University Medical Center Research Articles

Breast cancer relapse disease prediction improvements with ensemble learning approaches

Diagnosis and prognosis are especially difficult areas of medical research related to cancer due to the high incidence of breast cancer, which has surpassed all other cancers in terms of female mortality. Another factor that has a substantial influence on the quality of life of cancer patients is the fear that they may experience a relapse of their disease. The objective of the study is to give medical practitioners a more effective strategy for using ensemble learning techniques to forecast when breast cancer may recur. This research aimed to investigate the usage of deep neural networks (DNNs) and artificial neural networks (ANNs) in addition to machine learning (ML) based approaches, including bagging, averaging, and voting, to enhance the efficacy of breast cancer relapse diagnosis on two breast cancer relapse datasets. Results from the empirical study demonstrate that the proposed ensemble learning-enabled approach improves accuracies by 96.31% and 95.81%, precisions by 96.70% and 96.15%, sensitivities by 98.88% and 98.68%, specificities by 84.62% in both, F1-scores by 97.78% and 97.40%, and area under the curve (AUCs) of 0.987 and 0.978, with University Medical Centre, Institute of Oncology (UMCIO) and Wisconsin prognostic breast cancer (WPBC) datasets respectively. Consequently, these improved disease outcomes may encourage physicians to use this model to make better treatment choices.

Prospective profile of bacterial pathogens in hospitalized adult patients with community-acquired pneumonia: insights from multiplex real-time PCR and traditional culture techniques

Hospitalized community-acquired pneumonia (CAP) is mainly caused by bacteria and plays its role as primary bacteria alone or combined. The study aimed to determine the proportion of bacterial pathogens causing CAP in hospitalized adult patients and to examine the combination of these bacteria. This study was a cross-sectional descriptive design in prospect conducted on 341 adult patients with CAP hospitalized at the Respiratory Department of Nguyen Tri Phuong Hospital, Nhan Dan Gia Dinh Hospital, and University Medical Center from April 2021 to March 2023. Sputum samples were collected, assessed for reliability (according to the Barlett scale), and transported to Nam Khoa Company’s laboratory to perform traditional culture techniques and multiplex real-time PCR (MPL-rPCR). Male sex and age over 60 were 62.5% and 73.0%, respectively. Bacterial pathogens were detected by MPL-rPCR and traditional culture techniques at rates of 67.7% and 46.0%, respectively (p<0.001). More than one strain of bacteria was commonly found in each sputum. Klebsiella pneumoniae was detected by multiplex real-time PCR and traditional culture techniques at a high rate (18.5% & 13.5%), Acinetobacter baumannii (17.3% & 12.9%), Streptococcus pneumoniae (16.4% & 0.6%), H. influenzae (14.1% & 0.6%) and P. aeruginosa (4.4% & 3.8%). Atypical bacteria were only Mycoplasma, with 6.2%, and occurred as a combined bacteria. The rate of bacterial combination was 77.1%, and two or more combined bacteria was 58.4%. Bacterial pathogens are detected at 67.7% by MPL-rPCR and 46.0% by traditional culture techniques (p<0.001). Bacterial pathogens are multiform and increase in Gram-negative bacilli.

Neck rigidity: a pitfall for video head-impulse tests in Parkinson's disease.

Video head impulse tests (video-HITs) are commonly used for vestibular evaluation; however, the results can be contaminated by various artifacts, including technical errors, recording problems, and participant factors. Although video-HITs can be used in patients with Parkinson's disease (PD), the effect of neck rigidity has not been systematically investigated. This study aimed to investigate the effect of neck rigidity on video-HIT results in patients with PD. We prospectively recruited 140 consecutive patients with PD (mean age ± standard deviation = 68 ± 10 years, 69 men) between September 2021 and April 2024 at Korea University Medical Center. The video-HIT results were compared with those of 19 age- and sex-matched healthy participants. Neck rigidity was stratified as a subdomain of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale motor part (MDS-UPDRS-III). In 59 patients, the vestibulo-ocular reflex (VOR) gain was overestimated in at least one canal plane (58/140, 41%), mostly in the anterior canal (AC, n = 44), followed by the horizontal (HC, n = 15) and posterior canals (PC, n = 7). VOR gain overestimation was also observed in patients with no (18/58, 35%), subtle (20/58, 34%), or mild (17/58, 29%) neck rigidity. Multivariable logistic regression analysis showed that VOR overestimation was positively associated with neck rigidity (odds ratio [OR] [95% confidence interval] = 1.51 [1.01-2.25], p = 0.043). The head velocities of patients decreased during head impulses for the AC (p = 0.033 for the right AC; p = 0.014 for the left AC), whereas eye velocities were similar to those of healthy participants. Our findings suggest that neck rigidity may be a confounder that can contaminate video-HIT results. Thus, the results of video-HITs, especially for the AC, should be interpreted with the context of head velocity during head impulses in patients with neck rigidity.

Clinical management, pathogen spectrum and outcomes in patients with pyogenic liver abscess in a German tertiary-care hospital

Pyogenic liver abscesses (PLA) are life-threatening disorders and require immediate treatment, but structured evidence is sparse and treatment guidelines are not established. In a retrospective observational study of 221 adult PLA patients (mean age 63 years, 63% men) treated between 2013 and 2019 at the Leipzig University Medical Center, we characterized pathogen spectrum, clinical management and outcomes. Biliary malignancies (33%), cholelithiasis (23%) and ischemic biliary tract disease (16%) were most common causes of PLA. Comorbidities included malignancies (40%) and diabetes mellitus (35%). Abdominal ultrasound was the preferred initial imaging modality (58%). Enterobacterales (58%), enterococci (42%) and streptococci (18%) were identified as most frequent pathogens. 97% of patients were treated with antibiotics and 75% of patients underwent an invasive treatment procedure. The 30-day mortality was almost identical in patients with and without underlying malignancy (14.6% vs. 14.4%, p = 0.96), while the one-year outcome differed significantly (58.4% vs. 29.6%, p < 0.001). Positive blood cultures (OR 4.78, 95% CI 1.39 to 22.5, p = 0.023) and detection of Enterobacterales (OR 3.55, 95% CI 1.40 to 9.97, p = 0.010) were associated with increased 30-day-mortality. We conclude that ultrasound, extensive microbiologic diagnosis, adequate anti-infective therapy and early intervention are crucial for the management of PLA.

Early postoperative pain and 30-day complications following major abdominal surgery: a retrospective cohort study

BackgroundIncreasing evidence supports a positive relationship between the intensity of early postoperative pain, and the risk of 30-day postoperative complications. Higher pain levels may hamper recovery and contribute to immunosuppression...

Description of mitochondrial oxygen tension and its variability in healthy volunteers.

Describing mitochondrial oxygenation (mitoPO2) and its within- and between-subject variability over time after 5-aminolevulinic acid (ALA) plaster application in healthy volunteers. Prospective cohort study. Measurements were performed in Leiden University Medical Center, the Netherlands. Healthy volunteers enrolled from July to September 2020. Two ALA plasters were placed parasternal left and right, with a 3-hour time interval, to examine the influence of the calendar time on the value of mitoPO2. We measured mitoPO2 at 4, 5, 7, 10, 28, and 31 hours after ALA plaster 1 application, and at 4, 5, 7, 25, and 28 hours after ALA plaster 2 application. At each time point, five mitoPO2 measurements were performed. Within-subject variability was defined as the standard deviation (SD) of the mean of five measurements per timepoint of a study participant. The between-subject variability was the SD of the mean mitoPO2 value of the study population per timepoint. In 16 completed inclusions, median mitoPO2 values and within-subject variability were relatively similar over time at all time points for both plasters. An increase in overall between-subject variability was seen after 25 hours ALA plaster time (19.6 mm Hg vs 23.9 mm Hg after respectively 10 and 25 hours ALA plaster time). The mitoPO2 values and within-subject variability remained relatively stable over time in healthy volunteers. An increase in between-subject variability was seen after 25 hours ALA plaster time warranting replacement of the ALA plaster one day after its application. ClinicalTrials.gov with trial number NCT04626661.

PET/CT based transformer model for multi-outcome prediction in oropharyngeal cancer

Background and purposeTo optimize our previously proposed TransRP, a model integrating CNN (convolutional neural network) and ViT (Vision Transformer) designed for recurrence-free survival prediction in oropharyngeal cancer and to extend its application to the prediction of multiple clinical outcomes, including locoregional control (LRC), Distant metastasis-free survival (DMFS) and overall survival (OS). Materials and MethodsData was collected from 400 patients (300 for training and 100 for testing) diagnosed with oropharyngeal squamous cell carcinoma (OPSCC) who underwent (chemo)radiotherapy at University Medical Center Groningen. Each patient’s data comprised pre-treatment PET/CT scans, clinical parameters, and clinical outcome endpoints, namely LRC, DMFS and OS. The prediction performance of TransRP was compared with CNNs when inputting image data only. Additionally, three distinct methods (m1-3) of incorporating clinical predictors into TransRP training and one method (m4) that uses TransRP prediction as one parameter in a clinical Cox model were compared. ResultsTransRP achieved higher test C-index values of 0.61, 0.84 and 0.70 than CNNs for LRC, DMFS and OS, respectively. Furthermore, when incorporating TransRP’s prediction into a clinical Cox model (m4), a higher C-index of 0.77 for OS was obtained. Compared with a clinical routine risk stratification model of OS, our model, using clinical variables, radiomics and TransRP prediction as predictors, achieved larger separations of survival curves between low, intermediate and high risk groups. ConclusionTransRP outperformed CNN models for all endpoints. Combining clinical data and TransRP prediction in a Cox model achieved better OS prediction.

Preliminary outcomes of boron neutron capture therapy for head and neck cancers as a treatment covered by public health insurance system in Japan: Real-world experiences over a 2-year period.

Since June 2020, boron neutron capture therapy (BNCT) has been a health care service covered by health insurance in Japan to treat locally advanced or recurrent unresectable head and neck cancers. Therefore, we aimed to assess the clinical outcomes of BNCT as a health insurance treatment and explore its role among the standard treatment modalities for head and neck cancers. We retrospectively analyzed data from patients who were treated using BNCT at Kansai BNCT Medical Center, Osaka Medical and Pharmaceutical University, between June 2020 and May 2022. We assessed objective response rates based on the Response Evaluation Criteria in Solid Tumors version 1.1, and adverse events based on the Common Terminology Criteria for Adverse Events, version 5.0. Additionally, we conducted a survival analysis and explored the factors that contributed to the treatment results. Sixty-nine patients (72 treatments) were included in the study, with a median observation period of 15 months. The objective response rate was 80.5%, and the 1-year locoregional control, progression-free survival, and overall survival rates were 57.1% (95% confidence interval [CI]: 43.9%-68.3%), 42.2% (95% CI: 30.1%-53.8%), and 75.4% (95% CI: 62.5%-84.5%), respectively. Locoregional control was significantly longer in patients with earlier TNM staging and no history of chemotherapy. BNCT may be an effective treatment option for locally advanced or recurrent unresectable head and neck cancers with no other definitive therapies. If definitive surgery or radiation therapy are not feasible, BNCT should be considered at early disease stages.

Germline variation and risk of immune-related adverse events (irAEs): A real-world BioVU study.

10582 Background: IrAEs are prevalent in patients treated with immune checkpoint inhibitors (ICI) and mimic classical autoimmune diseases. IrAE risk prediction could improve clinical decision making and patient safety for ICI-treated patients. Classical autoimmune diseases show strong associations with germline polymorphisms and with Human Leukocyte Antigen (HLA) variants, though it is unclear if these same genetic risk factors predispose to irAEs. To identify both tolerant and irAE patients, we mined Vanderbilt University Medical Center (VUMC) BioVU, a biorepository of &gt;300K DNA samples linked to de-identified medical records and evaluated genome-wide and imputed HLA class I and II associations with irAE risk. Methods: We identified 1,472 ICI-treated BioVU subjects: 428 with ≥ 1 irAE, and 1044 with no irAEs ≤ 6 months from last ICI treatment. Genotyping was performed by Illumina MEGAEX array. Records were screened for use of irAE therapies ( e.g. systemic corticosteroids, infliximab, levothyroxine) after ICI treatment, with chart adjudication. Association tests were performed using Firth’s logistic regression adjusting for age, sex, ICI regimen, and 3 principal components to assess 1) HLA Class I and II alleles; 2) HLA evolutionary divergence; and 3) GWAS to evaluate total irAEs, organ-specific irAEs, or other specific irAEs (sample size permitting). Endocrine irAEs were excluded to be presented in a separate focused study. Results: In GWAS analyses, 53 SNPs and 23 SNPs were identified significantly (nominal p ≤ 5e-8) associated with GI and neuro-toxicity, respectively. We did not identify any significant HLA class I or II associations with irAE or organ-grouped irAEs, including most evolutionary divergence association tests. We noted marginal association (FDR=0.12, OR=6.85) of rheumatic irAEs with HLA-DRB1*10:01, an HLA class II allele with RA-specific epitope motif. Patients experiencing lung irAEs were more likely to have a high HLA class I and II evolutionary divergence sum (p = 0.013 and p=0.046, respectively). Assessment of associations with specific irAEs, validation of known associations with irAEs or autoimmune disorders, including polygenic risk scores, are underway. Conclusions: We had several SNP-irAE associations, though appropriate classification schemas to maximize power and detect genetic variation remain challenging. We will soon expand with 1,800 additional ICI-treated patients (n=~3,300 in toto), creating a robust resource for irAE genetic associations. [Table: see text]

Liver histology is associated with long-term clinical outcomes in patients with metabolic dysfunction-associated steatohepatitis.

Few studies have examined the risk of long-term clinical outcomes in patients with metabolic dysfunction-associated steatohepatitis in relation to liver histology. We aimed to study this using a real-world cohort. Adults (N = 702) recorded on Vanderbilt University Medical Center's Synthetic Derivative database (1984-2021) with evidence of metabolic dysfunction-associated steatohepatitis on liver biopsy were followed from the first biopsy until the first clinical event or last database entry (median: 4.7y). Risks of cirrhosis (N = 650), other noncirrhotic liver-related (N = 702) and cardiovascular-related outcomes (N = 660), and mortality due to liver, cardiovascular, or cancer events (N = 660) were determined as a function of baseline histology (fibrosis stage [F], lobular inflammation grade [LI], hepatocyte ballooning grade [HB], and steatosis score) adjusting for sex, age, diabetes, and weight-loss surgery. Cirrhosis risk was reduced for lower versus higher fibrosis stage (HR: F0-1 vs. F3: 0.22 [95% CI: 0.12-0.42]), LI1 versus LI2-3 (0.42 [0.19-0.97]), and HB1 versus HB2 (0.20 [0.08-0.50]). Lower fibrosis stage was associated with significantly lower risks of liver-related outcomes versus F4 cirrhosis (eg, F0-1: 0.12 [0.05-0.25]), whereas no differences were seen across baseline lobular inflammation, hepatocyte ballooning, and steatosis grades/scores. Lower versus higher lobular inflammation grade was associated with lower risks for liver-related outcomes in patients with weight-loss surgery. There was a trend for lower risks for cardiovascular-related and any long-term outcomes with lower versus higher fibrosis stage. Fibrosis stage and lobular inflammation and hepatocyte ballooning grades predict the risk of long-term outcomes, supporting the use of these histological features as potential surrogate markers of disease progression or clinical outcomes.

Effect of alternative dosing strategies on sustainable healthcare: A carbon footprint analysis of nivolumab and pembrolizumab treatment in the Netherlands.

e13564 Background: Hospitals contribute significantly to greenhouse gas (GHG) emissions and face a moral obligation to prioritize reduction of GHG emissions. Drugs constitute an important component of the GHG emissions of hospitals. Alternative dosing strategies (ADS) have been implemented to improve the cost-effectiveness of pembrolizumab and nivolumab (Table). However, the impact of these ADS on GHG emissions remains unknown. Therefore, this study aimed to analyse the effect of ADS implementation on the carbon footprint of treatment with pembrolizumab and nivolumab. Methods: Life Cycle Assessment (LCA) methodology was used to quantify the environmental impact. The impact category climate change was used to quantify the carbon emissions (CO2e). The GHG Protocol was used to categorize the emissions into scopes 1, 2 and 3. Life Cycle Inventory and Impact data from an academic hospital in Rotterdam were used in the LCA to calculate the CO2e for pembrolizumab and nivolumab, their different dosing intervals, and the impact of ADS. Results: In 2022, the carbon emissions related to nivolumab and pembrolizumab treatment were 445 tons CO2e, with an average of 94 kg CO2e per dosage. Pharmaceutical production was the main driver of treatment-related GHG emissions (93% of total emissions on average). Applying ADS, resulted in carbon emission reductions of 21.4-26.2% and 9.3-11.2% for pembrolizumab and nivolumab respectively (table 1). Conclusions: This study shows the substantial environmental impact of cancer treatments with pembrolizumab and nivolumab and calls for further implementation of ADS for pembrolizumab and nivolumab and other anti-PD-(L)1 monoclonal antibodies and more sustainable pharmaceutical production processes. These findings help to create environmental awareness and contribute to the promotion and understanding of sustainable low-carbon healthcare practices. Overview of registered doses of pembrolizumab and nivolumab, alternative dosing strategies and potential reductions in GHG emissions, based on real world data in The Erasmus University Medical Center in Rotterdam, the Netherlands. [Table: see text]

The prognostic value of blood cellular indices in pulmonary embolism.

Prognostication in acute pulmonary embolism (PE) requires reliable markers. While cellular indices such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII) appear promising, their utility in PE prognostication needs further exploration. We utilized data from the RIETE registry and the Loyola University Medical Center (LUMC) to assess the prognostic value of NLR, PLR, and SII in acute PE, using logistic regression models. The primary outcome was 30-day all-cause mortality. We compared their prognostic value versus the simplified Pulmonary Embolism Severity Index (sPESI) alone. We included 10 085 patients from RIETE and 700 from the LUMC. Thirty-day mortality rates were 4.6% and 8.3%, respectively. On multivariable analysis, an elevated NLR (>7.0) was associated with increased mortality (adjusted odds ratio [aOR]: 3.46; 95% CI: 2.60-4.60), outperforming the PLR > 220 (aOR: 2.36; 95% CI: 1.77-3.13), and SII > 1600 (aOR: 2.52; 95% CI: 1.90-3.33). The c-statistic for NLR in patients with low-risk PE was 0.78 (95% CI: 0.69-0.86). Respective numbers were 0.66 (95% CI: 0.63-0.69) and 0.68 (95% CI: 0.59-0.76) for intermediate-risk and high-risk patients. These findings were mirrored in the LUMC cohort. Among 9810 normotensive patients in RIETE, those scoring 0 points in sPESI and with an NLR ≤ 7.0 (35% of the population) displayed superior sensitivity (97.1%; 95% CI: 95.5-98.7) and negative predictive value (99.7%; 95% CI: 99.5-99.8) than sPESI alone (87.1%; 95% CI: 83.9-90.3, and 98.7%; 95% CI: 98.4-99.1, respectively) for 30-day mortality. The NLR is a significant prognostic marker for 30-day mortality in PE patients, especially useful to identify patients with very low-risk PE.

Deficiency of Abca1 and Abcg1 mediated cholesterol efflux pathways in smooth muscle cells enhances vasoconstriction but does not affect atherosclerosis

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): VIDI grant from Netherlands Organization of Scientific Research (NWO). Rosalind Franklin Fellowship from the University Medical Center Groningen. Both to Marit Westerterp, PhD Smooth muscle cells (SMCs) regulate blood flow distribution and blood pressure via vasoconstriction mediated by α-adrenergic receptors (α-ARs). Plasma membrane cholesterol may affect α1-AR signaling, but consequences for SMC-mediated vasoconstriction are unclear. Cholesterol loading promotes SMC-to-macrophage transition in vitro, which may enhance atherosclerotic plaque vulnerability. The cholesterol transporters ATP Binding Cassette A1 and G1 (ABCA1/ABCG1) are highly expressed by SMCs and mediate cholesterol efflux to apolipoprotein A1 and high-density lipoprotein (HDL), respectively. The role of ABCA1/ABCG1-mediated cholesterol efflux pathways in SMC-mediated vasoconstriction and atherogenesis remains poorly understood. We generated mice with SMC-specific Abca1/Abcg1 deficiency on the low-density lipoprotein receptor deficient (Ldlr-/-) background by crossbreeding Abca1fl/flAbcg1fl/flLdlr-/- mice with Myh11-CreERT2 transgenic mice and feeding them tamoxifen-diet. To induce SMC cholesterol accumulation and atherogenesis, we fed Myh11-CreERT2Abca1fl/flAbcg1fl/flLdlr-/- and Myh11-CreERT2Ldlr-/- mice Western-type diet (WTD) for 16 weeks. Combined SMC-Abca1/Abcg1 deficiency increased vasoconstriction in aortic rings induced by the α1-AR agonist phenylephrine, with reversal by methyl-β-cyclodextrin, substantiating its cholesterol-dependency. Unexpectedly, SMC-Abca1/Abcg1 deficiency induced urinary bladder enlargement by &amp;gt;20-fold, resembling bladder outlet obstruction (BOO). This was reversed by the α1-AR antagonist tamsulosin, indicating its dependence on bladder neck SMC constriction. Moreover, SMC-Abca1/Abcg1 deficiency decreased SMC markers and increased macrophage- and fibroblast-markers in the bladder wall, enhancing collagen deposition, consistent with SMC transdifferentiation. However, after 16 weeks WTD, SMC-Abca1/Abcg1 deficiency did not affect atherosclerotic lesion size, fibrous cap thickness, necrotic core, collagen, or macrophage content, suggesting that SMCs in atherosclerotic plaques were not affected. This may be due to low Abca1/Abcg1 expression in intimal compared to medial SMCs. We uncover a new role of SMC cholesterol efflux pathways in suppressing α1-AR mediated vasoconstriction and bladder SMC transdifferentiation, decreasing BOO. Our data may provide a mechanistic link for the association between BOO and diabetes in humans, particularly because diabetes is associated with decreased cholesterol efflux. SMC-Abca1/Abcg1 deficiency did not affect atherosclerotic lesion size or plaque composition, presumably due to low Abca1/Abcg1 expression in intimal SMCs of atherosclerotic lesions, as shown in mice and humans.

Sex-specific plasma-proteome of incident coronary artery disease

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): This work was supported by a Leiden University Medical Center MD/PhD research grant to V.Q. Sier and Dr. R. Noordam is supported by an innovation grant from the Dutch Heart Foundation. Purpose The onset and symptomatology of coronary artery disease (CAD) are different for men and women, yet insights into sex-specific biological mechanisms causing CAD are limited. To increase insight in the onset of CAD in men and women, we performed a sex-specific proteome-wide association analysis using data from a large cohort of middle-aged participants from the UK Biobank. Methods Associations between 2,923 plasma proteins and CAD incidence (angina pectoris, acute myocardial ischemia, chronic myocardial ischemia) were examined in European-ancestry participants from the UK Biobank who were free of CAD at baseline. Plasma samples were collected at baseline (2006-2010), and CAD incidence was monitored continuously for a median (interquartile range) follow-up of 5,013 (4775-5251) days. Using Cox proportional hazard modelling, the associations between CAD incidence and plasma protein levels were examined, adjusted for age, sex, body mass index, socioeconomic status, type 2 diabetes mellitus, and cholesterol-lowering and insulin drug use at baseline. The Metascape portal was employed for pathway analyses to identify (sex-specific) biological pathways. Results In a total sample comprising 40,829 individuals (55% women, mean age (sd) 56.9 (8.10)), featuring 3,155 incident CAD cases, our sex-combined model demonstrated significant associations between 93 proteins and hazard for CAD. Pathway analyses identified early plasma proteomic changes related to cytokine-cytokine receptor interactions (p=3.42e-17), matrix remodelling (p=9.24e-14, p=1.08 e-9), regulation of innate and adaptive immune cells (p=1.92e-12, p=3.88e-9), and angiogenesis (p=5.34e-9). Stratification by sex revealed distinct sex-specific proteomic patterns linked to CAD incidence, with 10 female-specific and 49 male-specific significant proteins. Through interaction analyses, we demonstrated that 8 proteins were distinctly associated with a significant increased hazard in women, while 20 proteins were significantly associated with increased hazard for CAD in men. Pathway analyses identified a significant female-specific relation between CAD incidence and matrix remodelling (p=9.72e-15, p=3.19e-13), angiogenesis/hypoxia (p=1.41e-12), and inflammatory signalling (p=7.18e-10, p=8.01e-10) pathways, whereas male-specific top pathways related to inflammatory signalling (p=9.58e-25), matrix remodelling (p=1.22e-17), and immune cell response/recruitment (p=3.08e-16, p=8.34e-12). Conclusion Using large-scale association analyses of proteomics data with CAD, we identified sex-specific proteomic profiles. Distinct patterns in more angiogenic (women) and more immune cell response (men) profiles were found. These findings contribute novel insights to the development of CAD, potentially guiding future sex-specific research and clinical strategies for disease prevention.Proteome-wide analysis for CAD incidence

Analysis of cell free DNA to predict outcome to bevacizumab therapy in colorectal cancer patients

To predict outcome to combination bevacizumab (BVZ) therapy, we employed cell-free DNA (cfDNA) to determine chromosomal instability (CIN), nucleosome footprints (NF) and methylation profiles in metastatic colorectal cancer (mCRC) patients. Low-coverage whole-genome sequencing (LC-WGS) was performed on matched tumor and plasma samples, collected from 74 mCRC patients from the AC-ANGIOPREDICT Phase II trial (NCT01822444), and analysed for CIN and NFs. A validation cohort of plasma samples from the University Medical Center Mannheim (UMM) was similarly profiled. 61 AC-ANGIOPREDICT plasma samples collected before and following BVZ treatment were selected for targeted methylation sequencing. Using cfDNA CIN profiles, AC-ANGIOPREDICT samples were subtyped with 92.3% accuracy into low and high CIN clusters, with good concordance observed between matched plasma and tumor. Improved survival was observed in CIN-high patients. Plasma-based CIN clustering was validated in the UMM cohort. Methylation profiling identified differences in CIN-low vs. CIN high (AUC = 0.87). Moreover, significant methylation score decreases following BVZ was associated with improved outcome (p = 0.013). Analysis of CIN, NFs and methylation profiles from cfDNA in plasma samples facilitates stratification into CIN clusters which inform patient response to treatment.

Computed Tomography Analysis of the Anterior Epitympanic Recess and Sinus Tympani Depths Among Filipino Adults at the De La Salle University Medical Center

Objective: To assess the depths of the anterior epitympanic recess (AER) and the sinus tympani (ST) among Filipino adults and to classify the AER and ST according to grade and type, respectively. Methods: Design:Retrospective Review of CT Scans Setting: Tertiary Private Teaching Hospital Participants:Scans of 182 non-pathologic ears from patients aged 18 and above with non-pathologic temporal bones (paranasal sinus, screening sinus, temporal bone, facial and cranial) with 0.62mm cuts seen from CT scans from January 01, 2010 to September 31, 2022 were analyzed. The depths of the AER and ST were measured separately and classified according to AER grade and ST type. Results: The mean depth of the AER (AER-D) was 3.64 mm (SD 1.17). No significant difference was seen between right and left ears. The AER grading of the anterior-posterior depth was found to be Grade 1 (&lt;3mm) in 54 ears (29.7%), Grade 2 (3-5mm) in 106 ears (58.2%), and Grade 3 (&gt;5mm) in 22 ears (12.1%). The mean depth of the sinus tympani (ST-D) was 3.30 mm (SD 0.80). Out of the 182 ears, 121 (66.5%) had Type A, 50 (27.5%) had Type B while 11 (6%) had Type C. Conclusion: Majority of the AER depths measured 3-5mm while most of the sinus tympani were Type A. These hidden recesses should be separately analyzed in preoperative planning for cholesteatoma surgery in order to prepare the adequate equipment to be used and approach towards these areas thereby reducing the risk for residual cholesteatomas and recurrence.

The Effect of Artificial Intelligence on Patient-Physician Trust: Cross-Sectional Vignette Study.

Clinical decision support systems (CDSSs) based on routine care data, using artificial intelligence (AI), are increasingly being developed. Previous studies focused largely on the technical aspects of using AI, but the acceptability of these technologies by patients remains unclear. We aimed to investigate whether patient-physician trust is affected when medical decision-making is supported by a CDSS. We conducted a vignette study among the patient panel (N=860) of the University Medical Center Utrecht, the Netherlands. Patients were randomly assigned into 4 groups-either the intervention or control groups of the high-risk or low-risk cases. In both the high-risk and low-risk case groups, a physician made a treatment decision with (intervention groups) or without (control groups) the support of a CDSS. Using a questionnaire with a 7-point Likert scale, with 1 indicating "strongly disagree" and 7 indicating "strongly agree," we collected data on patient-physician trust in 3 dimensions: competence, integrity, and benevolence. We assessed differences in patient-physician trust between the control and intervention groups per case using Mann-Whitney U tests and potential effect modification by the participant's sex, age, education level, general trust in health care, and general trust in technology using multivariate analyses of (co)variance. In total, 398 patients participated. In the high-risk case, median perceived competence and integrity were lower in the intervention group compared to the control group but not statistically significant (5.8 vs 5.6; P=.16 and 6.3 vs 6.0; P=.06, respectively). However, the effect of a CDSS application on the perceived competence of the physician depended on the participant's sex (P=.03). Although no between-group differences were found in men, in women, the perception of the physician's competence and integrity was significantly lower in the intervention compared to the control group (P=.009 and P=.01, respectively). In the low-risk case, no differences in trust between the groups were found. However, increased trust in technology positively influenced the perceived benevolence and integrity in the low-risk case (P=.009 and P=.04, respectively). We found that, in general, patient-physician trust was high. However, our findings indicate a potentially negative effect of AI applications on the patient-physician relationship, especially among women and in high-risk situations. Trust in technology, in general, might increase the likelihood of embracing the use of CDSSs by treating professionals.

Machine-learning guided differentiation between photoplethysmography waveforms of supraventricular and ventricular origin

Abstract Aims To test, whether a neural network-based classifier could aid in distinguishing photoplethysmographic (PPG) pulse waveforms of ventricular from those of supraventricular origin. Methods Thirty patients undergoing invasive electrophysiological studies for documented narrow complex tachycardias between May and December 2021 at a university medical centre were included in the trial. PPG waveforms were recorded using a PPG wristband (Empatica E4) in parallel to 12-lead surface electrograms (ECGs) and intracardiac electrograms from diagnostic catheters. Pulse waves were then annotated to either supraventricular (sinus rhythm, atrial pacing) or ventricular origin (ventricular pacing) based on invasive electrogram recordings, ECGs and stimulation protocols. 21147 data sets were split into test, training and validation data sets and used to develop, train and validate a convolutional neural network (CNN) for classifying PPG waveforms according to their origin into sinus rhythm, atrial or ventricular pacing. Results Datasets were complete for 27 patients. 74% were female and median age was 53 (range 18, 78) years, median BMI was 27±5, 19% had arterial hypertension, 11% had diabetes and 15% had coronary artery disease. During the electrophysiological study, typical AV-nodal re-entrant tachycardias could be induced in 63% of patients, 15% had inducible atrial tachycardias and the other patients had no inducible tachyarrhythmias. Our CNN-based classifier was able to correctly predict the origins of pulse waves in 95±1% for sinus rhythm, 96±1% for atrial paced rhythms and 95±1% for ventricular rhythms. Conclusion A neural network-based classifier trained on ground truth PPG data obtained by using invasive EP measurements for annotation could accurately predict atrial or ventricular origin from PPG waveforms alone.Graphical abstract

Termination without global capture: electrocardiographic and anatomical characteristics using 3D-electroanatomical mapping system in reentrant ventricular tachycardia

Abstract Background Termination without global capture (TWGC) is the phenomenon which a pacing stimulus applied during ventricular tachycardia (VT) terminates the tachycardia without generating a QRS complex, and is considered as an indicator for the critical component of the circuit. The details of the electrocardiographic and anatomical characteristics of the site using a 3D-electroanatomical mapping system (3D-EAM) remain unknown. Purpose This study aimed to retrospectively analyze the cases that showed TWGC during VT mapping and ablation, and to investigate the electrocardiographic characteristics and relationship with the substrate identified by 3D-EAM. Methods Of 632 cases of VT associated with structural heart disease from July, 2019 to July, 2023 at a university hospital and a university medical center, cases with TWGC were analyzed. Results TWGC was observed in 10 patients (median age 61 years, 9 males, 5 ischemic cardiomyopathy, median LVEF 31%) at least once (12 times) in 11 locations. Local capture was observed in 6. The QRS morphology generated by continued pacing after TWGC matched the clinical VT in only 5 VTs (42%). Five showed decremental conduction of stimulus to QRS interval following the TWGC. In 11 locations, 4 corresponded to scar area (&amp;lt;0.1 mV) in the voltage map, 6 to border zone (0.1-1.5 mV), and 1 had no information on 3D-EAM. Of 12 times of TWGC, 3 were at the entrance, 1 at the central isthmus, and 1 at the exit. Acute elimination of clinical VT was successful in 7 of 10. Conclusions More than half of the sites with TWGC were located at the border zone in 3D-EAM. TWGC also occurred in the central or exit area, and local capture was observed frequently.Termination without global capture

Feasibility and diagnostic yield of a photoplethysmography-based arrhythmia screening and integrated management pathway in a chronic obstructive pulmonary disease outpatient clinic

Abstract Background Guidelines recommend opportunistic screening for atrial fibrillation (AF) in high-risk populations, including chronic obstructive pulmonary disease (COPD) patients. Purpose We aimed to assess the feasibility and yield of a photoplethysmography (PPG) smartphone app-based pathway for AF detection within a COPD outpatient clinic. Methods Ninety-nine eligible patients from the COPD outpatient clinic at the Maastricht University Medical Center+ underwent a 14-days PPG app-based AF screening. PPG-based AF detection triggered an electrocardiogram (ECG) for AF diagnosis and initiation of a comprehensive AF management. Patients’ adherence and system usability were assessed. Results Patient onboarding was easy, and patients demonstrated good adherence to the protocol (101% [82%-123%]). The usability of the PPG app was satisfactory with a high score in the System Usability Score questionnaire (80.0 [55.0-92.5]). Among 99 patients (mean age 66±9 years; 54% female), 8% had a prior AF diagnosis. Premature beats were common, with 96% of patients showing isolated premature beats (&amp;lt;6 in 960 PPG recordings) and 32% frequent premature beats (≥6 in 210 PPG recordings). The PPG algorithm suspected paroxysmal AF in 6 new cases. AF could be confirmed in 2 patients through resting 12-lead ECG and 1-lead handheld ECG device. One patient who was lost to follow-up. In the remaining 3 patients with suspected AF PPG recordings, analysis of 24-hour, 48-hour and 7-day Holter recordings revealed high burden premature (supra)ventricular beats. Two of these patients manifested self-terminating short episodes of supraventricular tachycardia. Conclusion 14-days opportunistic PPG app-based screening is feasible in COPD outpatient care and results in the detection of new AF cases and premature beats. This novel digital approach offers a practical method to implement recommended AF screening in COPD patients.