due to a below-knee amputation. They share a household with their daughter, who is their primary caregiver. During an initial assessment, the APN observes the daughter’s significant emotional strain. Tearfully, she explains, “I can’t even leave the house for two hours to shop in peace.” The family has limited external support. The APN sets care priorities based on the family’s needs. Four days before the next home visit, the daughter is involved in a car accident, resulting in a tibia fracture requiring surgery. She can no longer fully care for her parents. With no supportive network, the family faces a sudden and complex crisis. The APN conducts a comprehensive family mediation to address their current concerns, especially the couple’s fear of being placed in a nursing home. The daughter is mainly worried about ensuring her parents’ personal care, mobility, and nutrition. Based on this assessment, the APN identifies local support services and, through shared decision-making, implements the following measures: a combination of visiting services and day care for the couple, along with home healthcare services. Additionally, neighborhood assistance is activated to expand the support network. Over the following six weeks, the family adjusts well, later reporting that they feel secure with the established support system.

Summary

The APNs applied multiple methods of education according to the individual case situations and used different materials and media to deal with the complex situations. These practical examples illustrate that patient education is a blend of structured and spontaneous approaches. The counseling process is non-linear and requires a high degree of flexibility. Simple situations often show complex intervention needs. This dynamic demands not only professional competence from APNs but also empathy and the ability to collaborate with patients to find solutions. APNs have the potential to play a significant role in primary healthcare. Their skills and expertise are essential for ensuring high-quality patient care and education.

References

Henderson Colette, Mackavey Carole, Petri Sophie; Wöhrle Olivia (2023) Germany pioneers an expansion of the advanced practice role. International Journal of Advancing Practice 1.
Stemmer Renate, Büchler Britta, Büttner Matthias, Dera-Ströhm, Christina Klein, et al. (2023) Effects of care of multimorbid patients in general practices by advanced practice nurses (FAMOUS): study protocol for a nonrandomized controlled trial. BMC Health Services Research 23.
Brehm Lara, Drevermann Ute, Gerz Maria, Kopp Ines, Leyendecker Christine (2024) Patientenedukation in der Primärversorgung. Erfahrungen von Advanced Practice Nurses im Forschungsprojekt FAMOUS. Padua. 19: 215-219.
McCormack, Brendan (2022). Person-centred care and measurement: The more one sees, the better one knows where to look. Journal of Health Services Research & Policy. 27: 85-87.

Correlation Between Pregnant Women’s Childbirth Attitude and We-media Use

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DOI: 10.31038/EDMJ.2025923

Abstract

Objective: To investigate the status quo of pregnant women’s attitude towards childbirth and the use of we-media to browse childbirth-related information, and to analyze the correlation between the two.

Methods: The Chinese version of female childbirth Attitude questionnaire was used to conduct a questionnaire survey on 304 pregnant women who were conveniently sampled from a Grade 3 A hospital in Hangzhou and recruited online.

Results: The score of women’s attitude toward childbirth during pregnancy was (90.30 ± 14.65), and the characteristics of the use of we-media to obtain maternity information showed diversification. The frequency and duration of we-media use were positively correlated with the score of the attitude toward childbirth. In terms of the use motivation, the attention of specific content may have a negative impact on different dimensions of women’s attitude toward childbirth.

Conclusion: The more frequently and longer pregnant women browse pregnancy-related information on we-media platforms, the more likely they are to hold negative attitudes towards childbirth. It is suggested that we media be used to disseminate more authoritative content of childbirth education to help women deeply understand the physiological process of childbirth, so as to reduce the fear of the unknown.

Keywords

Pregnant women, Childbirth attitude, We media use, Influencing factors

Introduction

Childbirth is a major turning point in a woman’s life and has a profound impact on her physical and mental health [1]. As a special physiological and psychological stage for women, pregnancy has increased the demand for maternal and child health information [2]. In recent years, we-media platforms have increasingly become an important channel for pregnant women to obtain maternity information due to their characteristics of immediacy, interaction and decentralization [3]. Childbirth attitude refers to an individual’s subjective cognitive, emotional and behavioral tendencies towards childbirth, including fear of childbirth, childbirth pain, childbirth mode choice and views on the use of medical interventions. A positive attitude towards childbirth contributes to maternal confidence and reduces the risk of postpartum depression [4]. Birth attitudes are shaped by a variety of factors, including personal subjectivity, traditional factors such as family support [5,6], and by the emerging media environment [7]. However, the quality of information on we-media platforms is uneven, and false or inaccurate maternity information may exacerbate the anxiety and fear of pregnant women, thus affecting their attitude towards childbirth [8]. Previous studies have shown that media exposure is associated with women’s childfear behavior [9], but there is still a lack of research on the relationship between we-media use and women’s attitude toward childbirth during pregnancy. Therefore, the purpose of this study is to explore the correlation between we-media use and pregnant women’s attitude towards childbirth, in order to provide a scientific basis for optimizing pregnant women’s access to information, improving their attitude towards childbirth and enhancing their childbirth experience.

Methods

This study was conducted from July to October 2024, through a combination of online and offiine methods, and adopted the snowball method recommended by friends to recruit research subjects. The researcher published a post on rednote to recruit research subjects, attracted potential participants by providing professional nutrition knowledge during pregnancy, and recruited them offiine simultaneously. Pregnant women who underwent prenatal check-up in a third-level A hospital in Hangzhou were selected as research objects by convenient sampling method. They were then encouraged to recommend their friends or relatives to participate, thereby gradually expanding the study sample. Inclusion criteria: ① in the gestation period; ② Age ≥18 years old; ③ In the past six months, I have used the small Red book platform to browse the content related to childbirth; ④ Normal cognitive function, with basic communication and writing skills; ⑤ Know about this study and agree to participate in the study. Exclusion criteria: ① Pregnant women with a history of mental illness. Before collection, obtain approval from the hospital Ethics Committee (No. ZN- 20240327-0098-01). The research team sent the two-dimensional code of the questionnaire was distributed to the study subjects through the questionnaire star link, and the research purpose, content and informed consent were set as required reading items. Participants could read and agree before filling in the questionnaire; The system sets that each IP address can be entered only once to avoid repeated entries. Adopt the form of anonymous independent filling, for regular answers, the answer time is too short less than 3min questionnaires will be excluded. After the survey, the collected questionnaires will be reviewed. A total of 310 questionnaires were sent out in this survey.

Measurement

General Information Questionnaire

Based on the literature review and combined with the purpose and content of this study, the design was self-designed, including general information such as age, ethnicity, education level, household registration type, marital status, expected delivery mode selection, delivery information sources, and use of we-media.

Chinese Version of Women’s Attitudes Towards Birth Questionnaire (WATBQ)

The Chinese version of the Female Childbirth Attitude Questionnaire was compiled by Stoll et al. [10] in 2014. The questionnaire consists of 22 items, including four parts: views on pregnancy and childbirth, views on delivery techniques, views on cesarean section and views on physical changes after delivery. Likert6- level scoring method was adopted, with scores ranging from 1 to 6 for “strongly disagree” to “strongly agree”. The higher the score of each dimension, the more negative the attitude towards childbirth in this dimension. The Chinese version of the Women’s Childbirth Attitude Questionnaire (WATBQ) was developed by our research team in strict accordance with the Brislin model. After cross-cultural adjustment, the Chinese version of the female childbirth attitude questionnaire included 22 items in 5 dimensions: views on childbirth, views on complications, views on delivery techniques, views on caesarean section and views on body changes after childbirth. The Cronbach’s α coefficient of the questionnaire was 0.890, and the retest reliability was 0.824, with good reliability and validity.

Data Analysis

All data were entered into Excel by double checking. SPSS 27.0 software was used for data processing and analysis. For categorical variables, frequency and percentage were used to describe them, and Chi-square test and Fisher exact test were used for comparison. The mean ± standard deviation was used for descriptive statistical analysis of the study variables conforming to the normal distribution. With the scores of childbirth attitude questionnaire as the dependent variable, single factor analysis was performed by t test and variance analysis. Pearson correlation analysis and Point-biserial correlation analysis are used for correlation analysis.

Results

General Information About Women During Pregnancy

A total of 304 pregnant women who met the eligibility requirements completed the survey, of which 78 were recruited online through rednote and 226 were recruited offiine in hospitals, as shown in Table 1.

Table 1: Demographic characteristics of the study participants (n=304).

Variable	Characteristics	Number (n)	Percentage (%)
Age	18-24 years	88	28.9
	25-30 years	187	61.5
	31-34 years	23	7.6
	≥35 years	6	2.0
Residence Type	Agricultural Household	179	58.9
	Non-Agricultural Household	125	41.1
Ethnicity	Han Ethnicity	277	91.1
	Others	27	8.9
Education Level	High School or Below	17	5.6
	Associate Degree	51	16.8
	Bachelor’s Degree	150	49.3
	Master’s Degree or Above	86	28.3
Marital Status	Married	294	96.7
	Unmarried	10	3.3
Occupation	Medical Staff	30	9.9
	Civil Servant/Teacher	69	22.7
	Worker	17	5.6
	Company Employee	97	31.9
	Self-Employed	37	12.2
	Farmer	5	1.6
	Unemployed	20	6.6
	Others	29	9.5
Monthly Household Income	≤4000 RMB	66	21.7
	4001-6000 RMB	115	37.8
	6001-8000 RMB	71	23.4
	≥8001 RMB	52	17.1
Source of Medical Expenses	Medical Insurance	225	74.0
	Rural Cooperative Medical Insurance	26	8.6
	Self-Paid	53	17.4
Gestational Week	<14 weeks	91	29.9
	14-27 weeks	115	37.8
	≥28 weeks	98	32.2
Number of Pregnancies	1	223	73.4
	2	67	22.0
	3	14	4.6
Number of Deliveries	0	258	84.9
	1	39	12.8
	2	7	2.3
Unplanned Pregnancy	Yes	43	14.1
	No	261	85.9
Participation in Prenatal Education	Yes	196	64.5
	No	108	35.5
Family Support for Delivery Method Choice	Yes	295	3.0
	No	9	97.0
Witnessed Delivery Process	Yes	111	36.5
	No	193	63.5

Women’s Childbirth Attitude Score During Pregnancy

The results showed that the total score of pregnant women’s attitude towards childbirth was (90.30 ± 14.65), and the scores of each dimension were shown in Table 2.

The Result of Characteristic Clustering of Pregnant Women’s Delivery Attitude Score

Table 2: Total and dimension scores of childbirth attitude questionnaire (n=304).

Dimension	Items	Total Score (Mean ± SD)	Average Item Score (Mean ± SD)
Total score	22	90.30 ± 14.65	4.10 ± 0.67
Perspectives on pain and loss of control	5	20.95 ± 5.13	4.19 ± 1.03
Perspectives on complications	3	13.15 ± 3.03	4.38 ± 1.01
Perspectives on obstetric technology	6	27.60 ± 5.77	3.89 ± 1.05
Perspectives on cesarean section	5	15.35 ± 3.52	3.93 ± 1.00
Perspectives on postpartum body changes	3	13.25 ± 3.04	4.42 ± 1.01

According to the total score of the childbirth attitude questionnaire and the average scores of items in each dimension, the pregnant women were divided into 2 clusters by K-means clustering. The distribution of the two groups was average, and the clustering effect was good. Table 3 shows the average scores of the two clusters in the total score of the childbirth attitude questionnaire and items in each dimension. There are significant differences in their mean values, reflecting different characteristics. Therefore, Cluster1 is named “Negative childbirth Attitude Group” and Cluster2 is named “positive childbirth Attitude Group”. In this study, there were 152 pregnant women in the positive childbirth attitude group and the negative childbirth attitude group, each group accounted for 50%.

Table 3: Comparison of two clusters across five dimensions.

Dimension	Cluster1 (n=152)	Cluster2 (n=152)	F	P
Total score	102.05 ± 8.55	78.55 ± 8.94	548.751	0.000**
Perspectives on pain and loss of control	4.85 ± 0.79	3.53 ± 0.78	216.485	0.000**
Perspectives on complications	4.93 ± 0.77	3.84 ± 0.93	123.664	0.000**
Perspectives on obstetric technology	4.56 ± 0.70	3.21 ± 0.90	214.504	0.000**
Perspectives on cesarean section	4.18 ± 0.98	3.68 ± 0.95	20.381	0.000**
Perspectives on postpartum body changes	4.92 ± 0.75	3.91 ± 0.99	100.054	0.000**

**P<0.01

Univariate Analysis of Pregnant Women’s Attitude Towards Childbirth

The results showed that there were 5 variables related to women’s attitude towards childbirth, including household registration type, monthly income per capita, gestational week, number of pregnancies and pregnancy education. For details, see Table 4.

Table 4: Univariate analysis of childbirth attitudes by demographic factors (n=304).

Variable	Category	Childbirth Attitude Score (Mean ± SD)	*t/F-value***	P-*value*
Household registration	Agricultural household	83.03 ± 10.47	-12.833^a	<0.001
	Non-agricultural household	100.70 ± 13.50
Monthly household income	≤4000 RMB	106.79 ± 11.96	141.152^b	<0.001
	4001-6000 RMB	92.69 ± 9.74
	6001-8000 RMB	84.31 ± 6.94
	≥8001 RMB	72.25 ± 8.28
Gestational Week	<14 weeks	77.69 ± 9.65	114.508^b	<0.001
	14-27 weeks	90.21 ± 9.11
	≥28 weeks	102.10 ± 14.03
Number of Pregnancies	1	95.25 ± 13.36	85.691^b	<0.001
	2	79.49 ± 4.86
	3	63.14 ± 4.66
Participation in Prenatal Education	Yes	102.76 ± 12.19	14.186^a	<0.001
	No	83.43 ± 10.90

^at-value and ^bF-value

Multiple Linear Regression Analysis of Pregnant Women’s Attitude Towards Childbirth

Five indicators with statistical significance in the univariate analysis were taken as independent variables, and the total score of pregnant women’s attitude towards childbirth was taken as dependent variable. The results of multiple linear regression show that the type of household registration, per capita monthly income of the family, the number of pregnancies and pregnancy education affect their attitude towards childbirth, as shown in Table 5.

Table 5: Multivariate linear regression analysis of childbirth attitudes (n=304).

Model	Unstandardized oefficients B	SE	Standardized Coefficients β	t-*value*	P-*value*
Constant	104.121	3.242		32.112	<0.001
Household registration	5.234	1.608	0.176	3.256	0.001
Monthly household income (Reference: ≤4000 RMB)
4001-6000 RMB	-9.015	1.660	-0.299	-5.429	<0.001
6001-8000 RMB	-12.013	1.940	-0.347	-6.191	<0.001
≥8001 RMB	-22.245	2.199	-0.573	-10.115	<0.001
Gestational weeks (Reference: < 14 weeks)
14-27 weeks	2.044	1.678	0.068	1.218	0.224
≥28 weeks	2.467	2.046	0.079	1.206	0.229
Number of Pregnancies	-3.567	1.394	-0.135	-2.560	0.011
Whether to attend pregnancy education	-4.408	1.740	-0.144	-2.533	0.012

R=0.826, R²=0.682, after adjusting R²=0.673, F=79.028, P<0.001

We-media Use in Pregnant Women

In this study, the average weekly frequency of non-medical we- media platforms used by pregnant women to browse childbirth- related information, the time of each use of non-medical we-media platforms to browse childbirth-related information, and the use of we- media platforms to browse childbirth-related content were counted. For details, see Table 6.

Table 6: Social Media Usage Characteristics of Participants

Item	Category	Number (n)	Percentage (%)
Usage frequency	<1 day/week	61	20.1
	2-3 days/week	76	25.0
	3-4 days/week	104	34.2
	5-6 days/week	52	17.1
	Daily	11	3.6
Usage duration per session	<1 hour	71	23.4
	1-2 hours	86	28.3
	2-3 hours	91	29.9
	3-4 hours	45	14.8
	>4 hours	11	3.6
Motivation for Use	Dietary and Lifestyle Advice During Pregnancy	243	24.2
	Other Women’s Delivery Experience	198	19.7
	Preparation for Delivery	210	20.9
	Process of Delivery and Potential Issues	191	19.0
	Risks and Benefits of Common Interventions and Techniques During Pregnancy and Delivery	162	16.1

Correlation Between Pregnant Women’s Childbirth Attitude and We-media Use

The results of correlation analysis showed that the total score and each dimension of female childbirth attitude were significantly positively correlated with the frequency of use of we-media (r=0.431, P < 0.01) and duration of use (r=0.435, P < 0.01). In terms of motivation, browsing diet and lifestyle recommendations during pregnancy through we-media platforms was only positively correlated with the perception dimension of complications (r=0.136, P < 0.05), while the risks and benefits of browsing common interventions and technologies that could be used during pregnancy and delivery were significantly positively correlated with the total score of childbirth attitudes and the perception dimension of cesarean section (r=0.211, P < 0.05). P < 0.01), browsing other women’s childbirth experience was significantly positively correlated with the total score of female childbirth attitude (r=0.230, P < 0.01), and there was no statistical difference between the preparation for childbirth and browsing the process and possible problems of childbirth through we-media platforms and the total score and all dimensions of female childbirth attitude (P < 0.05). See Table 7 for details.

Table 7: Correlation analysis between social media usage and childbirth attitudes (r-value, n=304).

Variable	Perspectives on pain and loss of control	Perspectives on complications	Perspectives on obstetric technology	Perspectives on cesarean section	Perspectives on postpartum body changes	Total score
Usage frequency	0.304**	0.215**	0.352**	0.351**	0.275**	0.431**
Usage duration	0.302**	0.220**	0.359**	0.365**	0.264**	0.435**
Dietary and Lifestyle Advice During Pregnancy	-0.004	0.136*	0.035	-0.066	0.068	0.034
Other Women’s Delivery Experience	0.204**	0.118*	0.140*	-0.075	0.481**	0.230**
Preparation for Delivery	0.051	0.028	-0.017	0.111	0.102	0.075
Process of Delivery and Potential Issues	0.041	0.067	0.082	0.020	0.039	0.078
Risks and Benefits of Common Interventions and Techniques During Pregnancy and Delivery	0.059	0.011	0.030	0.513**	0.008	0.211**

*P<0.05, **P<0.01

Discussion

Status Quo of Childbirth Attitude of Pregnant Women

The cluster analysis results of this study revealed that the negative childbirth attitude group scored 102.05 ± 8.55, while the positive childbirth attitude group scored 78.55 ± 8.94. The total childbirth attitude score among pregnant women was 90.30 ± 14.65, falling between the two groups but closer to the negative attitude group. Analysis identified key concerns among pregnant women, including fears about physical harm from childbirth, intensity of labor pain, potential harm to the fetus, and possible complications during delivery. These concerns align with findings from a prior study conducted in the United States [11].

Within the “Perspectives on Pain and Loss of Control” dimension, Item 1 (“I worry childbirth pain will be too intense”) had the highest score, indicating that pain is one of the most pressing concerns for pregnant women. Research by Joshi et al. [5] demonstrated that younger, educated career women place greater emphasis on pain management during childbirth, which aligns with the demographic characteristics of participants in this study. Additionally, the high scores for Item 5 and Item 7 reflect anxieties about fetal safety and childbirth complications, respectively. This underscores pregnant women’s heightened focus on the safety and outcomes of delivery, likely influenced by media coverage of childbirth complications and an inherent anxiety toward uncertainty, consistent with findings by Kurz et al. [12].

In contrast, the lower scores for Item 13 and Item 15 suggest that most women remain cautious about the use of obstetric technology and prefer natural childbirth. Aligning with Stoll et al. [10], this indicates that while pregnant women increasingly demand medical management during delivery, they simultaneously value the importance of natural childbirth and tend to opt for non-interventional approaches in the absence of medical indications. Women’s predominantly negative perceptions of childbirth, particularly the higher scores in the “Perspectives on Obstetric Technology” dimension, reveal a reliance on medical interventions during labor. These results are consistent with the survey of outpatient pregnant women reported by Pan Feng et al. [13], reflecting high trust in modern medical technology. Therefore, we should focus on the management of maternal pain and provide personalized psychological support. Medical staff should pay attention to the pain of childbirth, and formulate personalized care plan after timely evaluation of the pain degree. It is recommended that medical workers provide pregnant women and their families with comprehensive delivery information support, including labor progress, pain management and coping strategies, so as to enhance the sense of security and physical control of pregnant women.

Status Quo of We-media Use in Pregnant Women

This study investigated the frequency, duration, and motivations of pregnant women’s use of non-medical self-media platforms to access childbirth-related information. The results indicate that over one-third of participants (34.2%) used self-media platforms 3-4 days per week, reflecting a proactive attitude toward seeking childbirth- related information. However, the proportion of daily users (3.6%) was relatively low, which may be attributed to time constraints and selective information-seeking behaviors in their daily lives.

Regarding usage duration, 2-3 hours per session was the most common (29.9%), a finding significantly higher than the average 2.38 hours per week spent on pregnancy-related websites reported in the study by Wallwiener et al. [14]. This discrepancy may stem from differences in content and interaction styles: self-media platforms often provide richer interactivity and instant feedback, potentially increasing engagement and prolonging usage time. Only 3.6% of participants spent over 4 hours per session, suggesting that most pregnant women moderate their browsing time to avoid anxiety caused by information overload.

In terms of motivations, pregnant women primarily sought content related to diet and lifestyle (e.g., nutritional guidance, exercise routines), highlighting their strong focus on personal and fetal health. This aligns with findings from a Chinese study [15]. A separate Korean study further revealed that pregnant women prioritize daily life adjustments during early pregnancy and shift toward fetal development information in the second trimester [16]. Additionally, childbirth preparation and browsing others’ experiences were significant motivators, consistent with research by Fleming et al. [17] and Bjelke et al. [18], indicating that women seek to enhance their preparedness through shared narratives.

The diversity of information needs underscores the dual role of self-media platforms: while they serve as vital resources for pregnant women, they also raise concerns about information credibility. To address this, we recommend that healthcare professionals leverage the strengths of self-media—such as videos, infographics, and other multimedia formats—to establish scientifically validated information- sharing mechanisms. By disseminating evidence-based childbirth knowledge, these efforts can help pregnant women develop rational perceptions of delivery, alleviate prenatal anxiety, and empower them to embrace this critical life event with confidence.

Correlation Between Pregnant Women’s Childbirth Attitude and We-media Use

This study employed Pearson correlation analysis and Point- biserial correlation analysis to explore the relationship between pregnant women’s social media usage and their childbirth attitudes. The results revealed a positive correlation between both the frequency and duration of self-media use and childbirth attitude scores. This suggests that frequent and prolonged exposure to self-media content dominated by negative narratives may foster negative cognitive biases toward childbirth, thereby shaping psychological expectations and attitudes. Notably, Serçekuş et al. [19] found that 14.8% of women reported heightened fear of childbirth due to online information, underscoring the potential adverse influence of self-media content on maternal perceptions. Such effects may stem from the prevalence of fear-inducing stories, exaggerated emphasis on delivery risks, and sensationalized portrayals of complications on these platforms.

Further analysis of usage motivations showed that browsing dietary and lifestyle advice on self-media platforms was only weakly correlated with the “Perspectives on Complications” dimension (r = 0.136, P < 0.05). While such content may improve awareness of complications, it fails to positively influence overall childbirth attitudes and might inadvertently amplify concerns about risks. Conversely, accessing information about medical interventions (e.g., risks and benefits of cesarean sections) was significantly correlated with both total childbirth attitude scores and “Perspectives on Cesarean Section” (r = 0.211, P < 0.01). This aligns with evidence that mass media amplifies perceived birth risks [20] and often frames cesarean sections as life-saving interventions [21], potentially driving women to prioritize perceived safety over natural delivery.

Interestingly, no correlation was found between childbirth attitudes and activities such as childbirth preparation or browsing information about potential delivery complications on self-media. This implies that mere information access or preparatory behaviors may not suffice to shift entrenched attitudes. Therefore, this study recommends that internet regulatory authorities strengthen oversight of health-related content and standardize the dissemination mechanisms for pregnancy and childbirth information in media environments. By establishing an authoritative childbirth knowledge dissemination platform—serving as a hub for information exchange—the public can access accurate and reliable childbirth-related information. Concurrently, efforts should be made to balance childbirth narratives on self-media platforms, minimizing the sensationalization of negative content. These measures aim to empower women to develop positive perceptions of childbirth and gradually reshape societal stereotypes surrounding the delivery process.

Strengths and Limitations

This study offers novel insights into the interplay between self- media consumption and childbirth attitudes among pregnant women, providing a foundation for improving maternal support systems. By integrating both online and offiine recruitment strategies, the sample captured diverse demographics, enhancing the generalizability of findings.

However, the study has limitations. Its cross-sectional design precludes causal inferences, and the reliance on self-reported data introduces potential response bias. Additionally, the focus on a single geographic region (Hangzhou) and the exclusion of women with psychiatric histories may limit external validity. Future longitudinal studies should explore how interventions—such as curated educational content on self-media—could shift attitudes over time.

Conclusion

Pregnant women who frequently and extensively engage with self- media platforms for childbirth-related information are more likely to develop negative attitudes toward delivery. Specific content types, such as discussions of medical interventions or others’ childbirth experiences, further exacerbate these concerns. To mitigate this, regulatory bodies should enforce stricter oversight of health-related content on self-media, promoting scientifically accurate and balanced narratives. Healthcare institutions should leverage these platforms to disseminate authoritative guidance, empowering women with knowledge to reduce fear of the unknown. Future research should investigate how content quality, source credibility, and algorithmic curation on self-media shape maternal perceptions, enabling targeted strategies to foster positive childbirth experiences.

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Bilateral Presumed Nocardia Subretinal Abscesses Treated with Serial Intravitreal Injections in an Immunocompromised 20-Year-Old Female

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DOI: 10.31038/IDT.2025611

Introduction

Nocardia species are found in contaminated water and soil [1]. Infections occur due to inhalation of contaminated particles and manifest typically in the lungs, central nervous system, skin, and joints [1,2]. Ocular manifestations include keratitis, scleritis, subretinal abscesses, and endogenous endophthalmitis [1]. Cases of endogenous endophthalmitis have poor visual outcomes and require intravitreal antibiotics [3]. Here we describe a 20-year-old female who presented with pulmonary nocardiosis that disseminated to her brain, lumbar spine and eyes.

Case Report

The patient is an immunosuppressed 20-year-old female with a significant past medical history of moderate developmental delay and systemic lupus erythematosus (SLE) who presented to Akron Children’s Hospital with worsening chest pain following recent pneumonia treatment. A chest CT showed recurrent pleural effusions and pleural fluid culture grew Nocardia cyriacigeorgica. A brain MRI showed numerous enhancing lesions suggestive of disseminated nocardiosis. She was started on oral linezolid and IV ceftriaxone due to a trimethoprim sulfamethoxazole (TMP/SMX) allergy. Ophthalmology was consulted for baseline examination given initiation of long-term oral linezolid therapy.

On initial examination, visual acuity was 20/800 in the right eye and 20/100 in the left. Dilated exam was limited due to patient cooperation but revealed suspected exudative retinal detachment in both eyes. Exam under anesthesia showed subretinal abscess with large serous retinal detachment of the right eye (Figure 1) and a temporal subretinal abscess with serous retinal detachment of the left eye (Figure 2). These findings prompted bilateral intravitreal tap and inject with amikacin. Both vitreous and anterior chamber taps did not yield a positive culture. Weekly intravitreal ceftazidime injections were administered over the next 4 weeks. At discharge, visual acuity was hand motion in the right eye and 20/40 in the left with improvement of serous detachment and abscesses in both eyes. She was discharged on oral TMP/SMX 160mg TID after sensitization and IV ceftriaxone 2g BID with plans to remove the PICC line and switch to oral linezolid 200mg daily in 6 months.

Figure 1: Color fundus photo of right eye with active ocular nocardiosis on initial presentation.

Figure 2: Color fundus photo of left eye with active ocular nocardiosis on initial presentation.

Nine months after discharge, she returned to clinic with increased right eye pain and photophobia raising concern for nocardiosis reactivation. The patient was readmitted and an intravitreal tap and inject with ceftazidime was performed. The sample was improperly processed and did not yield useful data. Topical moxifloxacin, prednisolone QID, and daily atropine were initiated. After five days, her vision was hand motion right eye and 20/60 left eye with almost near resolution of the anterior chamber inflammation. Macular OCT and dilated exam showed stable subretinal fibrosis in both eyes (Figure 3). A PICC line was reinserted, and she was restarted on IV Ceftriaxone 2g BID at the end of her admission.

Due to age and comorbidities, the patient transitioned out of pediatric care. On last chart review, she has since developed choroidal neovascular membrane (CNVM) in the left eye for which she is receiving intravitreal bevacizumab injections.

Figure 3: Color fundus photo 9 months after serial intravitreal injections.

Discussion

Nocardia is a gram positive, filamentous, partial acid-fast bacteria that can be found in contaminated water and soil [1]. This patient with SLE on hydroxychloroquine, rituximab and a recent oral steroid taper highlights the increased vulnerability of the immunocompromised population. Primary Nocardia infection is most common in the lungs with the brain being the most likely site of dissemination [1,2]. Ocular involvement is seen in 3-5% of cases often affecting the cornea, sclera, and retina [1-3]. Furthermore, Nocardia is a rare source of endogenous endophthalmitis comprising only 3% of all endophthalmitis cases [2]. Treatment is difficult and visual outcomes are poor.

We present an immunocompromised patient with bilateral subretinal abscesses that were treated successfully with intravitreal antibiotics. Subretinal abscesses can be biopsied to confirm the diagnosis. In our patient, however, the combination of pulmonary, CNS and ocular lesions with a positive pleural fluid culture were sufficient to suggest a Nocardia intraocular infection [4]. Amikacin is a popular antibiotic utilized to treat Nocardia and was used for her first injection [3]. Given sensitivity studies showing susceptibility to ceftazidime and the small risk of associated amikacin macular toxicity, ceftazidime was used for all subsequent intravitreal injections [5]. Our case presented similarly to others in literature in that subretinal fibrotic scarring formed in place of the clearing abscesses [3].

There is no definitive regimen for duration or frequency of intravitreal injections to successfully treat ocular nocardiosis. Our patient developed a suspected reactivation in her right eye after she was switched from IV ceftriaxone to oral linezolid. The reason for the reactivation is unclear given that Nocardia species have near 100% susceptibility to linezolid [6]. Resistance to linezolid is also unlikely given the resolution of the lung and brain lesions. We hypothesize that her reactivation could be due to ending intravitreal injections too early. This case highlights the importance of close multidisciplinary follow up of immunocompromised patients when systemic immunosuppressive medications are adjusted.

References

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Hojjatie SL, Salek SS, Pearce WA, Wells JR, Yeh S, et al. (2020) Treatment of presumed Nocardia endophthalmitis and subretinal abscess with serial intravitreal amikacin injections and pars plana vitrectomy. Journal of Ophthalmic Inflammation and Infection 10-14. [crossref]
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Determinants of Subjective States in Combat Aviation

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DOI: 10.31038/PSYJ.2025712

Abstract

Combat pilots are responsible for ensuring the best they can towards their service and mission accomplishment. The operation of key cognitive determinants mediates between antecedent processes including actual abilities and anticipated fulfilment of future outcomes. In assessing the vocational development construct of combat pilots, we have underlined the limitations of their perceived abilities and belief enacting self-efficacy and response to relevant task information from the environment, both spatial and temporal. The appraised cognitive determinants engaged in information processing were essentially tied for expressing subjective states of knowledge, feelings, emotions and health threat perceived with a conscious experience. We externalized their subjective states by showing mental health difficulties in the demanding high-stakes environment of air combat.

Keywords

Cognitive load theory, Self-efficacy, Emotions, PTSD, PTSS

Introduction

The journey of the heroic Airman begins through the unbreakable commitment to a cause, nurturing the legacy of past comrades and personal conduct to promote a leader of character, courage and competency. This calls on the vital role of a cognitive oriented career development in ensuring combat effectiveness rigorously tied to the mission success. Cognitive factors such as mental workload and human performance are crucial to the pilot’s survival and recovery process. While, subjective states can materially contribute to accidents, much of the accident causation is attributed to suboptimal performance to various categories of errors associated with the increased level of automation complexity in the cockpit. Although aviators are selected on factors that are highly correlated with cognitive ability, thoughts and feelings maybe controlled but not eliminated.

The Vocational Journey

Probably the great battle of all for combat pilots begins with the conscious trained mind and the subjective psyche to hold the high standards interwoven in the creation of professional airmen. Accordingly, the vocational nature of airmen evolves with discipline correlated with perceived abilities, expected mission success and the innate desire to anticipate great achievements. This triangulation of cognitive determinants is continuously shapes the psychological construct of pilots’ recovery chances in any survival situation. The perceived ability of pilots to be maintained through continuous improvements, the expected fulfilment of a mission and the anticipated outstanding achievements are experience and knowledge acquired and stored in terms of building blocks known as schemas. Schemas are generalized knowledge structures of the Cognitive Load Theory that are renewed every time new information is ingested [1].

In underpinning the state of technology that the mission requires a pilot conversely trigger automated schemes and induces automatic responses [2]. Moreover, internal representations are continuously seeking internal cognitive consistency and validation against one another [3]. While the three determinants are highly correlated and augmenting the cognitive processing resources, they diverge with the mission situational factors. In particular, pilot’s effort and attention are devoted to the constant fluctuations of task demands [4]. Therefore, on assessing and interpreting this change, “There is evidence that people can fall into a trap of executing habitual schema, doing tasks automatically, which render them less receptive to important environmental cues” [5]. This dynamic process is highly dependent on pilot-aircraft-environment interaction. From a cognitive viewpoint the pilot attribute a certain degree of confidence towards the validity of information regardless of their source. This increases the odds of a pilot making errors or create biases [6]. While the basis for automating the cockpit was to reduce cockpit workload by off-loading many of the duties performed by the pilots to digital processors, it increased the pilot’s beliefs of imagined success and satisfactory performance [7]. Similarly, they perceived higher cognitive abilities consistent with their vocational background. In this position, the effects of career self- efficacy generated distortion mechanisms of their cognitive schema. It should be kept in mind that automated systems characterized by their authority, autonomy and complexity has continuously expanded interaction from individual (one pilot, one aircraft) to local interactions (one team, one squadron, ground control staff), then to organizational interactions (one nation, Air Force personnel) to global interactions (inter-nation deployment).

Subjective State of Knowledge

Self-efficacy belief hypothesized by pilots to attain specific performance goals is highly prone to bias since it influences their behavior and interactions. This condition is mostly evaluated with a degree of confidence influencing behavioral intentions rather than actual behavior along the temporal dimension of a flight sortie, or the whole mission. This favorable attitude and the subjective norm (professional expectations) leads to a targeted and improved behavior. However, when focusing on the inner experience, subjective states are challenging to decipher and separate from objective knowledge. Nonetheless, the pilot must “Stay ahead of the airplane” and anticipate future events [8]. More specifically, pilots are not passive spectators and must rely on their expectancy of recovery to determine the outcome of future events, not only with the conscious trained mind but also with the subjective psyche. Expectancy do not always come true and play a fundamental role in the accident causation, which is attributed to suboptimal performance and is prone to various categories of errors. This is determined by how a pilot approaches a situation and the relevance of cues adopted for the formation of a situation assessment [9]. The integration of expectancy into situational attributes and elicited degree of belief overestimates the confidence of pilots’ capability in the use of automation. Such a degree of confidence is seen as restraining factor in tactical situations which tend to “over generalize, over summarize and over rationalize” past mental events [10]. Subsequently, the fact that situation awareness represents a mixing of prior knowledge and current perception creates challenges for pilots’ recovery acts in emergency situations, in which stress affect the pilot’s working memory through provoked perseveration. This repetitive behavioral state along with difficult-to-control thoughts can have dramatic consequences during safety-critical tasks or progress towards goals [11].

Subjective State of Feelings and Emotions

The essence of the problem in many accidents involves difficult- to-control thoughts resting on emotions that won out over good sense. Emotions are just as important as cognitive abilities since emotional reactions during human-computer interaction have induced psycho-physiological conditions eliciting engagement, relaxation and stress that can alter a pilot’s arousal level [12]. Emotions are normally well controlled but not eliminated; increased emotional imbalance requires self-control and an effective attitude driven by personally relevant goals [13]. Any intense emotional reaction can blur a task activity with a lapse in control [14,15]. This sense of rapture, probably the sharpest of subjective feelings would steam a feared outcome lacking a time and context perspective [16]. The stimulus of fear ruminating with anxiety would affect the pilot’s arousal level in a threatening situation with a sense of escaping dangers. However, such a natural instinct remains controllable when pilots are willing to take part in combat and face an emergency. Fear opts the course of accident sequences while anxiety echoes a combat harrowing experience that is more intense than the situation at hand. This allows to elevate a priori the panicky avoidance (phobia) of a complicated situation [17]. In such a case, adaptation to flying is seen as a positive form of denial without experiencing fear [18]. Additionally, pilots who develop “fear of flying” might result from the breakdown of their defense mechanisms [19]. This is particularly true for pilots exposed to emergency scenarios seeking to reconstruct their fear defense. On the other hand, there are those willing to push the flying envelope with challenging physical demands and high information loads prone to potential stress. In this setting, counterphobic attitude to react to stress and emotional control are essential factors for distinguishing combat pilot aces from average combat pilots [20]. One emotion worth considering is a sense of resignation, the very absence of fear, pride or anger. Such a passivity state is a personal emotion, grounded partly in automation set to transform the pilot into a passenger who feels powerless to alter the course of events. However, pilots’ intension to resign from a encourage reengagement of new goals [21]. After all, humans are capable of maintaining the big picture and still need to be aware of what is happening when something goes awry.

Subjective State of Suffering

One of the most extreme human emotions is the occurrence of a major depression disorder (MDD) with the risk of suicide [22]. This symptom is usually well hidden amongst military and civil pilots and can have devastating effects on the population when pilots deliberately perform this act employing aircraft. During the last war, this risk foresaw a strategy for diagnosis of significant mental disorders of pilots suffering from psychological and psychoneurotic conditions. These states were strongly correlated with personality traits, and the interaction with stress and neuroticism decay over time [23]. In other circumstances, the mind gags (more akin to phobia) where the awareness of extreme detachment known as the breakaway phenomenon has been seen most likely attributable to the pilots’ insistence in pursuing an action against all the odds of survival. This separation transcends a profound sense of loneliness, typically occurring at high altitude. Although reassurance and resolution occur through the descent and approach phase, often it sensitizes the pilot and can recur. In extreme cases, especially after an accident signs of Post Traumatic Stress Disorder (PTSD) may develop with depression and abusive behavior, nightmares and phobic avoidance of flying. While the implication of problem-solving, attention and working memory are closely linked to traumatic experiences associated with post-traumatic stress symptomology (PTSS) [24]. Adverse mental states have been also associated with the analysis of physical/mental limitations and perceptual errors. On the former, this indicates that highest levels of exhaustion/fatigues as causes of that burnout negatively affect pilots’ performance. Moreover, emphasis has been placed on their working conditions and the lack of professional advancement [25]. On the latter, a common manifestation of perceptual errors relates to the profound disconnect from reality. This disentanglement is manifested through altered perception of time and space most commonly induced by Gravity-Induced Loss of Consciousness (G-LOC). Whereas pilots’ perceptual errors in the position, motion and attitude of the aircraft have been included spatial disorientation episodes and the concept of situational awareness (SA). G-LOC and spatial disorientation are the results of human sense organs adapted to the earthly life and a stable 1-G environment. This adaptation is highly disrupted when pilots are exposed to motion stimuli of different magnitude, frequency and direction than those practiced on the ground [26].

Conclusion

Technological advances have shaped human-systems interaction and contributed to improved SA. However, it is a paradox that when the workload is very high the pilot reverts to a more manual role. The people who report losing self-control over intense or unwanted emotions much of the time are subjected to some conscious overriding. While flying a pilot should ponder the implausible separation from the objective truth and subjective knowledge. Conversely, subjective processes can enhance the objective comprehension of the world. On fifth-generation combat aircraft, the visual intake is displayed on the helmet’s visor and therefore subjected to the pilot’s active scan and selection until a stimulus to prioritize the most relevant input for the immediate task. This capability entails to processing enough information to solve the problem through a “window of consciousness” as James W. (1890) prophesied, rather than become caught in a catch- up game. The psychological discern yearned to conquer the air ex-ante still provides room of an active topic in contemporary ex-post research.

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Orthorhombic Cassiterite and 13C-rich Diamond in a Sample from the Land’s End Granite, SW England, and Some Remarks on the Origin of the 13C-rich Diamond and Graphite

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DOI: 10.31038/GEMS.2025721

Abstract

A cassiterite sample from Land’s End granite, SW England, contains cassiterite crystals rich in orthorhombic phases. A precise classification is not possible by mixing remnants of different polytypes. Obviously, the main phase is the polymorph type Pbcn (PbO₂-type), which forms around 30 GPa. The possibility of the formation of polytypes of cassiterite at such high pressures is indicated by the proof of the presence of diamond. Some diamonds and graphite are rich in ¹³C, 28% and 11.45% respectively. Such a high concentration of ¹³C in diamond is only possible by effective isotope fractionation in a supercritical fluid. Significant higher ¹³C values, up to 95%, were found by the author.

Keywords

Land’s End Granite, Raman spectroscopy, Orthorhombic cassiterite, ¹³C-rich diamond and graphite, Supercritical fluid

Introduction

The naturally occurring form of cassiterite is usually tetragonal and crystallizes in the rutile-type structure. However, Thomas (2023a) has shown that cassiterite can also crystallize as an orthorhombic polytype and is widespread in the Erzgebirge and Schlaggenwald (Horni Slavkov, Czech Republic). Last time, a couple of experimental works on the different polytypes of cassiterites were performed [1-5]. From these experiments, it follows that the orthorhombic cassiterite types formed under high pressure and high temperature. Because the orthorhombic cassiterite of the Variscan tin deposits in the Erzgebirge region is part of the tetragonal cassiterite formed in the upper crustal region, it is, therefore, formally a low- pressure formation. The appearance of orthorhombic cassiterite here needs, thus, a plausible explanation [6,7]. Essential indicators for the occurrence of the high-pressure cassiterite polytypes are the paragenetic high-pressure minerals diamond, lonsdaleite, and others, which came from the mantle region via supercritical fluid, as well as the Lorenzian distribution of some trace and main elements [8]. Proofs for such new transport mechanisms are in Thomas et al. (2023a) [1]. In this contribution, we will show that orthorhombic cassiterite and diamond are not only related to the vast Variscan Erzgebirge region but also to the Cornubian Batholite and other places. Furthermore, we will give a further example of the diamond of the Land’s End granite batholite, England, which is exceptionally rich in ¹³C. Such strong isotope fractionation of carbon needs an explanation.

Sample Material and Raman Spectroscopy: Methodology

Sample Material

A concise description of the Land’s End Granite, their geology, mineralogy, and geochemistry was given by Drivenes (2022) [9]. We use an uncovered microprobe sample von Kristian Drivenes for the Raman spectroscopic studies. Before our studies, the owner removed the carbon coating from the sample with diamond paste. The main minerals are cassiterite, tourmaline (dravite, uvite, and olenite), quartz, rutile, and apatite (all determined with Raman spectroscopy). According to Drivenes (2022) [9], tourmalines contain Sn in relatively high concentrations, up to 2.53%. The owner of the sample has significant problems with the new findings.

Microscopy and Raman Spectroscopy

We performed all microscopic and Raman spectroscopic studies with a petrographic polarization microscope (BX 43) with a rotating stage coupled with the EnSpectr Raman spectrometer R532 (Enhanced Spectrometry, Inc., Mountain View, CA, USA) in reflection and transmission. The Raman spectra were recorded in the spectral range of 0–4000 cm^-1 using an up-to-50 mW single-mode 532 nm laser, an entrance aperture of 20 µm, a holographic grating of 1800 g/mm, and spectral resolution ranging of 4 cm^-1. Generally, we used an objective lens with a magnification of 100x: the Olympus long-distance LMPLFLN100x objective (Olympus, Tokyo, Japan). The laser power on the sample is adjustable down to 0.02 mW. The Raman band positions were calibrated before and after each series of measurements using the Si band of a semiconductor-grade silicon single-crystal (for the studies on cassiterite) and a water-clear diamond crystal (Mining Academy Freiberg: 2453/37 from Brazil) for the Raman studies on diamond. The run-to-run repeatability of the line position (based on 20 measurements each) is ±0.3 cm−1 for Si (520.4 ± 0.3 cm^-1) and 0.4 cm^-1 for diamond (1332.7 cm^-1 ± 0.4 cm^-1 over the range of 0–2000 cm^-1). The FWHM = 4.26 ± 0.42 cm^-1. FWHM is the Full-Width at Half Maximum. We also routinely determined the zero point of the Raman spectrometer for the first-order band position of the ¹³C-rich diamond.

Results

Orthorhombic Cassiterite

Usually, cassiterite in the classic Variscan tin deposits grows in the tetragonal rutile form (Figure 1). So, the occurrence and the proof of orthorhombic cassiterite in the upper crust raises a lot of questions regarding the formation processes. Explanations are in Thomas 2023a [1,6-8]. A Raman spectrum of typical tetragonal cassiterite from the Tannenberg mine near Mühlleiten/ Vogtland, Germany is shown in Figure 1.

Figure 1: Typical Raman spectrum of a tetragonal cassiterite crystal (Tannenberg mine near Mühlleiten/Vogtland, Germany). A high tourmaline content characterizes this deposit.

Five Raman lines are characteristic of the Raman spectrum of the tetragonal cassiterite (Figure 1): 777.1 cm^-1 (medium), 634.1 cm^-1 (very strong), 471.7 cm^-1(weak), 257.3 cm^-1 (very weak), and 75 cm^-1 (strong). The main line at 634.1 cm^-1 has a FWHM of 12.6 cm^-1. According to Chukanov and Vigasina (2020) [10], using a 633 nm He- Ne laser, four lines are typical for tetragonal cassiterite: 842, 776, 635s, and 475 cm^-1. Bands at lower Raman shift values (between 100 and 200 cm^-1) are mostly not given (for example, in the RRUFF database [11]).

Figure 2 shows a typical Raman spectrum of the orthorhombic cassiterite from Land’s End Granite, characterized by very strong bands in the low-frequency range.

Figure 2: Raman spectrum of orthorhombic cassiterite from Land’s End’s Granite. The strong Raman bands at 75.9 and 125.1 are typical for the polymorph cassiterite Pbcn type (PbO₂-type).

Typical for this Raman spectrum is the strong band at about 125.1 cm^-1 and the medium bands at 627.8 cm^-1 and 241.3 cm^-1, characteristical for the orthorhombic Pbcn polymorph of cassiterite [5]. Table 1 shows the mean and the standard deviation for measured Raman bands of the Pbcn cassiterite type.

Table 1: Results of the Raman measurements on different cassiterite crystals (orthorhombic Pbcn type) from Land’s End, Cornwall, SW England.

Band (cm^-1)	Intensity (rel.)	Raman mode	n
76.6 ± 2.5	vs	A_g	22
119.5 ± 2.3	vs	B_2g	13
236.9 ± 5.3	s	A_g	25
439.0 ± 2.3	s – m	B_2g	15
608.7 ± 3.5*	m – w	B_2g	26
631.1 ± 1.8	vs – m	B_1g, B_2g	22
835.9 ± 2.9**	w -vw	B_2g	19
vs – very strong, s – strong, m – medium, w – weak, vw – very weak; n – measured crystals
Some Raman lines are not stable under the 532 nm laser (50 mW on the sample). The best data are obtainable with a low laser power of 4 mW on the sample at a long measuring time of 2000 or 4000 s. This Raman band is a shoulder of the 631.1 band and can be a remnant of the Pnma-I (cotunnite) cassiterite type. * This Raman band is not present in the computed Raman modes (Balakrishnan et al., 2022) [5]. According to Hellwig et al. (2003) [2], that band is a high-pressure remnant of the Pnnm CaCl₂ type of cassiterite (14.8 GPa).

The data in Table 1 are representative of orthorhombic cassiterite of the Pbcn polytype (PbO₂-type). After Shieh et al. (2006) [3], the transition of polymorphs is sluggish. Therefore, we find that besides the Pbcn-type, remnants of the cotunnite and CaCl₂-type. Generally, the tetragonal cassiterites (P4₂/mnm) containing orthorhombic cassiterite phases also include the orthorhombic cassiterite polytypes: Pnnm (CaCl₂), Pbcn (PbO₂), Pbca (ZrO₂), and Pnma-I. The Pbcn and Pbca polytypes are metastable phases converted into more stable polymorphs under certain experimental conditions [5]. Nevertheless, we find these phases efficiently with the help of Raman spectroscopy. According to Girao (2018) [4], the essential phase transformations of tetragonal cassiterite happen at 14.8 GPa to the CaCl₂-type (Pnnm) and at 30 GPa to the PbO₂-type (Pbcn).

Table 2: ¹³C-rich diamonds and ¹³C-rich graphite calculated according to Enkovich et al., 2016 [12] and Gutierrez et al., 2014 [14], from Raman measurements (means).
Diamond:

Origin	Raman band (cm^-1)	¹³C in diamond (%)	n	References
Land’s End	1318.8	28.0	3	This work
Land’s End	1328.0 ± 2.8	12.5	10	This work
Ehrenfriedersdorf	1286.7 ± 6.5	95.1	10	Thomas (2025) [8]
Bornholm	1311.1 ± 4.2	52.1	62	Thomas (2024c) [15]
Ehrenfriedersdorf, Beryl	1318.4 ± 6.1 1328.6 ± 5.6	36.0 10.9	19 14	Thomas et al. (2023b) [16]
Zinnwald	1313.9 ± 6.1	46.1	18	Thomas (2025) [8]
Reinbolt Hills	1312.1 ± 2.5	50.0	16	Thomas (2023c) [17]

Graphite:

Origin	Raman band (cm^-1)	¹³C in graphite (%)	n	References
Land’s End	1573.9	11.45	3	This work
Land’s End	–	–	–	This work
Bornholm	1562. 6 ± 10.82	29.70	10	Thomas (2024c) [14]
Ehrenfriedersdorf	1518.1 ± 0.8	99.90	10	Thomas (2025) [8]
EhrenfriedersdorfBeryl	1569.8 ± 5.2	18.1	13	Thomas et al. (2023b) [18]
Zinnwald	1521.5 ± 8.5	96.0	10	Thomas (2025) [19]
Reinbolt Hills	1575.3	9.2	1	Thomas (2023c) [17]

¹³C-Rich Diamond

During the study of the sample, blue tourmaline crystals are striking. In the black cores of some blue tourmaline crystals, we found ¹³C-rich diamonds. The Raman spectrum is shown in Figure 3. That ¹³C-rich diamond was used for deleting the microprobe carbon film is improbable. The effort to produce ¹³C-rich diamond for sample preparation is enormous and is therefore highly unlikely.

Figure 3: Raman spectrum of a ¹³C-rich diamond crystal in blue tourmaline with the first- order diamond band at 1318.8 cm^-1. Also, the graphite G-band at 1573.9 cm^-1 is relatively low. The FWHM are 48.8 and 60 cm^-1 respectively.

As a first approximation, according to Enkovich et al. (2016) [12], results in a ¹³C concentration for the diamond of 28% and the graphite of 11.45%. That is an unusually high ¹³C value. Because the sample is repeatedly cleaned with diamond paste, remnants of diamond are possible. Therefore, a comparison with a similar diamond paste was necessary. Figure 4 shows a Raman spectrum of such a diamond from the paste used. The graphite band is nearby, wholly missing.

Figure 4: First order Raman spectrum of diamond of a DP diamond paste B from H. Struers, Chemiske Laboratorium, Copenhagen, Denmark. [2.2% ¹³C].

The first-order diamond band of the DP diamond paste B is at 1331.9 ± 0.22 cm^-1, and the FWHM is 5.4 ± 0.2 cm^-1. Thomas et al. (2023a) [13] listed the Raman spectroscopic result for technical diamonds used for geological sample preparation. Such a substantial shift from 1332.7 cm^-1 to 1318.8 cm^-1 could not observed. To be sure, we scrutinized the zero point of the Raman spectrometer steadily. Besides this, for the sample’s extreme ¹³C values, there are also ¹²C-rich nano-diamonds (mostly in cassiterite) present. From 10 different crystals, a mean of 1328.0 ± 2.8 cm^-1 and a FWHM of 33.3 ± 12.9 cm^-1 result. According to the mean comparison (0.999) between the ¹²C-rich diamond in cassiterite and the diamond used for polishing, a significant difference results. The same holds for the FWHM values.

Interpretation

Usually, in upper-crust tin deposits, neither orthorhombic cassiterites nor diamonds are present. Explanations for those unusual observations are in Thomas (2023a [1,8,9] and Thomas et al. (2023) regarding the different contributions to these problems. The strong ¹³C isotope enrichment in diamond and graphite is a further challenge. The simplest explanation is the interaction between the Earth’s mantle and the crust via supercritical fluids. Such fluids are brought from mantle depth not only water, CO₂, and CH₄ but also solid mineral phases such as foreign substances like diamonds, lonsdaleite, high- pressure SiO₂, cassiterite polymorphs, etc. Because supercritical fluids are characterized by high diffusion rates and extremely low viscosity, isotope fractionation should also be extensive.

Table 2 summarizes the current results of the measured ¹³C-rich diamonds and graphite. The ¹³C-values of the measured diamonds and related graphite are uncommonly high and are nowhere near the “classic” diamonds and graphite data [20].

Discussion

Thomas and coauthors show that in upper crust mineralizations, especially in the Variscan tin deposits of the Erzgebirge, however, also at other places (Bornholm pegmatite, Land’s End Sn deposit, and Reinbolt Hills pegmatite), there are indications of the interaction between deep mantle and upper crust [19] via supercritical fluids. A huge problem is that most natural diamonds have low ¹³C concentrations. According to Cartigny (2005) [20], the abundance for ¹²C is about 98.9% and for ¹³C 1.1%. Therefore, the ratios are expressed in parts per thousand relative to an internationally accepted standard. However, the finding of very high ¹³C values in natural diamond and graphite is a novum and needs an acceptable interpretation. Here, we interpret the formation of ¹³C-rich diamond and graphite as a result of a strong isotope fractionation of the species CO₂ and/or CH₄ in the supercritical fluid. Maybe the formation of this type of diamond and graphite happens directly at the upper crust during the transition from supercritical to the undercritical state. That is supported by the finding of SiC-whisker, diamond, and graphite in beryl [16,18]. The highest ¹³C concentration was found by the author in the cassiterite sample (Sn- 70) from the Sauberg mine near Ehrenfriedersdorf [8], and high ¹³C values results also for diamond in cassiterite from Zinnwald (sample Sn-23). Using the data from Enkovich et al. (2016) [12], the results for ¹³C of the Sauberg-diamond is 99.9% and for the Zinnwald (sample Sn-23) 46.1%. More work is necessary to clear some open questions.

Conclusion

There are clear hints that some diamonds, together with SiC, grow at low pressure and moderate temperatures [18] via supercritical fluids. The transition from the supercritical to the under-critical state is a scientific challenge. The proof of the diamond formation at one- atmosphere pressure and relatively low temperatures (1025°C) by Gong et al. (2024) is a clear paradigm shift. Our results aim in the same direction.

Acknowledgment

The author thanks Kristian Drivenes from the Geological Survey of Norway, Trondheim, for the loan of the Land’s End sample. A discussion with Adolf Rericha helped with some clarifications.

References

Thomas R (2023a) Unusual cassiterite mineralization, related to the Variscan tin mineralization of the Ehrenfriedersdorf deposit, Aspects in Mining & Mineral Science. 11: 1233-1236.
Hellwig H, Goncharov AF, Gregoryanz E, Mao H, Hemley RJ (2003) Brillouin and Raman spectroscopy of the ferroelastic rutile-to CaCl₂ transition in SnO₂ at high Physical Review B 67: 174110-1174110-7.
Shieh SR, Kubo A, Duffy TS, Prakapenka VB, Shen G (2006) High-pressure phases in SnO₂ to 117 Phys. Rev. B. 73: 014105-1–014105-7.
Girano HT (2018) Pressure-induced disorder in bulk and nanometric SnO₂. Material Université de Lyon. Pg: 139.
Balakrishnan K, Veerapandy V, Fjellvag H, Vajeeston P (2022) First-principles exploration into the physical and chemical properties of certain newly identified SnO₂ ACS Publ. 7: 10382-10393.
Thomas R (2024a) The CaCl₂ -to-rutile phase transition in SnO from high to low pressure in nature. Geol Earth Mar Sci. 6: 1-4.
Thomas R (2024b) Rhomboedric cassiterite as inclusions in tetragonal cassiterite from Slavkovský les – North Bohemia (Czech Republic). Geol Earth Mar Sci 6: 1-6.
Thomas R (2025) Extremely ¹³C-rich diamond in orthorhombic cassiterites in the Variscan Erzgebirge, Saxony/Germany. Geology, Earth and Marine Sciences. 7: 1-5.
Drivenes K (2022) Sn-rich tourmaline from the Land’s End granite, SW Journal of Geosciences. 67: 173-189.
Chukanov NV, Vigsina MF (2020) Vibrational (Infrared and Raman) Spectra of Minerals and Related Compounds. Springer. Pg: 1370.
Lafuente B, Downs, RT, Yang H, Stone N (2015) The power of database: the RRUFF In: Armbruster T, Danisi RM (eds.). Highlights in mineralogical crystallography. Berlin. Pg: 1-30.
Enkovich PV, Brazhkin VV, Lyapin SG, Novikov AP, Kanada H, et (2016) Raman spectroscopy of isotopically pure (¹²C, ¹³C) and isotopically mixed (^12.5C) diamond single crystals at ultrahigh pressures. Journal of Experimental and Theoretical Physics. 123: 443-451.
Thomas R, Davidson R, Rericha A, Recknagel U (2023a) Ultahigh-pressure mineral inclusions in a crustal granite: Evidence for a novel transcrustal transport mechanism. Geosciences. 94: 1-13.
Gutierrez G, Le Normand F, Aweke F, Muller D, Speisser C, et (2014) Mechanism of thin layers graphite formation by ¹³C implantation and annealing. Appl Sci. 4: 180- 194.
Thomas R (2024c) ¹³C-rich diamond in a pegmatite from Ronne, Bornholm Island: Proof for the interaction between mantle and Geol Earth Mar Sci. 6: 1-3.
Thomas R, Recknagel U, Rericha A (2023b) A moissanite-diamond-graphite paragenesis in a small beryl-quartz vein related to the Variscan tin-mineralization of the Ehrenfriedersdorf deposit, Germany. Aspects in Mining & Mineral Science. 11: 1310-1319.
Thomas R (2023c) Diamond in pegmatitic sillimanite from Reinbolt Hills/East Geol Earth Mar Sci 5: 1-3.
Thomas R (2023b) Growth of SiC whiskers in beryl by a natural supercritical VLS Aspects in Mining & Mineral Science. 11: 1292-1297.
Thomas R, Rericha A (2025) Extreme element enrichment by the interaction of supercritical fluids from the mantle with crustal rocks. Minerals. 33: 1-10.
Cartigny P (2005) Stable isotopes and origin of Elements. 1: 77-84.
Gong Y, Luo D, Choe M, Seong WK, Bakharev P, et (2024) Growth of diamond in liquid metal at 1 atmosphere pressure. Nature. 629: 348-354.

Research Progress on the Correlation Between Maternal-Fetal Attachment, Childbirth Experience and Maternal-Infant Attachment

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DOI: 10.31038/EDMJ.2025922

Abstract

The transition from pregnancy to childbirth and then to parenting is a time of rapid physiological, psychological, and social change, as a key turning point in the transformation of women’s roles, childbirth plays a vital role in the smooth establishment of mother-infant relationships. This paper based on the attachment theory, introduces the concepts of maternal-fetal attachment, childbirth experience and maternal-infant attachment, and systematically reviews the correlation between maternal-fetal attachment, childbirth experience and maternal-infant attachment, so as to provide theoretical basis and practical guidance for formulating relevant perinatal health care policies.

Keywords

Maternal-fetal attachment, Childbirth experience, Maternal-infant attachment, Relevance

In recent years, the parent-child relationship has been rethought as research in developmental psychology has polarized toward the two poles of the life course (“one old, one young”). Research has shown [1] that the parent-child relationship begins to form gradually during pregnancy and manifests itself in the form of maternal-fetal attachment. The term Maternal-Fetal Attachment (MFA) describes the emotional bond between a mother and her unborn fetus during pregnancy. During the perinatal period, establishing an emotional bond with the fetus and the newborn is one of the most important tasks of the mother [2]. However, the transition from pregnancy to labor and delivery and then to parenting is a process of rapid physiological, psychological, and social change for women, and labor and delivery, as a key turning point in the transformation of women’s roles, plays a crucial role in the successful establishment of the mother-infant attachment relationship [3]. In view of this, the childbirth experience may play a mediating role between mother-fetus attachment and mother-infant attachment. Currently, the national literature has only found studies on the current status of maternal-fetal attachment, labor and delivery experience, or a single variable of mother-infant attachment and its influencing factors. Therefore, based on attachment theory, this paper reviews the correlation between maternal-fetal attachment, labor and delivery experience, and mother-infant attachment, with a view to providing a theoretical basis and practical guidance for the formulation of relevant perinatal health policies, so as to enhance maternal labor and delivery experience and maintain mother-infant relationships.

Attachment

Attachment Theory (Attachment Theory) was first proposed in the 1960s by the British psychologist John Bowlby [4]. Bowlby defined Attachment as a biologically based innate system that guides individuals to stay close to an attachment figure when faced with a threat to protect themselves from harm [4]. Based on this, a special and strong emotional connection is formed between mother and child [5] (Bonding). Emotional bonding is an important theme within attachment theory. During the development of attachment theory, emotional bonding and attachment are two important concepts that need to be differentiated emphatically.

Maternal-infant Bonding (MIB) refers to the process of communication between mother and infant through behavior and emotion [6], which is mainly reflected in the sense of intimacy between mother and infant and the mother’s confidence in caring for the infant [7], as well as in the mother’s love for the infant and her sense of the infant’s uniqueness and importance, which is a kind of unidirectional emotional bonding, specifically referring to the mother’s emotions towards the infant. This bond is a unidirectional emotional bond, specifically referring to the mother’s feelings toward the infant. On the other hand, Maternal-infant Attachment (MIA) is a special and strong emotional connection between infants and their primary caregivers (usually mothers) established through emotional communication and behavioral interactions [8], which is a bi-directional emotional connection between mothers and infants, and is a phenomenon that can only be manifested by infants when they have developed the ability to express their emotions about separation and reunion. Therefore, mother-infant attachment has a specific developmental time period, with attachment establishment occurring from 6 weeks of birth to 6 to 8 months, with clarity of display occurring from 8 months to 18 months, and reaching the period of reciprocal relationships by 24 months [4]. In summary, it is possible to describe the mother-infant relationship as emotional bonding before 8 months. After 8 months it is described as attachment. However, the existing literature has not been subdivided by scholars on the concepts of mother-infant emotional connection and mother-infant attachment, which are usually referred to as mother-infant attachment.

With the development of attachment theory, some scholars pointed out that when a mother becomes a pregnant mother, she is also emotionally attached to the fetus in her womb. Therefore, maternal-fetal attachment was extended. Cranley [9] first defined maternal-fetal attachment as “the behavioral and emotional relationship of a pregnant woman interacting with her unborn fetus”. Based on Cranley’s conceptualization, Muller and Mercer proposed that the definition of maternal-fetal attachment should also include the mother’s imagination of the unborn fetus [10]. In addition, Condon proposed that maternal-fetal attachment consists of five key attributes: knowing the fetus, being with the fetus, protecting the fetus from physical or emotional harm, attending to the needs of the fetus, and avoiding separation from the fetus, with love being the core of maternal-fetal attachment [11]. Although scholars define maternal-fetal attachment differently, they agree that maternal-fetal attachment is a multidimensional structure that includes the mother’s thoughts, behaviors, emotions, and attitudes, and is an emotional connection that the mother creates to the fetus in the womb.

The Importance of the Childbirth Experience in Attachment Research

Currently, there is no uniform definition of the concept of childbirth experience. Salmon et al. [12] first proposed that childbirth experience is a multidimensional phenomenon based on women’s emotions and perceptions of childbirth, including three dimensions: emotional distress, physical discomfort, and satisfaction. Larkin [13] used a conceptual analysis approach to define the childbirth experience as a unique life event experienced by a woman, including the subjective mental and physiological processes, which are influenced by society, environment, organization, and policies, and this concept is agreed upon by most scholars. Childbirth, as an important turning point in the transformation of women’s roles, plays a crucial role in the successful establishment of the mother-infant relationship [14]. Positive birth experiences can empower women through labor and delivery, promote personal growth and self-knowledge, which in turn enhances women’s self-esteem, sense of responsibility, self-efficacy and self-confidence levels, actively participate in self and infant care and interaction, and promote the establishment of the mother-infant relationship [15]. In contrast, negative birth experiences, such as post-traumatic stress disorder after childbirth, can undermine the continued development of the mother-infant relationship. Kennell and Klaus et al. have shown [16] that after a negative birth experience, mothers may become preoccupied with their own physical and emotional needs and reduce their interactions with their infants, thereby weakening the mother-infant relationship. Smorti et al. have shown [17] that the birth experience can significantly affect the the relationship between prenatal and postnatal attachment. as the emotional bond between mother and infant evolves from pregnancy to postpartum. Given this, labor and delivery experiences may play a mediating role between mother-fetus attachment and mother-infant attachment. However, there is a lack of national research related to the inclusion of the labor and delivery experience in the domain of attachment.

Correlation Between Maternal-Fetal Attachment, Birth Experience and Mother-Infant Attachment

Research on the Correlation Between Maternal-Fetal Attachment and Mother-Infant Attachment

At this stage, there is a lack of research on the correlation between maternal-fetal attachment and mother-infant attachment in China, and the existing literature has only found studies on the status of maternal-fetal attachment or mother-infant attachment as a single variable and its influencing factors. Overseas research on the correlation between maternal-fetal attachment and mother-infant attachment first began in the 1980s, with studies focusing on the United States, Australia, Italy, and other European countries, and the existing literature suggests that the emotional bond between mothers and their infants continues to develop from pregnancy to the postpartum period. Prospective studies measuring maternal-fetal attachment and mother-infant attachment separately at different points in time have found that maternal-fetal attachment predicts mother-infant attachment and positively influences mother-infant attachment. A longitudinal study in an Australian region found [18] that stronger maternal-fetal attachment in the third, sixth, and ninth months of pregnancy predicted stronger postpartum mother-infant attachment in the eighth week of the infant’s life. Italian scholars Cataudella [1] investigated using the Maternal Antenatal Attachment Scale (MAAS) and the Maternal Postnatal Attachment Scale (MPAS), respectively, and showed that in mid-pregnancy, The results showed that pregnant women who showed a stronger emotional connection with their fetus in late pregnancy had a higher level of attachment to their infants in the postpartum 3 months. German scholars Dubber [19] measured maternal-fetal attachment and maternal-infant attachment at 32 weeks of late pregnancy and 3 months postpartum, and found that there was a significant negative correlation between maternal-fetal attachment and postpartum maternal-infant attachment disorder, i.e., the higher the level of mother’s attachment to the unborn fetus during pregnancy, the fewer postpartum attachment disorders. In addition, researchers investigating different populations have come to similar conclusions. Hildingsson [20] investigated 172 women with fear of childbirth and found that low levels of maternal-fetal attachment showed impaired mother-infant bonding, in which depressive symptoms played a mediating role. American scholars Karina [21] and others investigated 124 pregnant women with unintended pregnancies using the Prenatal Attachment Inventory (PAI) and the Mother-to-Infant Bonding Scale (MIBS) and found that maternal-fetal attachment would have an independent and positive effects on postpartum maternal-infant attachment, with higher levels of maternal-fetal attachment during pregnancy being a protective factor for postpartum maternal-infant attachment among women with unintended pregnancies. The positive association between maternal-fetal attachment and mother-infant attachment can be confirmed regardless of the measurement tool used. Thus, maternal-fetal attachment lays the foundation for postpartum mother-infant attachment. Early identification of maternal-fetal attachment disorders during pregnancy is especially critical in order to prevent possible attachment problems in the early postpartum period. Monitoring maternal-fetal attachment levels during pregnancy and providing timely interventions for possible maternal-fetal attachment problems in pregnant women can be considered to further enhance the quality of maternal-infant attachment in the early postpartum period.

Study of the Correlation Between Maternal-Fetal Attachment and Labor Experience

Currently, only 3 foreign studies on the correlation between labor and delivery experience and maternal-fetal attachment have been retrieved. Two of them suggest that maternal-fetal attachment contributes to the emergence of postpartum labor-related PTSD symptoms. The results of a cross-sectional study in Turkey [22] showed a negative correlation between maternal-fetal attachment and postpartum labor-related PTSD symptoms. Higher maternal-fetal attachment scores were associated with fewer postpartum labor-related PTSD symptoms. The results of a study by Italian scholars such as Tani [23] showed that the quality of maternal-fetal attachment was negatively associated with negative labor experiences (use of oxytocin and analgesics and duration of labor). In addition, labor-related PTSD symptoms can positively affect maternal-fetal attachment in PMSMs. In 2019, Norwegian scholar Susan [24] administered a questionnaire to 1, 493 PMSMs on labor-related PTSD symptoms at 17 weeks and maternal-fetal attachment levels at 32 weeks, and showed that women with labor-related PTSD symptoms who became pregnant again had a more higher levels of maternal-fetal attachment. However, there is only one study on this subject, and the results need to be further confirmed.

A Study of the Correlation Between the Experience of Childbirth and Mother-Infant Attachment

Findings on the relevance of the birth experience to mother-infant attachment are not consistent, with most studies suggesting that negative birth experiences for mothers, such as posttraumatic stress disorder after childbirth, disrupt the development of the mother-infant bond. In 2020, a Japanese regional study using the Postpartum Bonding Questionnaire (PBQ) surveyed 130 mothers at 1 and 4 months postpartum and showed a positive correlation between posttraumatic stress disorder after childbirth and failure of the mother-infant bond at 1 month postpartum [25]. Ponti found [26] that postpartum PTSD symptoms caused by traumatic birth experiences negatively impacted mother-infant attachment, either directly or indirectly through postpartum depression. American scholars such as Dekel [27] showed that women with postpartum PTSD symptoms had lower mother-infant attachment scores than women without postpartum PTSD symptoms, and that postpartum PTSD symptoms can hinder the establishment of mother-infant attachment. However, there is also a study that states that negative birth experiences can improve the mother-infant relationship. American scholar Babu [28] used the Maternal Attachment Inventory (MAI) to investigate 2205 women who gave birth during the COVID-19 pandemic and 540 women who had given birth before, and found that a large proportion of mothers who had traumatic birth experiences during the COVID-19 pandemic triggered the mother’s s psychological growth, leading to an improvement in the mother-infant relationship. In addition, a few studies have indicated no association between the two. 2022, Iranian scholars Moniri [29] found no statistically significant relationship between birth experience and mother-infant attachment using the Postnatal Bonding Questionnaire (PBQ) and the Childbirth Experience Questionnaire (CEQ) in 228 pregnant women at 6 weeks postpartum. There was no statistical significance between the two. In conclusion, the contradictions between the above results may be due to differences in year, country, measurement tools applied, and time point of mother-infant attachment measurement.

The Mediating Role of the Childbirth Experience in Maternal-Fetal Attachment and Mother-Infant Attachment

Currently, foreign literature on the relationship between labor and delivery experience, maternal-fetal attachment, and mother-infant attachment suggests that labor and delivery experience plays a mediating role in maternal-fetal attachment and mother-infant attachment. However, only 2 relevant literatures were retrieved. The results of Smorti [17] and other studies showed that traumatic birth experience plays a mediating role between maternal-fetal attachment and mother-infant attachment. Adverse maternal-fetal attachment is a risk factor for traumatic birth experience, which in turn hinders the development of mother-infant attachment. Damato et al.’s study [30] found that maternal-fetal attachment indirectly affects mother-infant attachment, with the birth experience being an important variable that influences the relationship between the two. Positive maternal-fetal attachment improves a woman’s ability to cope with labor and promotes a positive birth experience, which in turn facilitates the development of positive mother-infant attachment. Due to the limited amount of literature, further research is needed.

Summary

There may be a certain connection between maternal-fetal attachment, mother-infant attachment, and labor and delivery experience. At present, the existing domestic research only focuses on maternal-fetal attachment, maternal-infant attachment, and childbirth experience individually for current research or multifactorial analysis, and there is a lack of relevant research linking the three. The existing foreign studies start from the negative birth experience, such as postpartum post-traumatic stress disorder symptoms, future research can be analyzed in depth from the perspective of positive birth experience, to explore the mediating role of positive birth experience between maternal-fetal attachment and mother-infant attachment, and at the same time, combined with the intervening factors to develop precise intervention strategies, to provide a theoretical basis and practical reference for the development of perinatal health care policies, to establish This will provide a theoretical basis and practical reference for the formulation of perinatal health care policies, establish a deep emotional connection between mother and fetus, promote positive labor experience, improve labor outcomes, and maintain the mother-infant relationship.

Fund Program

The Ministry of education of Humanities and Social Science project(22YJAZH148).

References

Cataudella S, Lampis J, Busonera A, Congia F, Melis GB, Zavattini GC. From pregnancy to 3 months after birth: the beginning of mother-infant relationship from a maternal perspectiv J Reprod Infant Psychol. 2022. [crossref]
Xiyan Zhang. Study on the status quo of maternal-fetal attachment relationship and its influencing factors in late pregnant women[D]. Shihezi University, 2021.
Tichelman E, Westerneng M, Witteveen AB, van Baar AL, van der Horst HE, de Jonge A, Berger MY, Schellevis FG, Burger H, Peters LL. Correlates of prenatal and postnatal mother-to-infant bonding quality: A systematic review. PLoS One. 2019. [crossref]
Bowlby J. Attachment and loss: retrospect and prospect. Am J Ortho Psych, 1969. [crossref]
Ruilin Zhu, Xujuan Xu, Feng ZHANG, et al. Research progress on the correlation between breastfeeding and maternal-infant attachment[J]. Evidence-based Nursing, 2023.
Shuang Luo, Huaying Yin, Meimei Wang. Study on the status and influencing factors of maternal-infant emotional connection after discharge of premature infants in neonatal intensive care unit[J]. CPNJ, 2022.
Hill R, Flanagan J. The Maternal Infant Bond: Clarifying the Concept. Int J Nurs Knowl, 2020. [crossref]
Li Lei, Huaying Yin, Judan Tan. Study on the status quo and influencing factors of mother-infant attachment in NICU premature infants during hospitalization[J]. journal of nursing science, 2020.
Cranley MS. Development of a tool for the measurement of maternal attachment during pregnancy. Nursing Research.1981. [crossref]
Muller ME,Ferketich S. Assessing the validity of the dimensions of prenatal attachment. Maternal Child Nursing Journal.1992. [crossref]
Condon JT. The assessment of antenatal emotional attachment: Development of a questionnaire instrument. British Journal of Medical Psychology.1993. [crossref]
Salmon P, Miller R, Drew NC. Women’s anticipation and experience of childbirth: the independence of fulfillment, unpleasantness and pain. Br J Med Psychol. 1990. [crossref]
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Ling Zhang. The mediating role of prenatal depression between attachment and maternal-fetal attachment in early pregnant women in late pregnancy[D]. Anhui Medical University, 2021. [crossref]
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Kennell JH, Klaus MH. Early mother-infant contact. Effects on the mother and the infant. Bull Menninger Clin. 1979. [crossref]
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Rossen L, Hutchinson D, Wilson J, Burns L, Allsop S, Elliott EJ, Jacobs S, Macdonald JA, Olsson C, Mattick RP. Maternal Bonding through Pregnancy and Postnatal: Findings from an Australian Longitudinal Study. Am J Perinatol. 2017. [crossref]
Dubber S, Reck C, Müller M, Gawlik S. Postpartum bonding: the role of perinatal depression, anxiety and maternal-fetal bonding during pregnancy. Arch Womens Ment Health. 2015. [crossref]
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Use of Cannabidiol as an Adjuvant in Veterinary Anesthesia and Pain Management in Dogs and Cats

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DOI: 10.31038/IJVB.2025913

Abstract

Objective: To review the scientific literature on the use of cannabidiol (CBD) for dogs and cats, focusing on its analgesic efficacy and potential application as an anesthetic adjuvant.

Methods: An integrative review was carried out, covering studies published in the last 10 years in international databases. Articles were included if they addressed the efficacy and safety of CBD in pain management or veterinary anesthesiology in small animals (dogs and cats).

Results: Evidence indicates that CBD may help reduce chronic pain (e.g., osteoarthritis) and improve quality of life in dogs and cats, with a favorable safety profile. However, there is a lack of specific studies in an anesthetic context, preventing definitive recommendations on protocols, doses, and formulations.

Conclusions: CBD shows relevant therapeutic potential for veterinary analgesia; however, methodological heterogeneity and the absence of robust clinical trials suggest that further research is needed to validate its use as an anesthetic coadjuvant in dogs and cats.

Keywords

Cannabidiol, Dogs, CBD, Pain, Cats, Veterinary anesthesia

Introduction

The interest in the use of Cannabis sativa-derived compounds in both human and veterinary medicine has significantly increased over the past decade [1]. Among these compounds, cannabidiol (CBD) stands out as a molecule without significant psychoactive effects, identified as a promising candidate for managing various conditions, such as chronic pain, inflammation, epilepsy, and behavioral disorders [2],[3]. In the context of veterinary medicine, studies seek to evaluate the application of CBD in both dogs and cats, focusing on safety parameters, efficacy, and practical implications [4],[5].

In recent years, the multidisciplinary approach to pain management has led to the adoption of multimodal analgesic protocols, especially in small animals [6]. In this scenario, the potential modulatory role of CBD in pain control has become a relevant topic, considering the need for adjuvant methods to reduce the use of opioids and non-steroidal anti-inflammatory drugs (NSAIDs), along with possible implications for patient safety and quality of life [7]. Additionally, the hypothesis arises that CBD could act as an adjuvant in veterinary anesthesia, minimizing anesthetic doses and reducing adverse effects [8].

However, despite promising studies, methodological heterogeneity and the limitation of large-scale randomized clinical trials hinder the establishment of clear protocols [9],[10]. Several gaps remain concerning the specific pharmacokinetics of CBD in different species, optimal dosage regimens, possible interactions with anesthetic drugs, and risks of adverse effects [11].

Thus, the present article aims to review the available literature, elucidating the efficacy and safety of CBD in dogs and cats, as well as investigating potential applications as an anesthetic adjuvant in surgical procedures. To achieve this, an integrative review of the main available studies was conducted, addressing safety parameters, analgesic profile, pharmacological interactions, and perspectives on its use in routine veterinary anesthesia.

Materials and Methods

Review Design

An integrative review was chosen, which combines data from different study types (clinical trials, systematic reviews, case reports, and narrative reviews), allowing for a comprehensive and critical synthesis of findings [12]. The integrative model was selected to encompass the plurality of methodological designs in the literature, given the scarcity of large-scale randomized clinical trials on this topic.

Data Sources and Search Strategy

The search was conducted in the PubMed, ScienceDirect, Web of Science, Scopus, and CAB Abstracts databases, covering publications from 2013 to 2023. The following Boolean descriptors were used: (cannabidiol OR CBD) AND (veterinary anesthesia OR veterinary analgesia) AND (dogs OR cats).

Additionally, Portuguese keywords such as “canabidiol”, “anestesia veterinária”, and “analgesia veterinária” were included to track national studies.

Inclusion and Exclusion Criteria

Included

Original articles (clinical trials, observational studies, pharmacokinetic studies).
Reviews (systematic, integrative, narrative) on CBD in dogs and cats related to pain or anesthesia.
Publications in English or Portuguese, with full text available.

Excluded

Studies not involving dogs or cats.
Research where CBD was not related to analgesia, pain, or veterinary anesthesia.
Low methodological quality studies, as well as duplicates or inaccessible articles.

Quality Assessment and Data Extraction

The selected articles underwent methodological screening using tools such as CASP (Critical Appraisal Skills Programme) for observational studies and reviews and RoB 2 for randomized clinical trials [13],[14]

For each article, the following details were recorded:

Target population (species, breed, number of animals).
Study design (randomized, observational, case report, etc.).
CBD dosage and administration form (oil, full-spectrum extract, isolate, etc.).
Evaluated outcomes (pain scales, anesthetic parameters, adverse effects).
Main results in terms of efficacy and safety.

The data were synthesized in tables, comparing doses used, administration periods, pain assessment scales, and occurrence of adverse effects.

Results and Discussion

Study Characterization

The initial search retrieved 2,427 records. After removal of duplicates and application of inclusion/exclusion criteria, 45 studies remained for full-text review. Among these, 24 studies were deemed relevant for this review, encompassing:

Pharmacokinetic experiments in dogs and cats,
Case reports,
Randomized clinical trials focusing on canine osteoarthritis,
General reviews on cannabinoids in veterinary medicine [15],[9],[8],&[5].

Most studies focused on CBD application in chronic conditions, such as:

Osteoarthritis
Epilepsy [16]
Behavioral disorders.

A smaller number of articles specifically addressed cats, emphasizing species-specific pharmacokinetics

Regarding anesthetic applications, only occasional mentions were found about potential benefits in perioperative analgesia, but no consolidated protocols exist

Analgesic Efficacy and CBD Pharmacology

The endocannabinoid system, primarily composed of CB1 and CB2 receptors, has been identified as a mediator of CBD’s analgesic and anti-inflammatory effects [17]

Studies in dogs with osteoarthritis indicate a reduction in pain perception and functional improvement, especially when CBD is administered at doses of 2 to 2.5 mg/kg twice daily

In cats, the literature remains limited, but case reports demonstrate pain reduction and decreased inflammatory processes in conditions such as chronic gingivostomatitis. Wang et al. (2022) evaluated the pharmacokinetics of an oral CBD/CBDA paste in felines, concluding that the acidic form (CBDA) has higher bioavailability than CBD itself, with no severe adverse effects.

Safety and Adverse Effects

Most analyzed studies indicate a favorable safety profile for CBD in the short and medium term, with mild to moderate adverse effects. Reported adverse effects include:

Transient elevation of ALT (alanine aminotransferase).
Mild sedation.
Gastrointestinal disturbances.

Caution is advised for long-term treatments, especially in animals with comorbidities, as long-term safety data remain lacking

Another concern is low-quality CBD products or those with excess THC levels, which may pose toxicity risks [18]

Anesthetic Application: Potential and Limitations

The adoption of multimodal protocols in veterinary anesthesia aims to reduce opioid, inhalant anesthetic, and NSAID doses, minimizing side effects.

In this context, CBD could assist in perioperative pain control. However, the literature lacks clinical trials assessing perioperative variables and potential interactions with traditional anesthetics.

Legal Aspects and Ethical Considerations

The expansion of CBD use in companion animals depends on the regulation of the product and the development of official guidelines

In many countries, legislation regarding veterinary cannabinoids remains unclear, making standardized prescription difficult.

Discussion

The discussion should interpret the results clearly and concisely in terms of biological mechanisms and clinical relevance, integrating the research findings with the previously published literature. Despite the growing interest in CBD, studies specifically targeting veterinary anesthesia in dogs and cats are still lacking. Existing publications focus more on chronic pain, epilepsy, and behavioral disorders [19]. The results are mainly represented in the form of tables or figures when possible. In this work, Table 1 illustrates the main findings of recent studies, highlighting aspects of dose, pharmacokinetics, efficacy, and safety of CBD in different veterinary contexts. In general, a consistent reduction in chronic pain is observed, but little standardization in perioperative use.

Table 1: Main findings of recent studies, highlighting aspects of dose, pharmacokinetics, efficacy, and safety of CBD in different veterinary contexts.

Author	Article Title	Key Findings	Main Conclusions	Journal and Reliability
ALVARENGA, I. C. et al. (2023)	Cannabidiol plasma determination and pharmacokinetics…	Evaluated CBD pharmacokinetics in dogs over 36 weeks, showing dose-dependent accumulation; higher Cmax and AUC at weeks 18 and 36.	CBD accumulates with chronic use, reinforcing the need to monitor parameters and adjust doses in long-term treatments.	Frontiers in Veterinary Science
BARTNER, L. R. et al. (2018)	Pharmacokinetics of cannabidiol administered…	Compared CBD pharmacokinetics in dogs using three administration routes and two different doses; observed absorption and half-life differences.	Highlights the importance of selecting the appropriate formulation to optimize bioavailability in dogs, even though anesthesia was not directly addressed.	Frontiers in Veterinary Science
COELHO, J. C. et al. (2023)	Placebo-Controlled Trial of Daily Oral Cannabidiol…	Placebo-controlled trial showing significant improvement in cats with chronic gingivostomatitis after receiving 4 mg CBD every 12h for 15 days, with no severe adverse effects.	CBD as an adjunctive therapy for feline gingivostomatitis demonstrated pain/inflammation reduction and a favorable safety profile.	Animals
COLTHERD, J. C. et al. (2024)	Healthy cats tolerate long-term daily feeding of Cannabidiol	26-week study on healthy cats receiving 4 mg/kg/day CBD without THC. No significant adverse effects other than transient ALT elevation at week 4, which normalized later.	Results indicate good CBD tolerance in cats long-term, but caution and veterinary monitoring are advised.	Frontiers in Veterinary Science
DEABOLD, K. A. et al. (2019)	Single-dose pharmacokinetics and preliminary safety assessment…	Evaluated pharmacokinetics and safety of a single CBD dose in dogs and cats, showing absorption differences between species and mild adverse effects.	CBD had a safe profile in a single dose, but long-term studies are needed, especially in cats.	Animals
GAMBLE, L. J. et al. (2018)	Pharmacokinetics, Safety, and Clinical Efficacy…	Reported pain reduction and mobility improvement in dogs with osteoarthritis treated with CBD (2 mg/kg BID), with few adverse effects.	Demonstrated CBD’s analgesic efficacy in canine osteoarthritis, suggesting potential use in chronic pain management, though anesthesia was not specifically addressed.	Frontiers in Veterinary Science
HU, B. (2022)	Prevalence and characteristics of cannabis-induced toxicoses in pets…	Surveyed veterinarians about cannabis-induced toxicosis; found an increase in cases after legalization, mainly in dogs that accidentally ingested THC-containing products.	Most pets recover well from accidental intoxication, emphasizing the importance of educating pet owners and standardizing products to avoid THC exposure.	PLoS ONE
KOGAN, L. R. et al. (2019)	US Veterinarians’ Knowledge, Experience, and Perception…	Surveyed veterinarians in the U.S., revealing interest in CBD but limited knowledge and concerns about legal aspects and lack of robust studies.	Highlights a gap in veterinarian training and the need for research providing solid evidence on CBD use in dogs, impacting clinical protocols.	Frontiers in Veterinary Science
LIMA, T. M. et al. (2022)	Use of cannabis in the treatment of animals…	Systematic review including randomized clinical trials on CBD for osteoarthritis, epilepsy, and behavioral issues in dogs; found CBD effective in reducing pain and seizure frequency.	Supports CBD use in dogs for osteoarthritis and epilepsy, but notes lack of robust studies and methodological limitations; anesthesia was not directly addressed.	Animal Health Research Reviews
MIRANDA-CORTÉS, A. et al. (2023)	The role of cannabinoids in pain modulation in companion animals	Discussed cannabinoids’ mechanism of action in pain modulation (CB1 and CB2 receptors), examining analgesic and anti-inflammatory effects in dogs and cats.	CBD may be effective in managing acute, chronic, and neuropathic pain, but further studies are needed to establish anesthetic protocols.	Frontiers in Veterinary Science
MONTOYA, C. (2022)	Use of cannabis in the treatment of animals…	Systematic review focusing on cannabis use in dogs (osteoarthritis, epilepsy, behavioral disorders). Found promising but heterogeneous results with potential bias risks.	Evidence supports CBD as safe and effective for some canine conditions, but standardization and anesthetic studies are lacking.	Animal Health Research Reviews
POTSCHKA, H. et al. (2022)	Cannabidiol in canine epilepsy	Analyzed CBD studies in canine epilepsy, highlighting methodological flaws in randomized clinical trials (RCTs). Found positive results in seizure reduction, though inconclusive.		The Veterinary Journal
VAUGHN, D. W. et al. (2020)	Current Evidence and Future Directions for Research into Cannabidiol…	Review of CBD’s potential applications in inflammatory conditions, epilepsy, and chronic pain, emphasizing potential benefits and methodological limitations.		Veterinary Science Development
WANG, T. et al. (2022)	Serum Cannabinoid 24 h and 1 Week Steady State Pharmacokinetic Assessment in Cats…	Found higher absorption of CBDA compared to CBD in cats, with no significant adverse effects in the short term (1 week).		Frontiers in Veterinary Science

Conclusions

This integrative review highlights the potential of cannabidiol (CBD) as a safe and effective agent for pain control in dogs and cats, especially for chronic conditions such as canine osteoarthritis and feline gingivostomatitis. Although most studies in small numbers of animals report good tolerability rates, with mild side effects, long-term investigations confirming the safety of continuous use in different age groups and in animals with comorbidities are still lacking.

Regarding the application of CBD as an anesthetic adjuvant, the scientific literature remains incipient. There are few clinical trials that analyze perioperative variables and possible interactions with traditional anesthetics, which prevents the development of well-defined anesthetic protocols. Therefore, it is recommended to conduct robust and randomized studies, including different species, breeds and surgical protocols, to evaluate essential parameters such as hemodynamic stability, reduction of opioid consumption and pain scales in the immediate postoperative period. The methodological heterogeneity found in the literature (differences in doses, formulations, study designs) compromises the direct comparison between the results and the extrapolation of the doses used. Therefore, it is essential that future studies standardize doses (in mg/kg), structure periods of use (SID, BID) and detail the form of administration (oil, paste, full-spectrum extract), as well as rigorously monitor adverse effects. Finally, the regulation of CBD for veterinary use, associated with more research involving cannabinoids, could expand therapeutic options for pain management and promoting animal welfare. The development of multimodal anesthetic protocols, with less dependence on opioids and NSAIDs, may also benefit from the advent of new analgesic strategies, such as CBD. Thus, this work contributes to highlighting the urgency of additional studies that consolidate the role of CBD in veterinary anesthesiology and pain control in companion animals.

References

KOGAN L R. et al. US Veterinarians’ Knowledge, Experience, and Perception Regarding the Use of Cannabidiol for Canine Medical Conditions. Frontiers in Veterinary Science, 2019. [crossref]
DEABOLD K A. et al. Single-dose pharmacokinetics and preliminary safety assessment with use of CBD-rich hemp nutraceutical in healthy dogs and cats. Animals, 2019. [crossref]
BARTNER LR. et al. Pharmacokinetics of cannabidiol administered by 3 delivery methods at 2 different doses to healthy dogs. Frontiers in Veterinary Science, 2018. [crossref]
COLTHERD J C. et al. Healthy cats tolerate long-term daily feeding of Cannabidiol. Frontiers in Veterinary Science, 2024.[crossref]
WANG, T. et al. Serum Cannabinoid 24 h and 1 Week Steady State Pharmacokinetic Assessment in Cats Using a CBD/CBDA Rich Hemp Paste. Frontiers in Veterinary Science, 2022. [crossref]
GAMBLE LJ. et al. Pharmacokinetics, Safety, and Clinical Efficacy of Cannabidiol Treatment in Osteoarthritic Dogs. Frontiers in Veterinary Science, 2018. [crossref]
VAUGHN D W. et al. Current Evidence and Future Directions for Research into Cannabidiol and Veterinary Medicine. Veterinary Science Development, 2020.
MIRANDA-CORTÉS A. et al. The role of cannabinoids in pain modulation in companion animals. Frontiers in Veterinary Science, 2023. [crossref]
MONTOYA C. Use of cannabis in the treatment of animals: a systematic review of randomized clinical trials. Animal Health Research Reviews, 2022. [crossref]
LIMA T M. et al. Use of cannabis in the treatment of animals: a systematic review of randomized clinical trials. Animal Health Research Reviews, 2022. [crossref]
ALVARENGA I C. et al. Cannabidiol plasma determination and pharmacokinetics conducted at beginning, middle and end of long-term supplementation of a broad-spectrum hemp oil to healthy adult dogs. Frontiers in Veterinary Science, 2023. [crossref]
MENDES K DS, SILVEIRA R C C P, GALVÃO C M. Revisão integrativa: método de pesquisa para a incorporação de evidências na saúde e na enfermagem. Texto & Contexto – Enfermagem, 2008.
OXFORD. Critical Appraisal Skills Programme (CASP). [S.l.]: Oxford Centre for Triple Value Healthcare, 2020
STERNE J A C. et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ, 2019. [crossref]
COELHO J C. et al. Placebo-Controlled Trial of Daily Oral Cannabidiol as Adjunctive Treatment for Cats with Chronic Gingivostomatitis. Animals, 2023. [crossref]
POTSCHKA H. et al. Cannabidiol in canine epilepsy. The Veterinary Journal, 2022. [crossref]
SILVER R J. The Endocannabinoid System of Animals. Animals, 2019. [crossref]
HU B. Prevalence and characteristics of cannabis-induced toxicoses in pets: Results from a survey of veterinarians in North America. PLoS ONE, 2022. [crossref]
PETZKE F, ENAX-KRUMOVA E K, HÄUSER, W. Efficacy, tolerability and safety of cannabinoids for chronic pain in adults. Der Schmerz 2016.

A Qualitative Study of Factors Influencing Medication Adherence to Anticoagulants in Patients with Atrial Fibrillation from a Behavioral Economics Perspective

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DOI: 10.31038/EDMJ.2025921

Abstract

Objective: To explore the adherence influencing factors of anticoagulant medication adherence in patients with atrial fibrillation under the perspective of behavioral economics, and to provide a reference basis for constructing an anticoagulant medication adherence improvement program for patients with atrial fibrillation.

Methods: A descriptive qualitative study was designed, semi-structured interviews were conducted with 13 patients with atrial fibrillation, and thematic analysis was used to analyze the data and refine the themes.

Results: The factors influencing medication adherence to anticoagulants in patients with atrial fibrillation can be categorized into five themes: representative bias, psychological accounts, social norms, time inconsistency preference, and optimism bias.

Conclusion: Anticoagulant medication adherence in patients with atrial fibrillation is affected by a variety of factors, and behavioral economics can be applied to the study of management strategies for patients with chronic diseases, such as atrial fibrillation, and intervention strategies can be proposed from the perspective of psychology to improve patients’ adherence to medication.

Keywords

Atrial fibrillation, Anticoagulants, Adherence, Behavioral economics, Qualitative research

Atrial Fibrillation (AF) is one of the most common arrhythmias in clinical practice. According to the results of the seventh national census published by the National Bureau of Statistics of China [1], there are at least 6.9 million AF patients in China, and the number and prevalence of AF is expected to increase even more significantly in the future as the life expectancy of human beings increases. Stroke is the most common and serious complication of AF, and studies have shown [2], that 20% to 30% of ischemic strokes are caused by AF, and patients with ischemic stroke caused by AF have a higher rate of death and disability than non- AF patients, and require 0.5 times higher medical costs.

Oral anticoagulant therapy is the treatment of choice for stroke prevention in atrial fibrillation recommended by today’s national and international guidelines. In addition to reducing stroke risk and stroke severity in patients with AF, oral anticoagulant therapy also reduces the risk of AF-associated dementia [3], Oral anticoagulant therapy is the treatment of choice for stroke prevention in atrial fibrillation recommended by today’s national and international guidelines. In addition to reducing stroke risk and stroke severity in patients with AF, oral anticoagulant therapy also reduces the risk of AF-associated dementia [4], and adherence decreases with increasing age. Therefore, it is crucial to understand the factors influencing adherence to anticoagulant medication in patients with atrial fibrillation.

Behavioral economics is a combination of economics, psychology, sociology and other disciplines developed a cross-disciplinary, used to describe the decision-making behavior of individuals [5], in the study of human decision-making behavior, behavioral economics focus is not on the correctness or incorrectness of the decision itself, but rather to make a decision on the individual’s cognitive and psychological activity behavior. Behavioral economics theory uses cognitive mode and reflective mode preferences to help individuals make rational choices [6], showing more advantages in intervening in people’s decision-making behavior, which is not easy to cause individuals to resist the psychology, and the cost is low, which can promote individuals to make better decisions.

Therefore, this study introduces the behavioral economics perspective into the study of factors influencing treatment adherence in patients with atrial fibrillation, and adopts a qualitative research approach, aiming at obtaining more comprehensive factors influencing adherence in patients with atrial fibrillation, with a view to providing references and lessons for scholars in China to develop strategies for the management of adherence to anticoagulant drugs in patients with atrial fibrillation.

Objects and Methods

Objects

Purposive sampling method was used to select patients with atrial fibrillation who met the criteria for natriuresis from February to August 2024 in a tertiary hospital in Hangzhou City as the interview subjects. The study was reviewed by the Ethics Committee. Inclusion criteria: (1) Age >18 years old. With good language skills; (2) taking oral anticoagulants for >6 months; (3) voluntary participation in this study. Exclusion criteria: (1) presence of mental illness, hearing impairment, or intellectual disability; (2) inability to accept audio recording during the interview; (3) serious physical condition that prevented cooperation with the interviewer. Sampling was carried out following the principle of maximizing differences, and the sample size was used until the information was saturated. Thirteen interview subjects were finally included, 8 male and 5 female; ages 38 to 80 (57.38±10.744); 6 patients with junior high school or lower education and literacy, 4 high school, 2 secondary school or college, and 1 university; 9 patients currently residing in the city and 4 currently residing in the countryside; 4 patients living alone, 9 patients not living alone; 8 patients using urban and rural residents’ health insurance, and 5 used employee health insurance; 5 patients were on warfarin and 8 patients were on new oral anticoagulants; years of illness ranged from 1 to 10 years (5.15±2.672); 4 patients had a number of combined other diseases ≤1, 4 patients had a combination of 2 other diseases, and 3 patients had a combination of 3 or more other diseases.

Methods

Preparation of Interview Outlines

According to the research purpose, theory, and related literature research content of this study, the preliminary outline of the interview was drawn up after consulting the experts, and the outline was revised according to the preliminary literature research and the results of the pre-interviews of the two cases, and the outline of the interview was finally determined: (1) How has long-term use of anticoagulant medication brought about an impact on your life? (2) What are the current therapeutic drugs? (3) What factors do you focus on during the medication process? (What factors would make you feel that the drug is working) (4) Have you ever missed or stopped taking your medication on your own, and what was the reason? What did you do when you realized that you missed a dose? (5) Do you have any concerns when taking anticoagulants? (6) What difficulties have you encountered in the use of your medication? Who would you like to bring in to support you in these difficulties? (7) What are some of the factors that prevent you from adhering to your medication? (8) What do you think would help you to be more adherent to your anticoagulant medication? (Family members/healthcare professionals/patients/ society) (9) Do you usually know something about medication? Which aspects of knowledge do you pay more attention to? In what way do you usually learn about the disease?

Methods of Data Collection

The researcher conducted the qualitative interviews by contacting suitable interviewees in advance and booking the time and place for the interviews. Face-to-face semi-structured interviews were used, each interview lasted 30-45 minutes, and the whole interview process was audio-recorded. The interviews were conducted by the same researcher who had systematically studied qualitative research, and the researcher communicated with the interviewees in the form of questioning and answering according to the interview outlines, and adjusted the order of the outlines and asked follow-up questions according to the interviewees’ answers, in order to collect as much information as possible in the interviews.

Methods of Data Analysis

The qualitative interview data were transcribed verbatim within 24 hours of the end of the interview, and the audio recordings were listened to repeatedly to ensure the accuracy of the transcription and to supplement the interviewee’s tone of voice, etc., in conjunction with the interview transcripts. The transcribed text was then imported into Nvivo 12.0 software for management, coding, and analysis. Both transcription and analysis of the data were carried out independently by two researchers, and when disagreements existed, they were discussed and a third researcher was asked to reach a consensus. Thematic analysis was used to analyze the interview data, and data collection was synchronized with data analysis.

Findings

By analyzing and distilling the interview data of 13 patients with atrial fibrillation who were undergoing oral anticoagulant therapy, the influences on adherence to anticoagulant therapy in patients with atrial fibrillation were finally summarized into five themes.

Theme 1: Influenced by Representativeness Bias

Due to insufficient knowledge of AF and anticoagulants, patients are easily influenced by the experiences or descriptions of people around them and use the situation of a small sample to infer the situation of a large sample, thus ignoring the a priori probability, leading to poor decision-making and discontinuing medication on their own. Some patients with weak awareness of medication safety will choose whether to take medication based on their own experience, and some subjects found that a small number of people around them taking anticoagulants still experienced vascular adverse events, then they will ignore the a priori probability, and will question the efficacy and safety of anticoagulant drugs a priori: N4: “Isn’t there still a person who has taken the medication or had a cerebral infarction, a lot of, nothing to do with this medication. ” There were also subjects who believed that if other patients did not take anticoagulants without vascular adverse events, then they themselves could not adhere to the medication: N13: “There is a person in our village who also has a bad heart, for many years, did not take the medication, and now he has not had an attack.”

Complex Knowledge of Atrial Fibrillation and Anticoagulants

The reason for patients’ representative cognitive bias is partly because the knowledge related to atrial fibrillation and anticoagulants is too complex, and there are many drugs and foods that tend to react with anticoagulants, and it is difficult for patients who lack a professional medical background to fully grasp them, N1: “Atrial fibrillation those are professional knowledge, doctors they only know, and I haven’t read much, so how can I remember it. ” N6: “The doctor also talked to me about it, the usefulness of this medicine and so on, but after two days I forget.”

Lack of Access to Specialized Knowledge

Secondly, it is because patients lack channels to obtain specialized information. Some patients lack the subjective initiative to obtain disease-related knowledge, the doctor is the only way for most patients to obtain professional knowledge, N3: “The doctor told me how to eat how I eat, I do not understand.” “The doctor said is not very detailed, side effects and so on I do not quite understand, Baidu asked to see you do not dare to believe.” N8: “Still trust the doctor a little more, that is to say that the knowledge of the Internet may not be accurate.”

When the doctor failed to meet the needs of patients to obtain knowledge related to medication, some patients in order to obtain professional advice will choose to go online to seek help, however, the medical information on the network is difficult to distinguish between true and false, mixed, when the patient is difficult to identify the correct information, it will be blindly seeking medical treatment, N10: “I saw on TV, the kind of health program sold, said that the cardiovascular benefits, I would like to buy to try. I just want to buy it and try it.”

Theme 2: Influenced by Psychological Accounts

Patients will pre-divide the expenditure of the funds they have into several categories such as travel, medical care, daily expenses, etc. When the actual expenditure of patients for the treatment of atrial fibrillation exceeds their own psychological budget, there is a probability that they will choose to be non-compliant. Most atrial fibrillation patients are middle-aged or elderly and suffer from multiple chronic diseases, requiring long-term use of three or more medications. With the progression of the disease, the economic burden brought by long-term medication gradually increases, leading to negative emotions towards medication, thus affecting patients’ compliance with medication. n2: “If I take one box of dabigatran a day, I’ll take that imported box of 160, and that’s 6 boxes a month, and that’s a thousand boxes. If I take one box of Dabigatran a day, and I take that imported box of more than 160, that’s 6 boxes a month, that’s a thousand dollars.”

However, some patients still insist on taking medication even when their medical expenses exceed their psychological accounts, probably because medical expenses are different from daily expenses and are related to the safety of patients’ lives, so even if they spend more money, some patients still insist on taking treatment. N8: “The medication is definitely a little bit expensive, and there’s no way to cure the disease, the doctor said to keep taking it. ”

Theme 3: Influenced by Social Norms

Social norms are a standard of behavior for social members in a social group, which can constrain and guide individual behavior by influencing the decision-making behavior of social members [7]. The influence of social norms on the medication-taking behavior of patients with atrial fibrillation (AF) depends on the ability to be aware of other patients with AF taking their medication, understanding what to do as a patient with AF, and the perception of other people if they do not take their medication on time.

When patients with atrial fibrillation perceive social norms, i.e., realize that other patients with atrial fibrillation take their anticoagulant medications consistently and have a good prognosis, they realize the importance of adhering to their medications and the consequences of not adhering to their medications. However, most of the patients in this study did not take the initiative to communicate with other patients about their condition and did not know about the treatment of other patients. N10: “I usually don’t know much about the treatment of other patients and I don’t communicate with others about their condition.” N11: “What kind of medicines other people take, how many boxes a month, this kind of thing is after all other people’s privacy, and I don’t feel too good to ask.”

Some patients recognize that not taking medication as prescribed will bring greater financial and living burdens to their families, and out of a sense of responsibility to their family members, this group of patients has a high level of compliance, N12: “If I don’t stick to the medication, I’ll spend more money if I’m re-hospitalized, and my family will have to take time off from work to come to stay with me in bed.” However, there are also some patients who are not able to realize what patients with atrial fibrillation should do to comply with the doctor’s instructions, and increase or decrease their medication on their own according to their own experience, N5: “It feels that atrial fibrillation is not as serious as other heart diseases, and that I have to have an operation or something.” N2: “Originally the amount of two tablets at a time, I changed it to one tablet at a time by myself, sometimes a bit of chest tightness other than that there is no discomfort.”

Theme 4: Influenced by Inconsistent Time Preferences

Atrial fibrillation has a long course and develops slowly, and anticoagulation management requires long-term medication and adherence to healthy lifestyle habits, which costs a lot of time and money; however, anticoagulant medications are slow to work, and the benefits of adherence to medication are not immediately perceived, and patients have a poor sense of benefit from treatment in the moment, N9: “I took antihypertensive medication in the morning, and my BP came down that day, and I took rivaroxaban for a while It didn’t feel like it was helping.” In this case, patients with AF are faced with the intertemporal decision between investing large amounts of healthcare resources in the long term to improve cardiovascular status in the future, or investing a small amount of healthcare resources in the short term in exchange for a short-term reduction in overall healthcare expenditures and a reduction in the burden on the family, which, when encountered by patients with intertemporal decision- making, is influenced by the preference for temporal incoherence and can result in a tendency to choose the immediate reward of the undesirable behavior. choose the immediate rewards from bad behaviors and ignore the long-term benefits from healthy behaviors. N5: “Just then the frequency of checkups was very high, once a month, but now it may be slightly less, a few times a year, maybe because it was not very convenient during that time of the epidemic, and I just think that once a month is a bit of a hassle as well.” N6: “To check the hospital you have to go in and get blood drawn, you have to queue up, and then you have to wait for the results or something, half a day is gone, and my son has to go to work and doesn’t have that much time.”

Theme 5: Influenced by Optimism Bias

Even when recognizing that poor behavioral habits can affect their health, some patients remain optimistic that their risk of being harmed by such behaviors is lower than that of other patients, N3: “I didn’t even take any medication for my previous new crown, I made it through on my own, I’m in good shape with my resistance.” N7: “I’ll be fine with one or two less meals, I’m in good shape.” The reason for this is the influence of the optimism bias that one is less likely to have an obstructive vascular event than others [8].

Discussion

Enhancing Patient Health Education to Change Medication Beliefs and Perceptions

This study found that some patients with atrial fibrillation are affected by their own cultural limitations, health education is not in place and other factors, most patients do not have enough knowledge about atrial fibrillation and anticoagulant drugs, which leads to some patients questioning the efficacy and safety of anticoagulant drugs, resulting in some patients stopping their medication by themselves or increasing or decreasing the medication by themselves. Some studies have shown [9] that only when patients have a certain understanding of the drug, they can have positive beliefs about taking the drug, which will lead to the improvement of adherence. Behavioral economics theory suggests that human rationality is limited, and limited attention and memory are not enough to remember and process all the health information. Therefore, when conducting health education, the actual situation of patients’ literacy level and age should be considered, and the content of the education needs to be simple, direct, and relevant, in order to make the patients remember the information at the critical moment of decision-making. Some scholars have utilized vivid drawings and short words instead of complex medical knowledge to educate elderly patients with atrial fibrillation about anticoagulants, which effectively improved the anticoagulation compliance and self- management ability of elderly patients with atrial fibrillation [6] Tutorials such as brochures, educational videos, websites, software, lectures, and WeChat have also been proven to be an effective form of improving patients’ cognitive level, which suggests that clinical workers should combine diversified tutorials according to patients’ characteristics to improve the efficiency of the tutorials, improve the correct knowledge of anticoagulant drugs in patients with atrial fibrillation, reduce the uncertainty of the disease in patients with atrial fibrillation, and avoid representative cognitive bias and optimistic bias in the patients.

Promoting Socially Normative Behaviors to Change the Decision-making Environment

Behavioral economics theory suggests that individuals are influenced by the social environment in which they live and that their decision-making behavior is not only motivated by self-interest, but is also driven by group perceptions, whereby if other people act in accordance with a certain socially accepted behavioral norm, then that person is perceived as behaving appropriately, and conversely if they don’t, then they are disapproved [10]. However the extent to which an individual is influenced by social norms depends on the degree of interaction between the individual and the social environment. Social norms have been used by foreign scholars on studies of health promoting behaviors and have been remarkably successful [11]. In a study at the University of California, San Francisco, adolescents’ attitudes toward type 2 diabetes were effectively changed by establishing an online platform to promote mutual communication among adolescents, and organizing seminars and distributing public service advertisements to promote the dissemination of healthy behaviors, which showed that most of the adolescents were willing to change their poor living and dietary habits for the purpose of preventing diabetes due to the influence of their social environmen. This suggests that we can use the Internet and social media to promote and disseminate knowledge about atrial fibrillation and anticoagulant drugs, improve patient acceptance of anticoagulant drugs, and make standardized medication regimen a widely accepted social normative behavior for patients with atrial fibrillation; at the same time, the formation of a patient group of patients with atrial fibrillation, encouraging patients to communicate with each other, and inspiring patients to maintain a positive image of adherence to medication.

Fixing Current Preferences and Providing Extrinsic Motivation

Behavioral economics also refers to human time-inconsistent preferences as self-control problems, procrastination problems, problems with the short-term self and the long-term self, and when patients with atrial fibrillation have time-inconsistent preferences, they fail to adhere to their medication due to self-control problems, even if their knowledge of anticoagulant medication is correct [13]. Incentive strategy is the most widely used intervention strategy in studies on behavioral economics [14] for example, scholar Sebastian Linnemayr [15] used a small raffie incentive to intervene with young Ugandan AIDS patients, where weekly text messages would be sent to remind participants that antiretroviral therapy (ART) monitoring compliance would be eligible to participate in a raffie, and eventually ART adherence improved significantly; Barbara Riegel [16] used a telemedicine intervention, where patients were reminded to take their medication at a specified time every day via a smart device, and the medication record was monitored using an electronic bottle cap, and after 90 days of intervention, medication adherence improved significantly, and the rate of re-hospitalization was reduced significantly. This suggests that clinicians can improve anticoagulant medication adherence by motivating patients with atrial fibrillation to adopt healthy behaviors immediately through immediate rewards or regular feedback, and by translating long-term goals into multiple short-term goals, thereby overcoming individual time-inconsistent preferences.

Summary

This study started from the perspective of behavioral economics theory to explore the influencing factors of anticoagulant medication adherence in patients with atrial fibrillation, and ultimately refined the five themes of influencing factors, which suggests that clinical workers should pay attention to influencing the adherence to anticoagulant medication in patients with atrial fibrillation from multiple perspectives. In future research, behavioral economics can be applied to the study of management strategies for patients with chronic diseases such as atrial fibrillation, and intervention strategies can be proposed from the perspective of psychology to improve the subjective initiative of patients, as well as to improve the efficiency of long-term management of chronic diseases.

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Increased Plasma Serotonin 2A Receptor Autoantibodies Predicts Significant One-year Cognitive Decline in Middle-aged Adult Traumatic Brain Injury

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DOI: 10.31038/EDMJ.2025914

Introduction

Traumatic brain injury (TBI) contributes to substantially increased global disability [1] and has been associated with major depressive disorder and dementia [2] through unknown mechanisms. Chronic inflammation increased autoantibodies to a serotonin 2A receptor from older adult TBI patients suffering with accelerated cognitive decline over a two-year period [3]. Because middle-age (post 9/11 military veterans) who were exposed to multiple TBIs can experience even more rapid cognitive decline, here we tested whether baseline plasma serotonin 2A receptor autoantibodies (AA) predicts 1-year rate of decline in global cognitive functions or in pattern separation, a dentate gyrus dependent behavior. Biomarker that could predict subset of younger adult TBI at higher risk for accelerated cognitive decline would be useful in future evaluation of candidate neuroprotective treatments.

Participants and Methods

TBI Patients

Informed consent for the local Institutional Review Board- approved study was obtained from all participants prior to blood drawing or cognitive testing. Thirty-four middle-aged, adult TBI patients (40-60, mean 49.9 years old) including 33 male and 1 female participant enrolled in the study. Many of the post-9/11 U.S. military veterans had experienced repeated TBI exposures including direct force, blast or both kinds of TBI injury. Only one patient had experienced moderately-severe TBI, most of the other injuries were mild TBI. Thirty-three of thirty-four participants had baseline blood drawing for determination of plasma autoantibodies.

Protein-A Affinity Chromatography

Protein-A affinity chromatography was used to isolate the IgG fraction of plasma [4] in thirty-three middle-aged adults who had experienced one or more TBI exposures. The IgG fraction (1/40^th dilution=7.5 ug/mL) was stored at 0-4 degree C prior to determination of autoantibody level.

Peptide

A linear synthetic peptide corresponding to the second extracellular loop of the human 5HT2AR (QN..18) was synthesized at Lifetein, Inc (Hillsborough, NJ). The peptide had purity > 95% and was stored under desiccated conditions at −40 degrees C.. On the day of an enzyme-linked immunoassay experiment, an aliquot of lyophilized peptide was dissolved in sterile deionized water prior to immunoassay or bioassay.

Enzyme Linked Immunoassay

Enzyme Linked Immunoassay was performed as previously described using the QN..18 second extracellular loop of the 5HT2AR [5] as the target peptide antigen. Increased autoantibody binding in the QN..18 immunoassay was previously reported to correlate with neurotoxicity in a bioassay employing mouse N2A neuroblastoma cells [5] consistent with an agonist role for the circulating 5HT2A receptor autoantibodies.

Cognitive Tests

One year change in cognitive test performance was calculated as the [One year test score – baseline test score]. Higher one-year change in test score is indicative of improved performance with the exception of the Trail-making Part B in which longer time to task completion reflects worsening executive function.

Statistics

Statistical analysis was performed using unpaired Students’ t-test.

Results and Discussion

Baseline Plasma Serotonin 2A R Autoantibodies

Thirty-three TBI patients underwent baseline determination of plasma 5HT2AR AAB and completed baseline and one-year cognitive testing: St Louis University Mental Status Test (SLUMS) of working memory; digit symbol substitution test (DSST) of processing speed; and the behavioral pattern separation object task (BPS-O), a dentate gyrus hippocampal- dependent test.

Ten of thirty-three TBI patients (30.0%) had elevated plasma 5HT2AR AAB (i.e. binding of 1.5-fold background or higher; and 10/33 patients had no detectable plasma AAB (binding </= 1.25-fold background) (Figure 1). The mean one-year rate of change in SLUMs test declined significantly in AAB-positive vs AAB-negative TBI patients (-2.6 ± 2.47 vs 0.6 ± 1.62; P = 0.004) (Figure 2). Two of ten AAB-positive TBI patients experienced large one-year declines in SLUMs score to a level below the cut-off for dementia (not shown in Figure 2). The mean one-year rate of change in performance on the Trail-making Test, Part B (a measure of executive function) also worsened significantly in AAB- positive vs AAB-negative TBI patients (9.7 vs -13.4 sec; P = 0.04) (Figure 3). In the TMT-B test increased time (to task completion) is indicative of declining executive function. One-year change in performance on the DSST ( -1.5 vs 4.7; P = 0.02) also declined significantly in AAB-positive vs -negative TBI patients (Figure 4).

A 1/40^th dilution of the protein-A eluate fraction from human TBI plasma was tested for binding to the second extracellular 5HT2A receptor peptide. Background absorbance was 0.04 AU. Undetectable binding was defined as 0-1.25 times background; increase binding was defined as 1.5 times or more above background. The solid lines indicate the upper limits of undetectable (5HT2AR AAB negative) and lower limit of high binding (5HT2AR AAB positive) in the immunoassay.
Figure 1: Distribution of binding to the human 5HT2A receptor second extracellular loop peptide (QN..18) in enzyme linked immunosorbent assay.

Results are mean ± SD.
Figure 2: Significant association between baseline presence of 5HT2AR autoantibodies and significant mean one-year decline in SLUMs score.

Results are mean ± SD.
Figure 3: Significant association between baseline presence of 5HT2AR AAB and one-year decline in Trail-making Part B test performance.

Results are mean ± SD.
Figure 4: Significant association between baseline presence of 5HT2AR AAB and one-year decline in digit symbol substitution test performance.

Behavioral pattern separation object task is a dentate gyrus, hippocampal- dependent component of working memory which was reported to be age-dependent [6] and decline significantly with mild cognitive dysfunction in a small subset of older (75 yr old) adults [6]. Dentate gyrus newborn neurons express 5HT2A receptor, and autoantibodies from diabetic depression patients inhibited dendrite extension and decreased survival in cultured rat DG neurons [7]. Here we tested for a possible association between baseline presence of plasma 5HT2AR autoantibodies and 1-year change in performance on the BPS object task. Bias on the BPS task is a measure of the ratio of correct responses to lure (similar object) vs similar responses to the foil (a completely new object). A bias ratio of 1 is indicative of complete pattern separation and a ratio of 0 is consistent with complete loss of pattern separation. In nineteen TBI patients who completed baseline and 1-year pattern separation tests, there was no significant difference in one-year rate of change in BPS-O in 5-HT2AR AAB-positive vs -negative TBI patients (5.7 ± 3 vs 3.0 ± 7); (P > 0.05) (Figure 5).

Results are mean ± SD.
Figure 5: Lack of significant association between baseline presence of 5HT2AR AAB and one-year change in behavioral pattern separation object task performance.

There was no significant association between one-year rate of change in BPS-O and one-year rate of change in SLUMS test (Figure 6). Baseline BPS-O scores were widely- ranging in middle-aged TBI patients consistent with prior report of high degree of individual differences on pattern separation, object task [6] (Figure 7). Many middle-aged TBI patients had relatively preserved one-year BPS scores even though they had already experienced significant declines in the other cognitive tests of memory recall, executive function and processing speed. This suggests that in younger adult TBI population age 40-60, pattern separation may be less useful as an indicator of early cognitive decline than the SLUMS, Trail-making Part B and digit symbol substitution tests.

Figure 6: Lack of significant association between one-year rate of change in behavioral pattern separation and SLUMS test performance.

Figure 7: Distribution of baseline behavioral pattern separation test scores in 34 middle aged adult TBI patients.

In summary, the current results suggest that middle-aged adult TBI patients (age 40-60 years) (including those exposed to repeated TBI) can experience significant cognitive decline after a relatively short time period (one year) and that baseline presence of plasma 5HT2AR AAB was a significant predictor of cognitive decline across three different cognitive domains.

Acknowledgments

The study was supported by a grant (CBIR22PIL016) from the New Jersey Commission on Brain Injury Research (Trenton, New Jersey) to Dr. Mark Zimering.

The authors report no competing interests with any products or techniques employed in this study.

References

Ilie G, Adlaf EM, Mann RE, et al. (2018) Associations between self-reported lifetime history of traumatic brain injuries and current disability assessment in a population sample of Canadian adults, PLoS One. [crossref]
Kaup AR, Peltz C, Kenney K, Kramer JH, Diaz-Arrastia R, Yaffe K (2017) Neuropsychological Profile of Lifetime Traumatic Brain Injury in Older Veterans. J Int Neuropsychol Soc. 2017 [crossref]
Zimering MB, Grinberg M, Myers CE, Bahn G (2022) Plasma Serotonin 2A Receptor Autoantibodies Predict Rapid, Substantial Decline in Neurocognitive Performance in Older Adult Veterans with Endocrinol Diabetes Metab J. 2022 [crossref]
Zimering MB (2018) Circulating Neurotoxic 5-HT2A Receptor Agonist Autoantibodies in Adult Type 2 Diabetes with Parkinson’s Disease. J Endocrinol Diabetes. 2018 [crossref]
Zimering MB (2019) Autoantibodies in Type-2 Diabetes having Neurovascular Complications Bind to the Second Extracellular Loop of the 5-Hydroxytryptamine 2A Endocrinol Diabetes Metab J. 2019 [crossref]
Stark SM, Yassa MA, Lacy JW, Stark CE (2013) A task to assess behavioral pattern separation (BPS) in humans: Data from healthy aging and mild cognitive impairment. Neuropsychologia. 2013 [crossref]
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