Early Diagnosis Research Articles

Continuous monitoring of heart failure biomarker using a sensitive graphene-based electrical sensor

Abstract Heart Failure (HF) is a complex condition that imposes significant burdens on both patients and healthcare systems. The economic impact of HF therapy and management is substantial, underscoring the urgency for proactive measures to mitigate its development. Regular assessments play a pivotal role in identifying individuals at risk and initiating timely interventions to prevent or delay HF progression [1, 2]. NT-proBNP, an amine-terminated form of brain natriuretic peptide, emerges as a promising biomarker in the realm of chronic HF diagnosis, prognosis, and risk assessment [3]. Its utility lies in providing valuable insights into disease progression and prognosis. In recent years, biosensors based on Field Effect Transistors with Graphene (Gr) gate (GFET) have garnered attention for their rapid response, sensitivity, and on-chip integration [4]. Here, we present a sensitive miniaturized GFET sensor for continuous NT-proBNP measurement. The sensor is an array of GFET devices with sensing gates of a monolayer Gr decorated with aptamers as catch probes. Averaging over similar devices in an array approach ensures measurement consistency throughout the experiment. Moreover, the significant challenge posed by the Debye length in FET biosensors is effectively addressed through the functionalization with short folding aptamers [4]. The sensor is built based on a chip comprising an array of 28 individual micro GFETs (Fig. 1a). For the functionalization of Gr gates, we utilized 1-pyrene butyric acid N-hydroxysuccinimide ester as a linker between the aptamer probes and the Gr surface. Subsequently, the Gr surface was incubated with an amine-terminated aptamer solution (Fig. 1c). A schematic diagram of the sensory chip having a droplet of the sample is shown in Fig. 1b. To quantify NT-proBNP levels an 8µL droplet of the buffer solution containing a specific NT-proBNP concentration was deposited onto the sensor. The drain current (IDS) served as the sensor signal for each target concentration (Figs. 2a and 2b). The sensor signal decreased with increasing target concentration, while negligible response was observed when injecting blank buffers. This phenomenon can be attributed to the folding of aptamers upon binding to their target. Also, continuous measurement was conducted at a fixed gate voltage of 0.9V, recording the drain current while the target concentration gradually increased in the sample droplet. This process revealed a decrease in sensor current as we expected (Fig. 2c). The sensor exhibits remarkably low detection limits of 50 pg/mL and a linear range from 100 pg/mL to 10 ng/mL, which are highly conducive for early HF diagnosis and aligning well with reported NT-proBNP levels in patient biofluid [5]. The proposed sensor holds promise as a wearable device for continuous monitoring of high-risk patients. Additionally, this technology shows potential as a detection tool for acute heart failure in hospitalized patients.Sensor viewSensor responses

Synthetic assessment of cardiac autonomic modulation and Baevsky stress index in patients with synucleinopathies

Abstract Background The Baevsky Stress Index (BSTRi), calculated from Heart Rate Variability (HRV) data, has been proposed for quantitative assessment of physiological stress, with higher scores indicating higher levels of physical and/or psychological stress [1]. Cardiac autonomic modulation can be synthetically quantified by calculating the parasympathetic (PNSi) and the sympathetic (SNSi) indexes. The values of the BSTRi, SNSi, and PNSi in patients with synucleinopathies of different prognoses have not been reported yet. Purpose To quantify, in patients with Parkinson's disease (PD) and Multisystem Atrophy (MSA), the BSTRi, its correlation with the PNSi and the SNSi indexes, and their potential value for a synthetic assessment of cardiac autonomic modulation and early differential diagnosis between PD and MSA. Methods Holter ECG data of 66 patients with Parkinsonian syndromes were retrospectively analyzed after 10 years of follow-up. Out of them, 34 patients with a certain diagnosis of PD (17) and MSA (17) were selected for this study. HRV was analyzed with the Kubios software (version 4.0), providing automatic calculation of the BSTRi, PNSi, and SNSi [2], as well as of time domain (TD), frequency domain (FD), nonlinear (NL), and time-varying (TV) HRV parameters. HRV was calculated from selected short-term intervals (of 5 minutes), during daily activity (ACT5’), and non-REM sleep (NREM5’), and from 24-hours Holter recordings. Patients’ HRV findings were compared with those of 51 age-matched healthy subjects (HS). Results An example of individual automatic graphic summary is shown in Figure 1. Both short-term and 24-hour BSTRi and SNSi values were significantly (p < 0.05) higher in PD and MSA compared to those of HS, in all investigated conditions. Short-term PNSi was significantly higher in HS than in PD in all conditions, but only during NREM5’ in MSA patients (Table 1). No significant difference was found between the indexes of PD and MSA patients. As in HS (R=92), BSTRi was positively correlated with the SNSi in MSA (average R= 0.83 and 0.89 during ACT5’ and NREM5’, respectively), but less evident in PD (R=0.67). The inverse correlation between PNSi and SNSi (R=0.75 in HS) was lost in both MSA and PD. Conclusions Higher values of BSTRi in PD and MSA compared to HS suggest that patients with synucleinopathies do experience higher levels of psychophysiological stress, which may affect their quality of life negatively. However, since no significant difference was found in this study between BSTRi values of PD and MSA patients, BSTRi seems at present unreliable for early differentiation between the two diseases. Telematic assessment of BSTRi, SNSi, and PNSi could be useful for remote monitoring of PD and MSA patients’ psychophysiological stress, to provide timely intervention and adaptive treatment.Fig.1 Example of graphic summary (ACT5')

Monitoring inequities using routine administrative data: a case study of cancer screening in Ontario, Canada

Abstract Routine cancer screening is a critical primary care service to reduce cancer morbidity and mortality, through early detection, diagnosis, and treatment. We evaluated longitudinal changes in socioeconomic inequities in cancer screening in Ontario, Canada, by using linked provincial health administrative databases including 15.9 million records eligible for cancer screening. The rate of colorectal cancer screening increased between 2011 and 2020 (54% to 62%) with a reduction in the indices of inequity (slope index, SII: from 0.36 to 0.33; relative index of inequity, RII: from 0.69 to 0.54). However, the rate of cervical cancer screening decreased (from 76% to 68%), particularly in deprived areas (RII increasing from 0.47 to 0.54). Access to cancer screening is a challenge in deprived areas. Understanding the socio-economic determinants in access to screening across the life course can help develop tailored interventions to increase health equity.

Co-designed study with the Traveller Community in Ireland to determine cancer awareness & attitudes

Abstract Background Irish Travellers are a distinct ethnic minority group (formal recognition March 2017). They experience higher mortality than the general population at all ages for all causes of death. Study Aim To determine cancer awareness and attitudes among the Traveller Community in Ireland, and to identify barriers/enablers to cancer risk reduction behaviours and early diagnosis of cancer. Methods A co-designed multi-method study was developed in collaboration with Pavee Point, a national NGO for Travellers, the National Social Inclusion Office (NSIO) and the National Cancer Control Programme (NCCP) including: 1. Consultation with Pavee Point and NSIO representatives to inform the study proposal and methodology. 2. Co-design of methodology for ethics applications and subsequent data collection plan including interview topic guides and the development of a culturally appropriate version of the NCCP’s 2022 National Survey on Cancer Awareness, adding questions on social determinants of health and screening participation. 3. Collaboration with 12 peer-led Primary Health Care for Travellers Projects (PHCTPs), to provide in-person training for Traveller Community Health Workers to undertake a cross-sectional survey of 380 adult Travellers. 4. Collaboration with PHCTPs to undertake 20 semi-structured interviews with Travellers. 5. Conduct of semi-structured interviews with healthcare professionals to explore perceptions of barriers/enablers for Travellers engaging with the health system. Lessons Learned Working closely and collaboratively with our study partners, we gained valuable insights which enabled effective and efficient data collection across 8 counties, while exceeding our survey target sample size. Implications for Research: Collaborative, trusting, and respectful relationships are critical for all studies, but particularly when working with minority groups. Conclusions The study findings will inform policy for improved cancer outcomes among Travellers in Ireland. Key messages • Formation of a collaborative and respectful relationship with the Traveller community has facilitated successful research. • Traveller Community Health Workers (peer researchers) were key to the success of data collection.

Cardiac transthyretin amyloidosis in patients with conduction system disease

Abstract Background/Introduction Cardiac amyloidosis (CA) is characterized by extracellular deposition of misfolded proteins in the heart. The data suggest that cardiac amyloidosis is underappreciated as a cause of common cardiac diseases or syndromes. More than 98% of currently diagnosed cardiac amyloidosis result from fibrils consisting of monoclonal immunoglobulin light chains (AL) or transthyretin (ATTR). The natural history of ATTR cardiomyopathy commonly includes both the conduction system disease and arrhythmias, which may occur years before the onset of heart failure. Conduction abnormalities are commonly encountered among patients with CA and constitute an important cause of morbidity and mortality. Most reports agree that pacemakers are most common in wild type ATTR-CA, followed by hereditary ATTR-CA and, finally, AL-CA. Purpose As unexplained LV wall thickness ≥ 12 mm is a screening sign of possible cardiac ATTR, systematicscreening for CA in patients requiring permanent pacemakers with unexplained LV wall thickness of ≥ 12 mm seems to be rational and could possibly lead to early diagnosis of cardiac ATTR. To the best of our knowledge, the usefulness of such screening has not been investigated before. This project, therefore, aims to determine the prevalence of cardiac ATTR and its subtypes in this preselected group, and to propose the most suitable battery of diagnostic procedures for this purpose. Methods Population to be tested: Consecutive patients ≥50 years referred for permanent pacemaker implantation with unexplained LV wall thickness ≥12 mm determined by echocardiography. The research protocol was that of an open-label prospective study. Biochemistry samples including serum troponin I and NT-proBNP were collected before pacemaker implantation. All patients were screened for ATTR-CA according to the recommendations of the Position statement of the ESC Working group on myocardial and pericardial diseases. Tc-DPD scintigraphy scan served as a gold standard for determining the diagnosis of cardiac ATTR. Results Out of 100 consecutive patients meeting inclusion criteria, 15 % suffered from amyloidosis (12 patients were diagnosed with ATTR and 3 with AL cardiac amyloidosis). Table 1 shows a variety of parameters, many of which differed between patient groups with and without amyloidosis, confirming the wide range of parameters significantly associated with cardiac amyloidosis; our ongoing research in this field could lead to the development of a scoring system for detection of cardiac amyloidosis. Conclusions The prevalence of cardiac amyloidosis in the investigated group was 15 %. Systematic screening for ATTR in patients with unexplained LV wall thickness ≥ 12 mm requiring permanent pacemaker implantation seems to be rational and could possibly lead to an earlier diagnosis of cardiac amyloidosis, especially ATTR.

A comparative analysis of national dementia plans: preventive strategies in five European countries

Abstract Background About 8.5% of people aged +65 live with dementia in Europe. Preventive measures can avert up to 40% of cases. The aim of the study is to analyse National Dementia Plans (NDP) in Europe, to elicit how much dementia prevention is considered a priority and whether policies are evidence-based. Methods A qualitative comparative analysis was performed between NDPs of countries with the best healthy life expectancy in the elderly in Europe. The NDPs of France, Ireland, Italy, Spain, and Sweden were included. The consensus on actions and elements of prevention policies was evaluated, according to the WHO recommendations and to Cheung’s framework designed for evaluating chronic diseases policies. Results All the NDPs prioritised early diagnosis, public awareness, and community engagement for dementia risk reduction. They fostered the development of information system for data collection and established committees for progress monitoring. However, not all NDPs defined timelines for policy implementation and most of them expired years ago. NDPs included prevention research agenda, but their preventive actions did not address alcohol consumption, traumatic brain injury, and air pollution, representing 3 well-known risk factors attributable for the 15% of preventable cases. Neither integration of dementia with other chronic disease preventive strategies was present and a clear allocation of funds for NDPs always missed. Conclusions NDPs partially address risk factors of preventable cases. All countries need to update their NDPs, integrating new scientific evidence and allocating clear financial funds. This can potentially prevent millions of new cases, decreasing the burden of disease and improving the sustainability of health systems. Key messages • NDPs do not target adequately dementia in Europe. • New evidence-based preventive policies, including most recent identified risk factors, would have a clear impact on burden of disease and health systems’ sustainability.

Advancing Public Health Equity through Expanded Vaccination Services in prison: case studies from Italy and France

Abstract In Montpellier prison in France and San Vittore remand house in Italy, the provision of expanded, age-appropriate, coercion-free, and tailored vaccination services to PLP has emerged as a cornerstone in improving health outcomes within prison settings. The implementation of life course vaccination programs required the full integration of prison health into public health systems building on existing vaccination services covering HBV, flu and COVID-19. In San Vittore, a vaccination clinic aimed at people living in prison was set-up. Universal vaccination status assessment and vaccination catch-up was introduced targeting people admitted into prison. The vaccination clinic-related activities included information and awareness sessions on vaccination and health literacy offered regularly to PLP: increased vaccination knowledge is effective to enhance uptake. The vaccination clinic team consisted of infectious diseases physicians and a health assistant with an anthropological background, who ran the information and awareness sessions combining and adapting core content on vaccination with individual and community social and cultural contexts. Besides seasonal flu vaccination and anti-SARS-CoV-2 immunisation campaigns, vaccinations against pneumococcal pneumonia and herpes zoster were also offered to older and fragile individuals as per national immunization plan. One of the priority objectives of the vaccination clinic was the increase in vaccination coverage against HBV and HPV, not only as a tool for the prevention of infectious diseases, but as an innovative and effective tool of cancer prevention. As part of a more ambitious program to protect sexual health in prison and related to updated screening tools for the early diagnosis of lesions due to HPV infection, vaccination against HPV was also offered as part of a health empowerment project tailored to women in detention, with the aim of building self-awareness of their own health needs.

Prevalence of amyloidosis among patients with mild to severe aortic stenosis. Validation of screening parameters

Abstract Background Cardiac amyloidosis (CA) is an increasingly recognized cause of human heart failure. Up to 16% of patients with severe aortic stenosis (AS) undergoing transcatheter valve replacement have been reported to suffer concomitant transthyretin CA (ATTR). Since the diagnosis of CA implies distinct therapies with prognostic relevance, early diagnosis of CA is crucial. Different parameters have been described to improve screening accuracy for detection of CA, but it is unknown whether these parameters are valid, and the prevalence of CA is stable throughout the spectrum of AS. Purpose To validate screening parameters for the detection of CA in mild, moderate and severe AS. Methods Patient 65 years and above undergoing echocardiography with mild to severe AS, defined as calculated valve orifice area <2 cm2 by velocity-time-integral, and an intraventricular septum thickness > 11mm, fulfilling at least one of two additional criteria (Sokolow-Lyon-Index to left ventricular mass index ratio < 1.5 or stroke volume index < 35 ml/m2) were prospectively included and screened for CA using bone scintigraphy and immunofixation in blood and urine. Results 57 patients were included and completed the diagnostic work-up. Mean age was 83 ± 0.7 years and 71% were male. Overall, 15 (26%) of patients were diagnosed with CA (12 with ATTR and 3 with light-chain CA, Figure1A). 17 patients had mild, 21 had moderate and 19 patients were diagnosed with severe AS. Among patients with mild AS 41% were diagnosed with CA, whereas only 24% of patients with moderate and 16% of patients with severe AS suffered CA (Figure 1B), these results did not show statistically significant differences (p= 0.2, by Chi-Square Quadrat test). Patients with CA were less likely to have NYHA classes I or II (20 vs. 57%, p= 0.03), had higher values of NT-proBNP (4572 [2323; 6044] vs. 817 [589; 2571], p< 0.001) and high-sensitive troponin (66 [47; 103.5] vs. 22.5 [17; 33.6], p< 0.001) and were more likely to have an atrioventricular block of any degree (60 vs. 26%, p=0.04). Conclusion Prevalence of CA among patients fulfilling the criteria of this screening algorithm seems to be high independent of AS severity. Clinicians should not only focus on patients with severe AS to detect CA early. Further research is needed to estimate the prevalence of CA among all patients with AS. Figure 1 A: Among patients with an age >65 years, IVS >11mm, AS and SLI/LVMMI >1.5 or SVI <35 ml/m2 26% (red area) of patients were diagnosed with CA (n= 57). B: In patients with mild AS 41% were diagnosed with CA, whereas in patients with moderate AS only 24% and in patients with severe AS 16% had CA. These differences did not show statistical significance (p= 0.2). IVS: intraventricular septum, AS: aortic stenosis, SLI: Skolow-Lyon-Index, LVMM= left ventricular myocardial mass index, SVI: stroke volume index, CA: cardiac-amyloidosis. (Statistics performed by chi-square test using GraphPad Prism 9.0).

Cardiotoxicity in cancer immunotherapy: challenges in diagnosing and managing ICI-associated myocarditis

Immunotherapy has revolutionized cancer treatment, particularly through immune checkpoint inhibitors (ICIs), which enhance the body's immune response against tumors. However, these therapies can also trigger immune-related adverse events (irAEs), with myocarditis being one of the most severe but rare complications. This article reviews the pathophysiology, clinical manifestations, and current management strategies for ICI-induced myocarditis. While significant advancements have been made, the early diagnosis of this condition remains a challenge due to nonspecific symptoms. Current treatment relies heavily on the discontinuation of ICIs and the use of corticosteroids, but there is an urgent need for standardized diagnostic criteria and optimized therapeutic protocols. This review highlights the gaps in existing knowledge and emphasizes the importance of further research to improve patient outcomes. Understanding these complexities is crucial for ensuring that the benefits of immunotherapy outweigh the risks, ultimately improving the safety and efficacy of cancer treatments, as these treatments are essential for sustaining individual life.

Inhibition of M2 tumor-associated macrophages polarization by modulating the Wnt/β-catenin pathway as a possible liver cancer therapy method

The problem of liver cancer is becoming increasingly important due to the epidemic of metabolic diseases and persistent high alcohol consumption. This determines great attention to the development and improvement of methods for early diagnosis and treatment of liver cancer. Huang et al presented a study in the World Journal of Gastroenterology , in which they showed that the use of the traditional Chinese medicine Calculus bovis (CB) can suppress tumor growth in mice by inhibiting M2 tumor-associated macrophages (TAM) through modulating the activity of the Wnt/β-catenin pathway. The interaction of CB components with the Wnt/β-catenin pathway, M2 TAM polarization, and tumor dynamics were studied using network pharmacology, transcriptomics, and molecular docking. It is now generally accepted that the polarization of TAM and the differentiation of the functions of M1 and M2 phagocytes are of great importance for the progression of neoplasms. It is assumed that M2 TAM promote proliferation and migration of tumor cells. Attempts to medicinally influence the Wnt/β-catenin pathway in order to modulate phagocyte polarization now belong to one of the most promising areas of immunotherapy of oncological diseases. Undoubtedly, the work of the Chinese authors deserves attention and further development.

Role of pericoronary adipose tissue inflammation at CCTA after heart transplantation as non-invasive diagnostic tool of cardiac rejection and predictor of major adverse cardiovascular events

Abstract Background Long-term survival of heart transplanted (HT) patients is challenged by cardiac rejection and cardiac allograft vasculopathy (CAV). Until now, there are no established biomarkers for graft dysfunction, and the conventional approach for cardiac rejection surveillance is through the endomyocardial biopsy (EMB), an invasive and costly procedure. Purpose This study investigates the prognostic value of the pericoronary Fat Attenuation Index (FAI) and its role as a marker of inflammation and rejection in HT recipients. Methods A double-center observational retrospective study was conducted on a cohort of HT patients who underwent coronary computed tomography angiography (CCTA) between January 2016 and December 2022. FAI was measured with dedicated software and using the cut-off described in literature, we considered each coronary as "inflamed" if FAI was ≥ - 70,1 HU and "not inflamed" if FAI was < - 70,1 HU. Then, based on the number of inflamed coronary arteries for each patient, we divided the population into two comparison groups: high inflammatory (high INF) phenotype (alle three coronary arteries inflamed) and low inflammatory (low INF) phenotype (at least one coronary artery not inflamed). The primary endpoint was a composite of all-cause mortality, acute myocardial infarction, urgent revascularization and heart failure hospitalization. Furthermore, we investigated the correlation between FAI and cardiac rejection by looking for T cell-mediated rejection (TCMR) and antibody-mediated rejection (AMR) through EMB performed no more than six months before or after CCTA. Results A total of 101 HT patients were included; of this group 58 patients underwent EMBs within six months after or before the CCTA. The median duration of follow-up was 28 months. The composite endpoint occurred in 17 patients (16.8%). We documented 26 significative cardiac rejection episodes, 14 TCMR ≥ 2R and 12 AMR. The composite endpoint was achieved in 37.9% of patients with high INF phenotype compared to 8.3% with low INF phenotype (p < 0.001). In the multivariate analysis, the high INF phenotype remained an independent predictor of the composite endpoint in our population (HR: 10.5; 95% CI: 1.88-58.71; p = 0.007). Patients with TCMR and AMR had significantly higher FAI values. High INF phenotype correlated with the presence of ACR ≥ 2R (55.0% vs 7.9%, p < 0.001) and AMR (55.0% vs 2.6%, p < 0.001). Conclusion In HT patients, FAI is an independent predictor of major cardiovascular events. It is also associated with TCMR and AMR within six months from CCTA. FAI, therefore, may offer a non-invasive approach to stratify the prognosis of HT patients and serve as a valuable inflammatory biomarker for early diagnosis of cardiac rejection, supporting the use of CCTA in this setting of patients.Correlation FAI and MACECorrelation FAI and cardiac rejection

ATTR cardiac amyloidosis after lumbar spinal stenosis- a prospective cohort study

Abstract Background Systemic wild type transthyretin (ATTRwt) amyloidosis is underdiagnosed and generally diagnosed in manifest cardiac disease. Lumbar spinal stenosis (LSS) might be an early sign of ATTRwt and a possible screening target for early diagnosis. Aim To characterize patients with transthyretin amyloid deposits in ligamentum flavum six years after surgery for lumbar spinal stenosis, and assess prevalence of undiagnosed cardiac amyloidosis. Materials and methods In this prospective cohort study, 21 patients who had surgery for LSS in 2016-2018 and grade 3-4 ATTR deposits in ligamentum flavum, without manifest cardiac amyloidosis (CA) were followed up in 2022-2023, including biomarkers and multimodality cardiac imaging. Results Median age at follow-up was 79 years and 62% were male; 16% (3/19) of patients had DPD-scintigraphy and were diagnosed with ATTRwt cardiac amyloidosis. 48% (10/21) had a history of other tenosynovial conditions that associate to ATTRwt amyloidosis. on echocardiography. Conclusion In this prospective cohort study, 16% of patients were diagnosed with ATTRwt cardiomyopathy after a median of six years following surgery for lumbar spinal stenosis. These findings strengthen the hypothesis that LSS is a possible manifestation of ATTRwt amyloidosis and that analysis for amyloid in connective tissue and subsequent cardiac follow-up is of value.

Identification and validation of circulating microRNAs as biomarkers for heart failure with preserved ejection fraction

Abstract Background Heart failure (HF) is a syndrome due to cardiac insufficiency, manifested by excessive volume overload, increased sympathetic activity, and circulatory redistribution [1]. Heart failure with preserved ejection fraction (HFpEF) accounts for approximately 40%-50% of the total HF events, and its development is often accompanied by various complications, including hypertension, obesity, and metabolic syndrome. Biomarker associations in heart failure with reduced ejection fraction were mostly cardiac stretch based, while many biomarkers of HFpEF are also associated with inflammation [2]. To date, treatments that effectively improve the clinical prognosis of HFpEF are relatively limited, thus HFpEF remains one of the challenges that needs to be further explored. A full understanding of the molecular mechanisms of HFpEF is essential to improve the early diagnosis, treatment and prognosis of these patients. Purpose The study aims to explore key circulating miRNAs and related molecular pathways in HFpEF patients through bioinformatics analysis and machine learning, and to further validate them using a double-hit HFpEF mouse model. Methods We downloaded HF datasets including circulating miRNA expression profiles from the GEO database. LASSO regression, SVM-RFE, Random Forest and XGboost algorithm were conducted to identify key miRNAs for diagnostic model construction. We used R software, GO, KEGG and Cytoscape to better understand the functions of key miRNA targets. Besides, the mRNA-miRNA interaction networks were predicted by starbase. We also constructed a HFpEF mouse model subjected to high fat diet and L-NAME (0.5 g/L) in drinking water to discover the correlation between the screened circulating miRNA and HFpEF. Results After differential expression analysis of the combined HFpEF dataset, we identified 37 differentially circulating miRNAs, of which 15 were down-regulated and 22 were up-regulated. Subsequently, we screened by machine learning and identified 4 key miRNAs that may be involved in the progression of HFpEF, including hsa-miR-645, hsa-miR-296-5p, hsa-miR-199b-5p, and hsa-miR-509-3-5p. We validated these miRNAs based on their expression, and the ROC plots suggest that these miRNAs may have diagnostic capability in HFpEF. The results of GO and KEGG enrichment analyses showed that the target genes of the differentiated miRNAs were mainly enriched in the MAPK signaling pathway, mTOR signaling pathway, protein processing in endoplasmic reticulum, hippo signaling pathway, cell cycle, Foxo signaling pathway, hypertrophic cardiomyopathy, dilated cardiomyopathy, and circadian rhythm. The mRNA-miRNA interaction networks suggested that TMEM135 was regulated by both has-miR-199b-5p and hsa-miR-296-5p. The RT-PCR results also suggested that miR-199b-5p was upregulated in the HFpEF mice. Conclusion We validated 4 circulating miRNAs with strong correlation to HFpEF, which provide a more reliable basis for pre-symptomatic diagnosis.

WDR45 variants as a major cause for a clinically variable intellectual disability syndrome from early infancy in females.

Pathogenic variants of WD repeat domain 45 (WDR45) cause neurodegeneration with brain iron accumulation 5 (NBIA5), which is characterised by progressive neurological regression and brain iron accumulation in adulthood. Early diagnosis of NBIA5 patients is difficult because they often show only a non-specific developmental delay in childhood, but it is essential for lifelong medical management. We investigated 32 females with developmental delays for coding variants of WDR45 using Sanger sequencing. Whole-genome sequencing (WGS) and X chromosome inactivation (XCI) analysis were also performed. We identified two disease-causing variants, one of which was a novel stop-loss variant, c.1051delG p.(Val351CysfsTer60), in a female with severe developmental delay from early infancy with epileptic spasms. The XCI analysis (which we originally developed) suggested a random pattern in white blood cells. WGS did not reveal any other pathogenic variants, including those in two iron transporter genes. Together with our previous findings in the WGS study, WDR45 variants accounted for 12% (6/51) of the females with developmental delay, suggesting that WDR45 is a major gene in females with developmental delay. Pathogenic variants of WDR45 result in various phenotypes that do not necessarily correlate with variant types or XCI skewing patterns.

Overdiagnosis for screen-detected prostate cancer incorporating patient comorbidities

Abstract Background Evidence regarding the likelihood of overdiagnosis in prostate cancer (CaP) screening with PSA are mainly based on clinical trials, which include younger population with fewer comorbidities than those receiving the test in clinical practice. We aimed to assess the likelihood of overdiagnosis and associated variables using real-world data. Methods Retrospective cohort of men >40 years with PCa, who had been diagnosed being asymptomatic and after a positive PSA test in the previous 12 months in two hospitals (2004-2022). The probability of overdiagnosis was estimated considering the life expectancy of the Spanish male in the year 2022 and the Charlson Comorbidity Index (lead time 10 years). PSA values and Gleason score were included as independent variables. Results Of the 2,331 patients in the cohort, 1,070 (46%) met the inclusion criteria for this analysis. The median follow-up time was 5.7 years (IQR 3.2-8.6). The median age was 71 years (IQR 65-78) and 37% had more than one comorbidity. At diagnosis, the median life expectancy was 12 years (IQR 4-18) and the probability of overdiagnosis was 30.8% (IQR 17.6-52.4). Patients with PSA levels >10 mg/dl tended to be older and with more comorbidities than those with PSA levels 4-10 mg/dl, and thus, with shorter life expectancy. The median probability of overdiagnosis was higher in patients with PSA levels >10 mg/dl (41.4%, IQR 21.5-73.9) than in those with PSA levels 4-10 mg/dl (20.1%, IQR 12.8-30.4), p < 0.001. Correspondingly, patients with Gleason score ≥8 were more likely to be overdiagnosed (median 42.6%, IQR 23.6-68.6) than those with Gleason score ≤6 (median 20.1%, IQR 12.8-30.4) (p < 0.001). Conclusions In clinical practice, older patients with comorbidities showed high PSA levels and Gleason score ≥8, presenting low life expectancy at diagnosis and, therefore, high probability of overdiagnosis. This highlights the importance of considering the patient’s comorbidities when ordering a new PSA test. Key messages • A detailed assessment of the prevalence of comorbidities among CaP patients in real-life settings has significant implications for patient management. • The decision to make an early diagnosis should be based on individual life expectancy, where comorbidity is at least as important as age.

Machine-learning based prediction of obstructive coronary artery disease using integrated submodules of clinical information, chest x-ray, and electrocardiography

Abstract Background The early diagnosis of obstructive coronary artery disease (CAD) is critical. However, delays in diagnosis may occur due to subsequent high-cost tests, contributing to substantial medical expenses. A more insightful interpretation of fundamental diagnostic tools, such as chest x-ray (CXR) and electrocardiography (ECG), could mitigate medical costs and facilitate a timely diagnosis. Purpose This study explores the application of machine learning to interpret each modality and create a consolidated prediction model for significant CAD, aiming to construct a diagnostic model based on primary tests, including CXR, ECG, and clinical information. Methods Clinical information-ECG-CXR paired data were generated from 19,140 patients, with CAD confirmed through coronary angiography (CAG). Machine learning (ML) was employed to develop submodules for each modality, and various integration methods were explored. The area under the curve (AUC) served as the outcome metric for predicting obstructive CAD. Results The development set comprised data from 17,976 patients, with CAG-confirmed obstructive CAD observed in approximately 60% of patients. The obstructive CAD group exhibited characteristics such as advanced age, male predominance, a higher prevalence of chest pain, and more risk factors. The ML model, incorporating clinical information, CXR, and ECG with submodules, demonstrated the optimal prediction of obstructive CAD (AUC 0.722). This model significantly outperformed the model without submodules (0.722 vs. 0.638, p<0.0001) in obstructive CAD prediction. Conclusions Through the integration of submodules encompassing clinical information and basic tests, leveraging a high-quality database, the integrated ML algorithm offers improved prediction capabilities for CAG-confirmed obstructive CAD. This underscores the potential role of machine learning in clinical decision-making based on diverse modalities with distinct characteristics.

Incorporating intrathoracic pressure fluctuation can improve noninvasive prediction of left ventricular end-diastolic pressure

Abstract Introduction Heart failure (HF) is a leading cause of mortality and morbidity, with a prevalence above 10% in elderly population (1). Left ventricular end-diastolic pressure (LVEDP) is a known indicator for all types of HF. An invasive pressure catheter is the gold standard for measuring LVEDP (2). However, it involves an in-hospital procedure and is costly, which limits the accessibility. A noninvasive strategy would improve early diagnosis and reduce the burden on secondary care. Several noninvasive classifiers are able to detect elevated LVEDP (3-5), with some receiving FDA clearance (6). While beneficial for triaging patients, these classifiers cannot quantify the severity and track disease progression. Developing a noninvasive LVEDP regression model requires accounting for respiration dynamics. Even invasively, the dynamics make measuring LVEDP challenging. This study uses an error metric from ANSI/AAMI/ISO 81060-2:2019 (AAMI) (7) to evaluate the effect of respiration on noninvasive LVEDP regression results. Methods The dataset (147 patients, 21+ yrs old, mean 65 ± 10 yrs; 68% male) consisted of patients referred for nonemergent left heart catheterisation inclusive of direct assessment of LVEDP. Noninvasive data was collected by a modified brachial cuff with a single-lead electrocardiogram (ECG). Invasive data was acquired using a Millar pressure catheter. LVEDP was derived based on the time of the R-wave of the ECG (8). For each patient, 40 secs of noninvasive data with synchronised catheter signals were analysed to build an LVEDP regression model. Inputs were generated from the ECG and brachial pressure waves based on fiducials identified in both signals. Leave-one-subject-out cross-validation (LOSO CV) was used to train and test the algorithm. The impact of respirophasic variation on the model was analysed by comparing the prediction with the mean LVEDP and the range of the mean ± standard deviation (std) (i.e. AAMI error metric). Results The results, evaluated using Bland-Altman and correlation analysis, showed a decrease in the mean absolute error (MAE) from 3.6 mmHg to 1.4 mmHg, the std from 4.9 mmHg to 3.0 mmHg, and the correlation (r) from 0.57 to 0.77 when incorporating intrathoracic pressure swings (Fig.1 and Fig.2). A Levene test on the residuals of the two error determinations showed a significant difference (p-value < 0.01). Conclusion Irrespective of the error metric, the model performance meets the AAMI standard for blood pressure (BP) measurement. Moreover, when respiratory motion is included, agreement with invasive LVEDP improves considerably. From a clinical perspective, this emphasises the importance of targeting end-expiratory LVEDP. With respect to noninvasive BP measurement, it suggests that both brachial BP evaluation and LVEDP prediction should attempt to quantify fluctuations. While the challenge remains, these results indicate that noninvasive LVEDP prediction could be realised in the near future.Fig.1 Prediction vs mean LVEDP.Fig. 2 Prediction vs mean +/- std.

Long‐Term Monitoring of ApoE4 within Aqueous Humor Using Intraocular Lenses Containing Target‐Responsive Inverse Opal Hydrogel

Neurodegenerative diseases, including Alzheimer's disease (AD), pose significant challenges to global healthcare because of their irreversible postsymptomatic progression. Conventional radiographic techniques have limitations in early detection, owing to the time lapse between symptom recognition by individuals and precise inspection using medical instruments. Current research explores ophthalmic approaches to address this gap, investigating the physiological link between ocular health and brain diseases. Intraocular lenses (IOLs), widely used in cataract and refractive surgeries, provide a safe and minimally invasive platform for the continuous monitoring of neurodegenerative disease biomarkers, including those associated with AD. By integrating biomolecule‐responsive sensors with IOLs, it becomes feasible to achieve early diagnosis and long‐term, noninvasive monitoring postimplantation. Herein, a fluorescently labeled inverse opal hydrogel (FIOH) is merged with IOLs for ApoE4 detection, a key risk factor for AD. The permeability and inherent photonic properties of FIOH facilitate the cumulative enhancement of the fluorescence signal. In a simulation of the aqueous humor circulation, the detection limit for ApoE4 is determined to be 0.1 nM. Therefore, FIOH‐integrated IOLs hold promise not only for early detection but also for providing a reliable platform for the continuous, noninvasive monitoring of neurodegenerative diseases after the initial, minimally invasive implantation.

Derivation and external validation of new ESC 0/1-h algorithm cut-offs for high-sensitivity troponin T and I in the cancer population

Abstract Background The diagnostic performance of high-sensitivity cardiac troponin T/I (hs-cTnT/I) and the efficacy of the European Society of Cardiology (ESC) 0/1h-hs-cTnT/I-algorithms for the early diagnosis of non-ST-elevation myocardial infarction (NSTEMI) is reduced in cancer patients presenting to the emergency department (ED) with chest pain.[1] Purpose This study aimed to derive and externally validate new cut-offs for the ESC 0/1h-hs-cTnT/I-algorithms in chest pain patients with active or past cancer. Methods Patients presenting with acute chest discomfort to the ED were prospectively enrolled in an international multicenter diagnostic study. Final diagnoses were centrally adjudicated by 2 independent cardiologists applying the fourth universal definition of myocardial infarction using all available medical records, cardiac imaging, and serial hs-cTnT/I. Hs-cTn concentrations were measured at presentation and after 1 hour. New assay-specific cutoffs for the ESC 0/1h-hs-cTnT/I-algorithm were derived and externally validated in two independent cohorts. Results Among 541 and 516 eligible patients with 0h and 1h hs-cTnT and hs-cTnI values, respectively, application of the current ESC 0/1h-hs-cTnT/I algorithm triaged 317 (58.6%) and 306 (59.3%) patients to either rule-out or rule-in, leaving 224 (41.4%) and 210 (40.7%) patients in the observe-zone of the ESC 0/1h-hs-cTnT/I algorithm, respectively. The novel ESC 0/1h-hs-cTnT cut-offs ruled out NSTEMI with a cut-off <8 ng/L at presentation (if chest pain onset >3 hours) or <14 ng/L together with a 0/1-hour delta <3 ng/L, ruling-out 241 patients (44.5%) with a sensitivity and negative predictive value (NPV) of 99.2% and 99.6%, respectively. The novel ESC 0/1h-hs-cTnI cutoffs ruled out NSTEMI with a cut-off <7 ng/L at presentation (if chest pain onset >3 hours) or <10 ng/L together with a 0/1-hour delta <3 ng/L, ruling-out 281 patients (54.5%) with a sensitivity and NPV of 99.1% and 99.6, respectively. Findings were confirmed in both internal and external validation (Figure 1). A total of 167 (32.8%) patients died at 5-years, of whom 61 died of cardiovascular causes, and 30 (5.9%) patients had an MI at 5 years. 5-year all-cause mortality for the rule-out group was similar for both the current and the novel ESC 0/1-h algorithm, although the novel one identified patients in the observe zone group as having the highest mortality (Figure 2). Incidence of 5-year cardiovascular mortality or AMI provided by the current ESC 0/1h-algorithm was similar for the rule-in and observe zone groups for both hs-cTnT and hs-cTnI. Conclusions In chest pain patients with a history of cancer, new derived assay-specific cutoffs for the ESC 0/1h-hs-cTnT/I-algorithm achieved a higher proportion of patients triaged to either rule-out or rule-in without decreasing safety. The low mortality rate of the rule-out group identified by the new algorithm further reassures on the safety of the new derived cut-offs.Sensitivity analysis in the APACE cohort5-year all-cause mortality

The impact of the 2022 definition of pulmonary hypertension on long-term clinical outcomes in patients with heart failure with preserved ejection fraction

Abstract @ Backgrounds: In recent years, the definitions of pulmonary hypertension (PH) have been revised for early diagnosis and risk stratification of patients with PH. Using the 2015 definitions, the development of a precapillary component of PH in addition to a postcapillary PH was associated with right heart dysfunction and poor prognosis in patients with heart failure (HF) with preserved ejection fraction (HFpEF). However, the prognostic impact of revised definitions of PH in patients with HFpEF has not been fully evaluated. Purpose We investigated the impact of the 2018 and 2022 ESC/ERS definitions of PH on long-term clinical outcomes using data from a prospective, multicenter, observational study of patients with HFpEF (PURSUIT-HFpEF). Methods A total of 250 patients hospitalised with acute HF who underwent right heart catheterisation after initial HF treatment were divided into PH categories according to the 2018 and 2022 definitions: isolated postcapillary PH (Ipc-PH), precapillary PH, combined postcapillary and precapillary PH (Cpc-PH), and unclassified PH. The incidence of the composite endpoint of all-cause death and HF rehospitalisation after discharge was compared across the PH categories. Results The overall prevalence of PH defined as a mPAP > 20 mmHg was 54%. Applying the 2022 definition, 42 patients (17%) were reclassified as either precapillary PH or Cpc-PH, resulting in a significant increase in the propotion of patients classified as having PH with a precapillary component (precapillary PH and Cpc-PH) compared with the 2018 definition (26% vs. 11%, p<0.0001). At a median follow-up of 822 days after discharge, PH with a precapillary component was associated with poor clinical outcomes according to the 2018 definition (Figure 1A), but according to the 2022 definition, clinical outcomes did not differ across the PH categories (Figure 1B). PVR ≥3 Wood units (WU) was a significant prognostic indicator, but there was no significant difference between the PVR 2-3 WU and PVR ≤2 WU categories (Figure 2). Conclusions The 2022 definition showed no association between PH classification and clinical outcomes. In patients with HFpEF, PVR ≥3 WU was identified as the key factor increasing the risk of all-cause death and HF hospitalisation.Figure 1Figure 2