Control Patients Research Articles

Investigation of the pathogen-specific antibody response in periprosthetic joint infection.

Periprosthetic joint infections (PJIs) are a very demanding complication of arthroplasty. Diagnosis of PJI and pathogen identification pose considerable challenges in clinical practice. We hypothesized that the pathogen-specific immune response to PJI reflects the infection process, provides clinically relevant information on disease course, and has the potential to further optimize antimicrobial therapy. We conducted a prospective matched cohort pilot study with 13 patients undergoing two-stage septic revision arthroplasty (PJI patients) between 06/2020 and 06/2021, as well as 11 control patients undergoing one-stage aseptic revision arthroplasty (Non-PJI patients). Pre-, intra- and postoperative serum samples were collected at standardized time points. We developed a custom Luminex®-based quantitative bead-based suspension array (Infection Array; IA), and used it for simultaneous measurement of antibody specificities against 32 pathogens commonly associated with PJI in 267 serum samples. The IA was able to trace the dynamics of the pathogen-specific humoral immune response in all patients against PJI-related pathogens, prominently coagulase-negative staphylococci and streptococci. Pathogen-specific serum antibody titers declined in 62% of PJI patients over the course of treatment, while no changes in antibody titers were observed in 82% of Non-PJI patients during this study. Our serological data strongly suggested that antibody signatures reflect an immune response to microbial invasion. Our results provide insights into the pathophysiology of PJI and information on the individual disease courses. The IA is therefore a promising and novel serological tool of high resolution for monitoring the immunoproteomic footprints of infectious pathogens in the course of PJI.

Operative Complications, Vaginal Bleeding, and Practice Considerations for Patients on Testosterone Undergoing Gender-Affirming Hysterectomy

Study ObjectiveTo evaluate operative complications and healthcare utilization in transgender patients on testosterone undergoing minimally invasive gender-affirming hysterectomy compared to control patients. DesignWe performed a retrospective cohort study. Operative reports were used to gather information on intraoperative complications. We collected information on postoperative complications, electronic medical record (EMR) messages, phone calls, emergency department utilization, and clinic visits through a 90-day postoperative period. Healthcare utilization reasons were categorized as vaginal bleeding, pain, vaginal discharge, dysuria, urinary retention, bowel concern, incision concern, or other. SettingTertiary care academic medical center. PatientsPatients aged 18 to 55 who underwent a benign minimally invasive hysterectomy with or without oophorectomy performed between January 2014 and December 2022. The testosterone-using cohort consisted of patients who had a gender identity of male, transgender male, genderqueer, or nonbinary with documented testosterone use prior to surgery (n = 88). The control cohort consisted of patients who identified as female, genderqueer, or nonbinary with no documented testosterone use (n = 242). InterventionsNot applicable. Measurements and Main ResultsPatients using testosterone were younger, had a lower body mass index, lower American Society of Anesthesiologists class, and were more likely to be nulliparous. The median time patients used testosterone was 2.5 years (1.5–5.0). Patients on testosterone are at increased risk of intraoperative perineal lacerations requiring repair (RR 3.3, CI 95% [1.03–10.5]). A higher number of patients on testosterone reported vaginal bleeding via EMR message or phone call (RR 1.74 CI 95% [1.1–2.7]) compared to controls. No difference in reasons for emergency department visits was noted. The use of postoperative vaginal estrogen started at the postoperative visit was more frequent in the testosterone-using patients (7 [8.0%] vs 4 [1.7%], p = .01). ConclusionThis study demonstrates that testosterone use preoperatively may increase risk of intraoperative vaginal laceration requiring repair. Testosterone use also correlates with increased reports of vaginal bleeding through EMR message, phone call, and clinic visit. These results contribute new evidence to include in preoperative counseling and support existing evidence surrounding the safety of gender-affirming hysterectomy.

Designing a Care System based on the Internet of Things for Patients with Multiple Sclerosis

Abstract: Multiple sclerosis (MS) is a neurodegenerative disease that is a major health problem. This issue requires the development of new tools to control patients' activity and reduce care costs. The monitoring system based on the Internet of things is a suitable solution for this concern. In this study, the researchers developed a tool that uses an Arduino board and four accelerometer sensors, heart rate and pulse oximetry sensors, temperature sensors, and Bluetooth modules to monitor the factors related to the health of multiple sclerosis patients. In this method, the information obtained from the sensors connected to the patient's body is placed on the memory board and displayed with the help of an LCD. In the next step, the Bluetooth module transmits the information obtained from these sensors to a mobile application. This application has the ability to share and store information. This information, together with the date display on the LCD, in addition to notifying the person of the resulting changes; it is also sent periodically to the doctor. In general, this tool, together with a mobile device, helps to increase the selfcare of patients, increases the interaction between the patient and the doctor, reduces the frequeI. nt visits of patients to care centers, and helps to improve the quality of life of patients..

Differential preoperative transcriptomic profiles are related to the quality of left ventricle reverse remodelling one year after valve replacement in patients with severe aortic valve stenosis

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Spain´s Ministerio de Economía y Competitividad [(PI21/00084, CIBERCV (CB16/11/00264), co-funded by Fondo Europeo de Desarrollo Regional (FEDER)] Instituto de Investigación Sanitaria Marqués de Valdecilla, IDIVAL (INNVAL21/24; PREVAL22/09) Background Aortic valve stenosis (AS) promotes a progressive remodelling of the left ventricle (LV) characterised by cardiomyocyte hypertrophy and increased deposition of extracellular matrix elements. These adaptive plastic changes may evolve towards heart failure over time. The extent of LV remodelling and its persistence after valve replacement are significant prognostic factors for the long-term outcome of AS patients. The biological processes that determine the reverse remodelling rate after surgery of AS patients are unknown. Purpose To ascertain preoperative LV transcriptomic determinants of favourable reverse remodelling one year after surgery in AS patients. To this end, a genome-wide transcriptomic analysis was performed in LV biopsies from AS patients and surgical controls. Methods and Results The study was performed in AS (n=24) and control patients (n=12) (age and sex matched) followed up for one year after surgery. RNA-seq was performed on LV biopsies obtained during surgery. AS patients were stratified according to the quality of the reverse remodelling at one year in good (LV mass index ≤51 g/m2.7, n=12) or poor (LV mass index >51 g/m2.7, n=12) performers. RNA-seq libraries were prepared and sequenced using an Illumina Next Seq Unit. Resulting reads were mapped against GRCh38.99 version of the human transcriptome. The results from the principal component analysis revealed a distinctive expression gene pattern for the AS condition, accounting for 60.1 % of the variance, with no difference for the sex condition (8.7 %). Differential gene expression was considered significant when yielding a Benjamini-Hochberg adjusted p-value < 0.05. Compared to controls, 339 and 443 genes were differentially expressed in AS with good and poor reverse remodelling, respectively, with 509 overlapping. Gene Set Enrichment Analysis (GSEA) of differentially expressed genes in patients with poor reverse remodelling compared to control patients, showed a significant enrichment (NES > 1.5) in genes associated with angiogenesis, epithelial-mesenchymal transition (EMT), and heart growth. The down-regulated genes (NES < 0) were associated with transcription processes, such as histone modification and RNA processing-related genes, highlighting the significance of epigenetic mechanisms in AS patients exhibiting poor reverse remodelling. In contrast, such transcriptomic profile patterns were not observed in AS with good-reverse remodelling. Conclusion Aortic stenosis patients with good or poor reverse remodelling one year after aortic valve replacement exhibited distinct preoperative LV transcriptome profile. Gene ontology enrichment analysis revealed angiogenesis, EMT, and epigenetic processes as critical biological functions associated with poor reverse remodelling in AS patients.

Risk Factors for Postoperative Chylothorax Occurrence Following Pediatric Congenital Heart Surgery

Objectives: Chylothorax, a rare but potentially life-threatening complication post congenital heart surgery, warrants early identification of risk factors to implement preventive strategies and timely interventions. This study aims to determine risk factors associated with chylothorax occurrence at our cardiac intensive care unit. Methods: We conducted a nested case-control study involving 2042 children who underwent congenital heart surgery at Nhi Dong 1 hospital (Ho Chi Minh City, Vietnam) from Feb 25th, 2015, to October 12th, 2019. Among these, 38 chylothorax cases were matched by sex and year of surgery to 76 randomly selected control patients. Univariate analysis and logistic regression were performed to identify independent factors associated with chylothorax occurrence after congenital heart surgery. Results: Neonatal cardiac surgery, RACHS-1 risk category ≥ 3, aortic arch repair, the arterial switch operation, prolonged bypass time (median 160 mins vs 87 mins) and aortic clamp time (median 89.5mins vs 51 mins), delayed sternal closure and unexpected reoperation were all associated with postoperative chylothorax occurrence on univariate analysis. Additionally, body weight < 4.5 kg (p=0.027), postoperative dysrhythmias (p=0.004), and high volume of chest tube output (> 10% of total expected blood volume) within the first 6 postoperative hours after cardiac intensive care unit admission (p=0.014) emerged as independent risk factors for postoperative chylothorax occurrence with odds ratios and 95% confident interval of 2.78 (1.12-6.87), 3.38 (1.29-8.86) & 3.82 (1.55-9.39), respectively. These factors served as predictors of postoperative chylothorax occurrence with a sensitivity of 42.1%, specificity of 90.8%, positive predictive value of 69.6% and a negative predictive value of 75.8%. Conclusions: High chest tube output within the first 6 postoperative hours, postoperative dysrhythmias, and body weight of < 4.5kg at surgery significantly increase the risk of postoperative chylothorax in our institution. Keywords: Postoperative chylothorax, chylothorax post pediatric cardiac surgery, pediatric chylothorax

Increased Active Inflammation in the Colon is Not a Reliable Predictor of an Elevated Risk of Dysplasia in Patients With Primary Sclerosing Cholangitis and Ulcerative Colitis.

Although the increased risk of colorectal neoplasia in patients with both primary sclerosing cholangitis (PSC) and ulcerative colitis (UC; termed PSC-UC) is well documented, the mechanism through which concomitant PSC increases the risk of colorectal neoplasia remains unclear. Given that the risk of colorectal neoplasia in UC is positively correlated with increased histologic inflammation, this study sought to investigate whether increased histologic inflammation could be used to stratify the risk of dysplasia development in patients with PSC-UC. Twenty patients with PSC-UC and dysplasia were compared with 30 control patients with PSC-UC who had no history of neoplasia. For each patient, all surveillance biopsies were scored using a 4-point scoring system: (1) no epithelial neutrophils = 0, (2) cryptitis only = 1, (3) cryptitis plus crypt abscess in <50% of crypts = 2, and (4) crypt abscess in ≥50% of crypts, erosion, neutrophilic exudate, and/or ulceration = 3. A score was designated for each biopsy, and both mean and maximum inflammation scores were calculated from all biopsies taken during each colonoscopy. The inflammation burden score was calculated for each surveillance interval by multiplying the average maximum score between each pair of surveillance episodes by the length of the surveillance interval in years. The average scores derived from all colonoscopies for each patient were used to determine the patient's overall mean, maximum, and inflammation burden scores. In both the dysplasia and control groups, the 3 summative inflammation scores were calculated independently for the entire colon, right colon, and left colon. The dysplasia group consisted of 14 (70%) men and 6 (30%) women, with a mean age of 27 years at UC diagnosis and a long history of pancolitis (mean duration: 17y). A total of 49 dysplastic lesions were detected in the dysplasia group, and 8 (40%) of the 20 patients had multifocal dysplasia. The majority of dysplastic lesions belonged to nonconventional subtypes (n = 28; 57%) and were located in the right colon (n = 37; 76%). Irrespective of the colon segment, there was no significant difference in the 3 summative inflammation scores between the dysplasia and control groups (P > 0.05). However, in each group, the 3 summative inflammation scores were significantly higher in the right colon than in the left colon (P< 0.05). In conclusion, patients with PSC-UC exhibit increased histologic inflammation in the right colon compared with the left colon, regardless of the presence of dysplasia. Although this may provide an explanation for the predominance of right-sided colorectal neoplasia in patients with PSC-UC, increased histologic inflammation does not reliably predict an elevated risk of dysplasia in patients with PSC-UC. These findings reinforce the current recommendation for annual endoscopic surveillance for all patients with PSC-UC, irrespective of the extent and severity of inflammation.

Lack of Prognostic Value of T-Wave Alternans for Implantable Cardioverter-Defibrillator Benefit in Primary Prevention.

New methods to identify patients who benefit from a primary prophylactic implantable cardioverter-defibrillator (ICD) are needed. T-wave alternans (TWA) has been shown to associate with arrhythmogenesis of the heart and sudden cardiac death. We hypothesized that TWA might be associated with benefit from ICD implantation in primary prevention. In the EU-CERT-ICD (European Comparative Effectiveness Research to Assess the Use of Primary Prophylactic Implantable Cardioverter-Defibrillators) study, we prospectively enrolled 2327 candidates for primary prophylactic ICD. A 24-hour Holter monitor reading was taken from all recruited patients at enrollment. TWA was assessed from Holter monitoring using the modified moving average method. Study outcomes were all-cause death, appropriate shock, and survival benefit. TWA was assessed both as a contiguous variable and as a dichotomized variable with cutoff points <47 μV and <60 μV. The final cohort included 1734 valid T-wave alternans samples, 1211 patients with ICD, and 523 control patients with conservative treatment, with a mean follow-up time of 2.3 years. TWA ≥60 μV was a predicter for a higher all-cause death in patients with an ICD on the basis of a univariate Cox regression model (hazard ratio, 1.484 [95% CI, 1.024-2.151]; P=0.0374; concordance statistic, 0.51). In multivariable models, TWA was not prognostic of death or appropriate shocks in patients with an ICD. In addition, TWA was not prognostic of death in control patients. In a propensity score-adjusted Cox regression model, TWA was not a predictor of ICD benefit. T-wave alternans is poorly prognostic in patients with a primary prophylactic ICD. Although it may be prognostic of life-threatening arrhythmias and sudden cardiac death in several patient populations, it does not seem to be useful in assessing benefit from ICD therapy in primary prevention among patients with an ejection fraction of ≤35%.

Clinical phenotypes of adults with monogenic and syndromic genetic obesity.

Considering limited evidence on diagnostics of genetic obesity in adults, we evaluated phenotypes of adults with genetic obesity. Additionally, we assessed the applicability of Endocrine Society (ES) recommendations for genetic testing in pediatric obesity. We compared clinical features, including age of onset of obesity and appetite, between adults with non-syndromic monogenic obesity (MO), adults with syndromic obesity (SO), and adults with common obesity (CO) as control patients. A total of 79 adults with genetic obesity (32 with MO, 47 with SO) were compared with 186 control patientswith CO. Median BMI was similar among the groups: 41.2, 39.5, and 38.7 kg/m2 for patients with MO, SO, and CO, respectively. Median age of onset of obesity was 3 (IQR: 1-6) years in patients with MO, 9 (IQR: 4-13) years in patients with SO, and 21 (IQR: 13-33) years in patients with CO (p < 0.001). Patients with genetic obesity more often reported increased appetite: 65.6%, 68.1%, and 33.9% in patients with MO, SO, and CO, respectively (p < 0.001). Intellectual deficit and autism spectrum disorder were more prevalent in patients with SO (53.2% and 21.3%) compared with those with MO (3.1% and 6.3%) and CO (both 0.0%). The ES recommendations were fulfilled in 56.3%, 29.8%, and 2.7% of patients with MO, SO, and CO, respectively (p < 0.001). We found distinct phenotypes in adult genetic obesity. Additionally, we demonstrated low sensitivity for detecting genetic obesity in adults using pediatric ES recommendations, necessitating specific genetic testing recommendations in adult obesity care.

Neuropathological findings in Down syndrome, Alzheimer's disease and control patients with and without SARS-COV-2: preliminary findings.

The SARS-CoV-2 virus that led to COVID-19 is associated with significant and long-lasting neurologic symptoms in many patients, with an increased mortality risk for people with Alzheimer's disease (AD) and/or Down syndrome (DS). However, few studies have evaluated the neuropathological and inflammatory sequelae in postmortem brain tissue obtained from AD and people with DS with severe SARS-CoV-2 infections. We examined tau, beta-amyloid (Aβ), inflammatory markers and SARS-CoV-2 nucleoprotein in DS, AD, and healthy non-demented controls with COVID-19 and compared withnon-infected brain tissue from each diseasegroup (total n = 24). A nested ANOVA was used to determine regional effects of the COVID-19 infection on arborization of astrocytes (Sholl analysis) and percent-stained area of Iba-1 and TMEM 119. SARS-CoV-2 antibodies labeled neurons and glial cells in the frontal cortex of all subjects with COVID-19, and in the hippocampus of two of the three DS COVID-19 cases. SARS-CoV-2-related alterations were observed in peri-vascular astrocytes and microglial cells in the gray matter of the frontal cortex, hippocampus, and para-hippocampal gyrus. Bright field microscopy revealed scattered intracellular and diffuse extracellular Aβ deposits in the hippocampus of controls with confirmed SARS-CoV-2 infections. Overall, the present preliminary findings suggest that SARS-CoV-2 infections induce abnormal inflammatory responses in Down syndrome.

Frequency of CYP2C19, P2RY12, ITGB3, ITGA2, and eNOS3 gene polymorphism in patients with myocardial infarction

The aim of the study was to assess the distribution of polymorphic variants G681A (*2) of the CYP2C19 gene, H1/H2 of the P2RY12 gene, T1565C of the ITGB3 gene, C807T of the ITGA2 gene, and T786C of the eNOS3 gene in the population of the Grodno region, and to study their associations with myocardial infarction (MI). The study of the population consists of 493 people, including 400 patients with MI aged 31 to 74 years and 93 people of the control group aged 32 to 60 years. Research data (clinical and genotyping performed by polymerase chain reaction) were analyzed using STATISTICA 10.0 software. The prevalence of carriage of genotypes associated with high residual platelet reactivity and variability in response to dual antiplatelet therapy among patients with MI was 25.2 % for the G681A polymorphic locus of the CYP2C19 gene (GA + AA), and for the H1/H2 polymorphic locus of the P2RY12 gene (H1/H2 + H2/H2) – 40.0 %, for the C807T polymorphic locus of the ITGA2 gene (CT + TT) – 65.8, for the T1565C polymorphic locus of the ITGB3 gene (TC + CC) – 25.5, for the polymorphic locus T786C of the eNOS gene (TC + CC) – 69.2 %. Among the individuals of the control group, the frequency of occurrence of these genotypes was 18.3, 46.2, 60.2, 37.6, 48.4 %, respectively. In patients with MI, compared to the control group, the TT genotype of the eNOS gene was less common (χ2 = 13.6, p = 0.0002), the CC genotype of the eNOS gene (χ2 = 5.4, p = 0.02) and the allele 786C of the eNOS gene (χ2 = 15.1, p = 0.0001) were more often detected. The carriage of the 786C allele of the eNOS gene increased the risk of MI in the studied population (OR = 2.0, 95 % CI: 1.41‒2.82, p = 0.0001). Gender differences were not found in the distribution of genotypes and alleles within the studied groups. There were no differences in carriage by the number of combinations of minor alleles between the control group and patients with MI. The most common combinations of minor alleles in both groups were comparable.

Digital health in the electrophysiological lab: Initial experience, safety and feasibility using remote support for arrhythmia ablation-Results of REMOTE-VA study

Abstract Background In most electrophysiology (EP) labs, electroanatomical mapping (EAM) systems are operated on site by qualified staff or field technical engineers (FTE). Due to lack of skilled personnel, the FTE usually must travel between different hospitals and procedures must be planned in advance. Ablation of ventricular arrhythmias (VA) represents the most complex procedure in the field. The use of remote support (RS) to guide complex EP procedures has the potential to increase flexibility, reduce travel times and maximise healthcare resources. Purpose To evaluate the safety and feasibility of RS as compared to on-site support guided catheter ablation procedures for VA. Methods All patients undergoing ventricular tachycardia (VT) or premature ventricular complex (PVC) ablation using remote support were included. The electronical system of the hospital was searched for 30 days postprocedural emergency department (ED) visits, unplanned ambulatory presentations, and readmissions. RS guided three-dimensional (3D) mapping was achieved by connecting the EAM software with an integrated audio-visual solution for remote support. Internet connection-based headphones and high-resolution cameras ensured the communication between the operator and the FTE, who worked exclusively from home office. The control group consisted of an equal number of patients matched for the type of procedure and undergoing on-site guided procedures. All ablations were performed using high density 3D mapping, as per institutional standard. Results Between October 2022 and October 2023, a total of 25 patients underwent VT (32%) or PVC ablation in our centre using RS and were compared to 25 patients undergoing the same procedures under on-site guidance. In the RS group one patient underwent epicardial VT ablation and another one bipolar ablation for VT Storm. The demographic data were similar between the groups. The median procedure time was 120 (93, 143) minutes in the RS group and 112 (95, 138) minutes in the control group (p=0.95), while the fluoroscopy time was 11.4 (7.0, 14.0) and 7.26 (5.0, 10.9) minutes respectively (p=0.08). The procedural success was achieved in 96% procedures in the RS group and in 100% in the control group. No technical issues or changes to on-site support were reported. One minor intraprocedural complication was noted among the control patients, while 24% of the patients in each group developed minor complications until discharge. Two patients in the RS group and one in the control group had ED visits, while only one patient in the control group had an unplanned ambulatory presentation. One unplanned readmission was reported in the control group (Table 1). Conclusions Even in the most complex procedures including epicardial ablation, the use of RS was feasible and safe in this single centre study. This approach has the potential to increase the feasibility in case of emergency procedures, reduce travel times, and maximise healthcare resources.

Heterogenous atrial conduction in patients with hypertrophic cardiomyopathy and atrial fibrillation

Abstract Background/Introduction Hypertrophic cardiomyopathy (HCM) is characterised by myocardial thickening, fibrosis, and disarray, affecting both ventricles and atria. This pathology extends to atrial tissue, potentially influencing conductivity and contributing to arrhythmias, notably atrial fibrillation (AF). Pulmonary vein isolation to treat AF in HCM patients yields less satisfactory results compared to other patient groups. Improved understanding of the pathophysiology of AF in HCM patients could improve treatment stratification and delivery. Purpose This study aims to analyse atrial conduction properties in HCM patients with AF, compared to age, body mass index and sex-matched control patients. Methods Pre-ablation electroanatomic mapping data from 10 HCM patients and a matched control group of patients with structurally normal hearts undergoing AF ablation was retrospectively analysed. All patients underwent pre-ablation electroanatomic mapping during proximal coronary sinus pacing. This data was analysed using OpenEP software to quantify voltage mapping, conduction velocity and wave collision points. Conduction velocity was calculated using both plane fitting and triangulation methods. Wave collisions were identified by calculating the percentage of points with conduction velocity field divergence values less than -1.5. Results HCM patients exhibited significantly reduced mean left atrial bipolar voltage and greater low voltage burden &amp;lt;0.5mV than matched control patients (1.43mV vs. 2.14mV, p=0.0177; and 38.28% vs. 15.68%, p&amp;lt;0.0001), (Figure 1A and B). Wave collision points were significantly more prevalent in the HCM group (5.4% vs. 1.6%, p=0.0004), indicating more heterogeneous conduction (Figure 1C). Figure 2 shows example of divergence map with local electrograms around wave collision points. Both methods of quantifying conduction velocity showed comparable results. While average conduction velocity showed no statistically significant difference (plane fitting method - 0.61m/s in HCM group vs. 0.64m/s in control group, p = 0.465; triangulation method - 0.61m/s in HCM group, 0.64m/s in control group, p=0.393), a trend toward lower velocities in HCM patients was observed (Figure 1D and 1E). Conclusion HCM patients demonstrate significantly lower bipolar voltage and significantly greater low voltage areas than matched control patients. Atrial conduction in patients with HCM is significantly more heterogenous than matched control patients. These findings highlight marked conduction abnormalities in HCM patients which are likely to contribute to AF pathogenesis.

Comparison between Novel and Conventional Electrocardiographic Markers of Atrial Cardiomyopathy for identification of Persons at Risk for Ischemic Stroke

Abstract Background Atrial cardiomyopathy is associated with increased risk for future atrial fibrillation (AF) and ischemic stroke. Several ECG-derived parameters have been reported to assess the risk for future ischemic stroke. Purpose To predict risk of future ischemic stroke by comparison of the novel parameter duration of the amplified digital sinus-p-wave (APWD; 80mm/mV; 175mm/sec) vs previously described p-wave indices and clinical risk factors (cerebrovascular disease (CVD), CHADS-VASc-score). Methods P-wave-derived parameters were measured on digital 12-lead-sinus-ECGs (recorded +/- 6 months from the clinical stroke event) using the software "ECG-Precision-Analysis V-1-2023". and clinical CHA2DS2-VASc Score was assessed in 80 patients with ischemic stroke (no history of AF, no oral anticoagulation (OAC)) and compared to 80 control patients (without OAC, AF or ischemic stroke within the next five years). Results Patients with ischemic stroke vs control patients presented a higher CHA2DS2-VASc Score (3.7 vs 3.2, p=0.04), had more frequently heart failure (25% vs 13%, p=0.04) and cerebrovascular atherosclerotic disease with stenosis &amp;gt;40% ((22.5% vs 10%, p=0.032). P-wave indices were as follows in patients who developed ischemic stroke within the next 12 months versus patients without stroke within a follow-up period of five years, respectively: APWD (144 vs 128ms, p&amp;lt;0.0001), non-amplified SPWD (118 vs 116ms, p=0.081), A-PTF-V1 (-4660 vs -3860µV*ms, p=0.005), durations and amplitudes of terminal-p-wave in V1 (A-Duration-V1 (83 vs 79ms, p=0.119), A-Amplitude-V1 (-50µV vs -50µV, p=0.028), and advanced interatrial block (aIAB in 25% vs 3.8% of patients; p&amp;lt;0.0001. The novel ECG-derived parameter (duration of the amplified sinus-P-wave &amp;gt;140ms) was the best predictor for future ischemic stroke (accuracy: 74%, sensitivity and specificity: 61% and 86%, respectively; PPV: 82%; area under ROC: 0.776). Sensitivity and specificity of the SPWD, aPTFV1 and aIAB were significantly lower (SPWD&amp;gt;120ms: sensitivity 35% and specificity 78%, PPV: 61%; aPTFV1 ≤-5000µV*ms, accuracy: 61%, sensitivity 46%% and specificity 75%, PPV: 65%; aIAB: accuracy: 61%, sensitivity 25% and specificity 96%, PPV: 87%). Conclusions Among the currently identified ECG markers of atrial cardiomyopathy, the novel APWD and advanced interatrial block have the best predictive performances for diagnosis of persons at risk for ischemic stroke.Comparison between ECG ParametersPredictive Accuracy of Parameters

Mapping Conformational Changes in the Saliva Proteome Potentially Associated with Oral Cancer Aggressiveness.

Diverse proteomics-based strategies have been applied to saliva to quantitatively identify diagnostic and prognostic targets for oral cancer. Considering that these targets may be regulated by events that do not imply variation in protein abundance levels, we hypothesized that changes in protein conformation can be associated with diagnosis and prognosis, revealing biological processes and novel targets of clinical relevance. For this, we employed limited proteolysis-mass spectrometry in saliva samples to explore structural alterations, comparing the proteome of healthy control and oral squamous cell carcinoma (OSCC) patients with and without lymph node metastasis. Thirty-six proteins with potential structural rearrangements were associated with clinical patient features including transketolase and its interacting partners. Moreover, N-glycosylated peptides contribute to structural rearrangements of potential diagnostic and prognostic markers. Altogether, this approach utilizes saliva proteins to search for targets for diagnosing and prognosing oral cancer and can guide the discovery of potential regulated sites beyond protein-level abundance.

Intermittent hypoxia is significantly associated with low-voltage areas in patients with atrial fibrillation complicated by obstructive sleep apnea

Abstract Background Obstructive sleep apnea (OSA) is one of risk factors for atrial fibrillation (AF); however, how OSA affects the structural and electrical atrial remodeling is not well described. This study aimed to determine the association of OSA with left atrial (LA) size and LA low-voltage area (LVA), a known arrhythmogenic substrate for AF. Methods Eighty-three patients undergoing catheter ablation of AF (forty-nine with OSA [apnea–hypopnea index: AHI ≥ 5/h] and thirty-four control patients without OSA by full polysomnography or portable monitor) were studied. In all cases, LA maps were created using a three-dimensional electro-anatomical mapping system in sinus rhythm or pacing from the right atrium. LVA was defined as a bipolar voltage &amp;lt; 0.5 mV. %LVA is defined as ratio of LVA to LA area. Results LVA and %LVA were larger in OSA group as compared to Control group (6.0 ± 6.6 vs. 2.6 ± 3.2 cm2, P = 0.003 and 7.5 ± 8.5 vs. 3.5 ± 4.6 %, P = 0.008, respectively). On the other hand, there was no difference in LA size between the two groups. In addition, 3% oxygen desaturation index (ODI) was significantly correlated with %LVA (r = 0.282, P = 0.010), but not with LA size (r = 0.053, P = 0.637). Multiple regression analysis demonstrated that 3%ODI ≥ 30 (3.088, 1.078-8.851, P = 0.036) was significantly associated with %LVA after adjustment. Conclusion In patients with AF complicated by OSA, significant enlargement of the LVA was observed, but there was no evidence of enlargement in LA size. Intermittent hypoxia may be one of the mechanisms of this atrial electro-anatomical remodeling.figure 1figure 2

Exercise-induced regional heterogeneity of myocardial left ventricular contraction in hereditary long QT syndrome

Abstract Background Hereditary long QT syndrome (LQTS) is characterized by prolonged ventricular repolarization and an increased risk for ventricular arrhythmias (VA) and sudden cardiac death. Dispersion of ventricular repolarization in LQTS may be more pronounced during exercise and not only impacts the heart’s electrical functions but also the pattern of mechanical contraction. Little is known about the intraventricular heterogeneity of wall motion abnormalities in LQTS patients. Methods In this cross-sectional study we quantify regional, transmural, and longitudinal alterations in left ventricular (LV) contraction at rest, during exercise, and recovery in genetically confirmed LQTS patients and healthy controls to evaluate their value in differentiating high risk patients as defined by a history of VA. ECG and echocardiographic assessments were conducted during rest, peak ergometer activity (105 to 125 bpm), and four minutes into recovery phases. Longitudinal strain (LStr) parameters were measured for each LV segment separately. We differentiated LStr variations as heterogeneity of LStr amplitude (hetLStr; standard deviation [SD] or mean range) and dispersion of time-to-peak LStr (disLStr; SD or mean range). Here, we present the analyses of disLStr. Results At present, 15 patients with genetically confirmed LQTS (LQT1: 8, LQTS 2: 7; mean QTc 475 ± 46 ms) have been included of which 9 had a history of VA. In addition, we collected data from 8 age- and gender-matched control patients (mean QTc 401 ± 18 ms). LV ejection fraction and LStr were not significantly different between the LQTS and control groups. However, LQTS patients exhibited a significantly lower mean LStr in both the endocardial and epicardial layers across all phases compared to control. We observed a significantly more pronounced disLStr across all segments in the LQTS group during the rest and recovery phases in the endocardial layer and during all phases in the epicardial layer. Regional differences (apical vs. basal) were found in all LQTS patients only endocardially at rest. Globally, disLStr showed transmural differences (epicardial vs. endocardial) in both asymptomatic and symptomatic LQTS patients during peak exercise and recovery. Upon segmental analysis, it was observed that symptomatic patients exhibited these transmural differences apically already at rest (p=.004), as well as in the basal region during peak exercise (p=.01), and in the apical region during recovery (p=.02). Conclusion LQTS patients show regional (base to apex) and transmural (endocardial to epicardial) heterogeneities in myocardial contraction at rest, during exercise, and recovery as compared to healthy patients. These regional variations in myocardial contraction patterns may be more pronounced in high risk LQTS patients. Ongoing analyses of hetLStr are in progress to corroborate our findings.

#1492 Metabolic switch in CD8+ T cells may influence immune response in chronic antibody-mediated rejection (CAMR)

Abstract Background and Aims CAMR is the main cause of chronic graft injury and subsequent graft loss, but its pathogenesis is still largely unclear. Our group demonstrated an increase in CD8+ T cells infiltrating biopsies from CAMR patients (PMID: 20595199), but their role remains to be defined. Recently, immunometabolism has emerged as a field connecting cell energy metabolism with the immune cell differentiation and functions. Particularly, the permanent aerobic glycolysis of CD8+ lymphocytes induces their transition from naïve to activated state and effector T cells (PMID: 37315709). Thus, the aim of the study was to investigate the molecular mechanisms underlying the development of CAMR by the analysis of gene expression profiles of CD8+ T lymphocytes in conjunction with their metabolic state. Method We enrolled 14 patients with biopsy-proven CAMR and 12 stable transplant recipients with normal graft histology and function (control group). CD8+ T cells were purified by CD8 MicroBeads (Miltenyi Biotec) then counted (TC20™ Automated Cell Counter). Gene expression profiles of CD8+ T lymphocytes isolated from both groups were assessed using Agilent microarrays. Data obtained were statistically and functionally evaluated (IPA software) and validated by qPCR. Oxygen consumption rate (OCR) in CD8+ and CD8- cells was measured by a Resipher oxygen sensing lid (Lucid Scientific Inc., USA). The contribution of mitochondrial respiration to OCR was investigated in isolated CD8+ T cells from CAMR and controls treated with rotenone/antimycin A (Rot/AA), oligomycin (Olygo) or carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP) to evaluate spare respiratory capacity (SRC), ATP-linked respiration, proton leak and maximal respiration. Results Gene expression profiles of CD8+ T cells showed a characteristic alteration of lipid metabolism in CAMR patients with the triglyceride biosynthesis pathway (p = 2.69E-3) as the most altered pathway and several genes de-regulated all potentially involved in the altered metabolic state of CD8+ T cells. Among others, we validated the increased expression of Nicotinamide Phosphoribosyltransferase (NAMPT) (FC = +2.39), the rate-limiting enzyme of nicotinamide adenine dinucleotide (NAD+) salvage pathway involved in the glycolysis progression, mostly activated in effector T cells. We then decided to evaluate the OCR and the metabolic state of CD8+T cells. Basal OCR was higher in CD8+ rather than CD8- cells, but with different trends among cells isolated from control and CAMR patients. Indeed, CD8+ cells from CAMR patients showed higher OCR compared to control, while OCR was lower in CD8- from CAMR rather than control patients. CD8+ OCR from both CAMR and control patients was mostly dependent on mitochondrial respiration, since it was deeply reduced by Rot/AA treatment. Interestingly, inhibitory response to Oligo treatment by CD8+ cells from CAMR patients was modest, while OCR was noticeably stimulated by FCCP in these cells, suggesting that mitochondrial oxygen uptake was not ATP linked but rather associated with increased uncoupling. These data suggest that CD8+ T cells from CAMR patients are activated effector T cells primarily utilizing aerobic glycolysis. To confirm this hypothesis, we evaluated the gene expression levels of: i) HIF1a, which involves permanent dependence on glycolysis even in the presence of oxygen (Warburg effect); ii) fatty acid transporter CD36, whose levels mimic an energy dependence on the beta oxidation of fatty acids, a process activated in memory T cells. We confirmed an increased expression of HIF1a and a reduced expression of CD36 in CD8+T cells from CAMR patients compared to controls (p&amp;lt;0.05), that confirm the T effector phenotype. Conclusion Our data suggest that CD8+ T cell from CAMR patients showed permanent dependency on glycolysis leading to altered immune phenotype and response, thus indicating novel opportunities to modulate the immune system for therapeutic purposes in kidney transplanted patients and reduce graft rejection.

#1156 Outcomes after kidney transplantation in ANCA-associated vasculitis

Abstract Background and Aims ANCA-associated vasculitis with glomerulonephritis (AAV-GN) can lead to end-stage kidney disease (ESKD), requiring replacement therapy with dialysis or kidney transplant (KT). Few large studies evaluated the outcome of these patients after KT. Our aim was to describe, in comparison with a control group, the occurrence of the following events: delayed graft function recovery, graft survival, relapse, acute rejection, overall survival; and to study the risk factors associated with these events. Method This was a retrospective, multicenter (6 French centers), observational study including patients who received a KT between 2005 and 2023 for ESKD secondary to AAV-GN. Each vasculitis case receiving a KT was matched with 2 controls, matched on gender, center, recipient age (±5 years) and transplant period (±1 year). Event-free survival and the associated risk factors were analyzed. Results 369 patients were included, including 123 with AAV-GN and 246 control patients. The median post-KT follow-up for all patients was 58 months. There was no difference in the occurrence of DGF between the groups (18 vs 17%, p = 0.9). In univariable analysis, graft survival was lower in the AAV-GN group compared to the controls (76% vs 81% at 10 years, p = 0.017) (Fig 1A). 10 patients experienced a relapse after KT. ANCA positivity at the time of transplantation appeared to be correlated with relapse. There was no difference in the incidence of acute rejection between the groups (p = 0.44). In univariable analysis, overall survival tended to be lower in AAV-GN patients compared to controls (62% vs 73% at 10 years, p = 0.084) (Fig. 1B). Conclusion Kidney transplantation is an interesting option for patients with AAV-GN: the relapse rate is low, and the occurrence of acute rejection is comparable to a population of control patients. However, in AAV-GN, graft survival and overall survival appear to be poorer than in control patients. Comparison with a matched AAV-GN population remaining on dialysis would be of interest to go further.

#1162 Paraneoplastic podocytopathy in patients with solid cancer: clinical characteristics and new insights into pathophysiological processes about 21 cases

Abstract Background and Aims Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) may occur in patients with solid cancer but this rare association has never been extensively investigated. Here, we report the first series of patients presenting this association, also named paraneoplastic podocytopathy with nephrotic syndrome (PPNS) . Previous study has demonstrated the specific induction in both podocytes and Reed-Sternberg cells of C-Maf Inducing Protein (CMIP) in patients with MCD and Hodgkin lymphoma. Here, we examined whether this molecular relationship was also relevant in patients developing PPNS in the setting of solid cancer. We have investigated the potential CMIP expression in kidney biopsies and in tumor tissues. Method We collected data from patients who presented with histologically proven cancer and concomitantly developed a nephrotic syndrome (± 3 months) related to MCD or FSGS Follow-up data were collected after 3, 6, 12 months and at last visit. We identified a control group of idiopathic nephrotic syndromes (INS) matched on sex, age and histological type, in order to compare the characteristics of these controls with patients with PPNS. Expression of CMIP was studied by immunohistochemistry and by immunofluorescence confocal microscopy on kidney biopsy and tumor samples. We used kidney biopsies from INS and tumors from patients without associated nephrotic syndrome as controls. Results Twenty-one PPNS patients and 21 controls with INS without cancer were identified. The median age of PPNS patients was higher (68 years) than usually observed in INS. Most of them (76%) had a MCD. A broad spectrum of cancers was found (bronchopulmonary, prostatic, colorectal…) . Baseline characteristics were similar between PPNS patients and INS controls, with a median urinary protein creatinine ratio of 865 and 900 mg/mmol, blood albumin t 15 and 15.3 g/L. Estimated glomerular filtration rate were 48 and 60 ml/min/1.73 m² respectively (no significant difference) . At presentation, PPNS patients were more likely to have hematuria (p = 0.031) , a lower median hemoglobin level than controls (p = 0.039) . Moreover, PPNS patients were less often treated with immunosuppressive drugs (p = 0.004) . After 12 months of follow-up, PPNS patients had a less favorable outcome than INS controls, with a mortality rate three times higher (30% vs 9.5%, p = 0.098) and a much lower rate of complete remission of nephrotic syndrome (25% vs 73.7%, p = 0.008, Table 1). CMIP labeling was performed on 13 tumor samples and 16 kidney biopsies in PPNS patients, and on 5 kidney biopsies with INS, and on 5 control tumor samples. Podocyte labeling of CMIP is observed on all but one kidney biopsy. CMIP labeling was positive on all case tumors, but only a scarce staining was detected in control patients with solid cancer without nephrotic syndrome (Fig. 1). In PPNS patients, confocal microscopy analysis on tumoral tissue showed high expression of CMIP in some epithelial cells and in immune infiltrating cells.. In addition, we found that CMIP was specifically express in CD4 T lymphocyte subset (Fig. 2), but not in CD20, FOXP3 or PD1 lymphocytes, defining a novel FOXP3−/PD1− CMIP high CD4+T lymphocyte subpopulation, within immune cell infiltrates. Conclusion We report the first series of patients with PPNS, who have a more severe renal and overall prognosis than controls. We show that patients with PPNS display higher induction of CMIP, both in the tumor and in podocytes. Strikingly, we identified within immune infiltrates a new subset of T-cell harboring a particular phenotype (CD4+, CMIPhigh, FOXP3−, PD1−) , which is not detected in patients with solid tumor without nephrotic syndrome and which could play a key role in the pathophysiology of PPNS.

#1149 Long-COVID in hemodialysis patients: a matched case-control prospective study

Abstract Background and Aims Long-COVID is defined as persistent symptoms after COVID-19 infection. It has been reported that up to 40% of COVID-19 survivors experience long-COVID (O'Mahoney et al. The Lancet, 2023). We aim to determine if hemodialysis (HD) patients experience long-COVID. Method HD patients diagnosed with COVID-19 via RT-PCR test were enrolled from January to April 2022 from 4 clinics in New York City. COVID-19 Yorkshire Rehabilitation Scale (C19-YRS) was administered at baseline (i.e., as soon as possible after diagnosis), and 1 and 6 months after baseline. C19-YRS measures symptoms such as dyspnea, fatigue, decreased cognition, etc. before and after COVID-19 infection. Pre-COVID symptom severity at baseline was used as the comparator when determining differences between pre- and post-COVID periods. Controls were also enrolled as symptoms resembling long-COVID symptoms are prevalent in HD patients who did not have COVID-19 (e.g., fatigue, lowered quality of life, cognitive impairment). Controls were matched to case patients by age (&amp;lt;50 years, 50-70 years, &amp;gt;70 years), vintage (&amp;lt;1 year, 1-5 years, &amp;gt;5 years), sex, and race. In control patients, a modified C19-YRS that excluded questions specifically around COVID-19 infection was administered at the time of enrollment, and 1 and 6 months thereafter. Symptom severity is graded from 0-10 (10 being the worst) and global health score is reported with 10 being the best. Patient demographic and clinical data were obtained from medical records. Paired t-tests tests were used to examine differences in symptom severity pre- and post-COVID-19 infection in case patients. Unpaired t-tests or Chi-squared tests were used to examine differences at each time point in cases and controls. Linear and generalized mixed models were used to examine the effect of time on continuous and discrete long-COVID symptom severity, respectively. Results We studied 30 patients, 15 cases and 15 controls. There were no significant differences between the two groups in age, vintage, sex, race, ethnicity, diabetes, or hypertension (Table 1a). Baseline C19-YRS was administered 43 ± 24 days (range 9-108) after COVID-19 diagnosis. Five patients were hospitalized because of COVID-19 infection. C19-YRS results are shown in Table 1b. Compared to the pre-COVID period, case patients experienced significantly increased dyspnea at baseline; anxiety, depression, and dyspnea at 1 month; fatigue and dyspnea at 6 months. Further, fatigue and ability to perform personal care worsened in case patients from baseline to 6 months. Compared to the cases, controls had significantly higher global health scores at 1 month and a lower prevalence of dyspnea at rest and fatigue at 6 months. Conclusion Following COVID-19 infection, patients report worsening long-COVID symptoms compared to (a) the pre-COVID period and (b) matched controls, specifically fatigue, dyspnea at rest, and decreased perceived health. Further studies are warranted to investigate the long-term consequences of long-COVID in HD patients.