Subclinical Episodes Research Articles

Incidence and Clinical Predictors of Atrial Fibrillation in Patients with Dual-Chamber Pacemakers: A Retrospective Analysis

Abstract Atrial fibrillation (AF) is a prevalent cardiac arrhythmia, affecting millions worldwide and increasing in frequency with age. Despite progress in treatment and prevention, AF remains a significant contributor to stroke, heart failure, and overall cardiovascular morbidity. One particularly challenging type of AF, paroxysmal atrial fibrillation (PAF), is often asymptomatic, leading to delayed diagnosis and increasing the risk of severe complications like stroke. The advent of cardiac implantable electronic devices (CIEDs) has significantly improved the ability to detect subclinical AF or atrial high-rate episodes (AHRE), even in patients with no symptoms. These devices, particularly pacemakers, offer long-term, continuous monitoring of atrial rhythms, making them an invaluable tool for diagnosing AF early and assessing its burden in real time. This study focused on a cohort of patients from the Oltenia region who received dual-chamber pacemakers with no prior diagnosis of AF. The research aimed to monitor the incidence of AF in these patients over a follow-up period of 12 to 18 months and to identify potential clinical predictors for developing AF. A total of 91 patients were assessed in this study, all of whom received dual-chamber pacemakers by the pacing guidelines for conditions such as atrioventricular block and sick sinus syndrome. None of the patients had a history of AF at the time of implantation. Follow-up results indicated an incidence of AHRE in 13.19% of patients, with significant predictors including advanced age and the presence of hypertension. These findings align with the broader literature, which consistently associates both factors with an increased risk of AF. The study underscores the importance of continuous monitoring in pacemaker patients, particularly for detecting asymptomatic AF, which may necessitate specific therapeutic interventions. Although the study’s sample size was limited, its findings contribute valuable insights into managing AF in pacemaker patients, particularly regarding early detection and potential risk factors. Future research with larger cohorts is necessary to confirm and expand these results.

Management of Device Detected Subclinical Atrial Fibrillation

Abstract Purpose of Review Whilst the management of clinically apparent atrial fibrillation (AF) is well-described and evidenced, the same is not true for subclinical atrial fibrillation (SCAF) and atrial high rate episodes (AHRE). In this review article we discuss the management of device-detected AHRE/SCAF in light of recent major trials and meta-analyses. Recent Findings Anticoagulation in AHRE/SCAF reduces thromboembolic risk but causes an increase in bleeding events. Of note, ischaemic stroke risk in untreated AHRE/SCAF has been observed to be lesser than that of untreated clinically evident AF. With regard to reduction of AHRE/SCAF prevalence or burden, increased physical activity has been associated with reduced AHRE/SCAF incidence in a dose-dependent manner. There exists mixed evidence for both angiotensin 2 inhibition therapy and statin therapy in the prevention of AHRE/SCAF in studies with smaller populations. Ongoing studies are assessing the impact of sodium-glucose cotransporter-2 inhibition on AHRE/SCAF. Although there is no evidence for atrial overdrive pacing in preventing AHRE/SCAF, limited evidence suggests pacing lead position and reducing ventricular pacing may minimise AHRE/SCAF. Summary The identification of AHRE/SCAF poses unanswered questions regarding treatment. The benefit of anticoagulation in reducing ischaemic stroke is lesser than that seen in clinical AF. As such, anticoagulation decisions in AHRE/SCAF should take into consideration individual bleeding risk, thromboembolic risk, and arrythmia burden. Management of co-morbidities and physical activity show promise in reducing AHRE/SCAF. Further study is required to investigate the impact of various pharmacologic interventions and pacing considerations on the reduction of AHRE/SCAF.

Atrial High-Rate Episodes and Subclinical Atrial Fibrillation: State of the Art and Clinical Questions with Complex Solutions.

Atrial high-rate episodes (AHREs) and subclinical atrial fibrillation (AF) are frequently registered in asymptomatic patients with cardiac implantable electronic devices (CIEDs) and insertable cardiac monitors (ICMs). While an increased risk of thromboembolic events (e.g., stroke) and benefits from anticoagulation have been widely assessed in the setting of clinical AF, concerns persist about optimal clinical management of subclinical AF/AHREs. As a matter of fact, an optimal threshold of subclinical episodes' duration to predict stroke risk is still lacking and recently published randomized clinical trials assessing the impact of anticoagulation on thromboembolic events in this specific setting have shown contrasting results. The aim of this review is to summarize current evidence regarding classification and clinical impact of subclinical AF/AHREs and to discuss the latest evidence regarding the potential benefit of anticoagulation in this setting, highlighting which clinical questions are still unanswered.

Clinical presentation and genetic characterization of early-onset atrial fibrillation in patients affected by long QT syndrome: A single-center experience.

Early-onset atrial fibrillation (AF) has already been observed in approximately 2% of patients with genetically proven long QT syndrome (LQTS). This frequency is higher than population-based estimates of early-onset AF. However, the concomitant expression of AF in LQTS is likely underestimated. The purpose of this study was to examine the clinical presentation, genetic background, and outcomes of a cohort of patients with LQTS and early-onset AF referred to a single tertiary center. Twenty-seven patients diagnosed with congenital LQTS were included in the study based on the documentation of early-onset (age ≤50 years) clinical or subclinical AF episodes in all available medical records, including standard electrocardiograms, wearable monitor or cardiac implantable electronic devices. Seventeen patients experienced clinical AF during the follow-up period. Subclinical AF was detected in 10 patients through insertable or wearable cardiac monitors. In our series, the mean heart rate during AF episodes was found to be relatively low despite the patients' young age and the low or minimal effective doses of beta-blockers used for QTc interval control. All patients exhibiting LQTS and early-onset AF were genotype positive, carrying mutations in the KCNQ1 (66%), KCNH2, KCNE1, and SCN5A genes. Notably, most of these patients carried the same p.(R231C) mutation in the KCNQ1 gene (59%) and were from the same families, suggesting concurrent expression of familial AF and LQTS. LQTS patients are prone to developing clinical and subclinical AF, even at a younger age. The occurrence of early-onset AF in the LQTS population could be more frequent than previously assumed. AF should be considered as a potential dysrhythmia related to LQTS. Our study emphasizes the importance of carefully researching clinical and/or subclinical episodes of AF through strict heart rhythm monitoring in the LQTS population.

NFAT signaling is indispensable for persistent memory responses of MCMV-specific CD8+ T cells.

Cytomegalovirus (CMV) induces a unique T cell response, where antigen-specific populations do not contract, but rather inflate during viral latency. It has been proposed that subclinical episodes of virus reactivation feed the inflation of CMV-specific memory cells by intermittently engaging T cell receptors (TCRs), but evidence of TCR engagement has remained lacking. Nuclear factor of activated T cells (NFAT) is a family of transcription factors, where NFATc1 and NFATc2 signal downstream of TCR in mature T lymphocytes. We show selective impacts of NFATc1 and/or NFATc2 genetic ablations on the long-term inflation of MCMV-specific CD8+ T cell responses despite largely maintained responses to acute infection. NFATc1 ablation elicited robust phenotypes in isolation, but the strongest effects were observed when both NFAT genes were missing. CMV control was impaired only when both NFATs were deleted in CD8+ T cells used in adoptive immunotherapy of immunodeficient mice. Transcriptome analyses revealed that T cell intrinsic NFAT is not necessary for CD8+ T cell priming, but rather for their maturation towards effector-memory and in particular the effector cells, which dominate the pool of inflationary cells.

Nurse-driven protocol for the management and follow-up of subclinical atrial fibrillation episodes in pacemaker patients

Abstract Background Atrial high-rate episodes (AHREs) compatible with atrial fibrillation (AF) detected in pacemakers are associated with an increased risk of stroke. Nurses trained in pacemaker (PM) follow-up can detect theses AHREs during patient’ scheduled visits and provide the best care option to the patients. Purpose To evaluate a nurse protocol applied in these patients focused on a) identifying those with AHREs and taking into account the timing of these events and their duration, and b) provide the best care and follow-up then after. Methods and Results To create our protocol, we evaluated PM patients without a previous history of AF and classified the incidence of AHREs into 3 groups: >5 minutes to 24 hours; >24 hours and patients who are in clinical AF (documented on ECG) at the time of the visit. We also evaluate the time elapsed since PM implantation (£ 3 months vs > 3 months) and the type of atrial electrode fixation (active vs passive). In a prior study we analyzed 110 patients with AHREs >5 minutes and <24 hours (56% male, age 75 ± 9 years, mean CHA2DS2VACS scores of 3.5 ± 1.5). After 24 ± 9 months, 40 patients (36.4%) presented AHREs, and CT images showed ischemic brain lesions in 26 of them (23.6%). The presence of AHREs at 3 months was more frequent in patients with a recent MP implantation (17% vs 4.5%) and with a significant relationship with the type of active fixation of the electrode. The presence of ischemic lesions on CT was related to the detection of AHREs during follow-up, but not with AHREs in the first 3 months. Therefore, we designed a dedicated protocol for follow-up in these patients (AHREs >5 minutes and <24 hours) after PM implantation with repetitive follow-up visits assessing the evolution of AHREs. In cases of >24 hours and those with ECG documented AF, Guidelines recommendations were followed. Conclusions In PM patients, the presence of AHREs might be related to serious clinical complications. On the other hand, AHREs occur regularly during the first 3 months after PM implantation, maybe related to the procedure itself and the use of active fixation for the atrial lead. AHREs in this period may not be related to major complications and individual risk should be carefully assessed before starting anticoagulation. A dedicated protocol for closer follow-up visits in these patients might help to identify those at risk and prevent clinical events.

Experience and insights from a prolonged electrocardiographic monitorization with a wearable system after an embolic stroke of unknown source.

Embolic cerebrovascular events that remain of unknown etiology after a thorough diagnostic evaluation, are known as Embolic Strokes of Undetermined Source (ESUS). Subclinical atrial fibrillation (AF) represents a significant underlying cause of ESUS. Our aims were to examine the overall diagnostic yield of a prolonged cardiac monitoring wearable system (PCMw) after an ESUS to detect AF and factors associated with it, including the time frame from the ESUS event to PCMw initiation. Additionally, to evaluate the frequency of unexpected arrhythmic events (UAE) and their prognostic implications. We retrospectively analyzed 200 ECG recordings (3-leads, 30days duration) by means of a PCMw in patients with an ESUS to detect AF lasting longer than 30s, between 2017 and 2021. UAE were defined as arrhythmia events that were not correlated to the main reason of prolonged cardiac monitoring. AF was detected in 21 patients (10.5%). Patients with AF had more left atrial enlargement (OR=4.22 [1.59-6.85]; p=.01) and atrial arrythmias in the initial 24-h Holter during hospitalization (OR=5.73 [2.03-16.49]; p=.001). The detection of AF was significatively higher if the PCMw was worn within the first 30days after the ESUS compared to beyond 30days (17% vs. 10.3%; p=.002). Fifty three patients (26.5%) had UAE during PCMw. In six of them these findings led to targeted treatment. PCMw represents a feasible non-invasive device that could reliably detect subclinical AF episodes after an ESUS. Diagnostic yield was significatively higher when used within the first 30days after the event, especially in selected patients. UAE were common, but did not impact prognosis.

Luteolin inhibits herpes simplex virus 1 infection by activating cyclic guanosine monophosphate-adenosine monophosphate synthase-mediated antiviral innate immunity

BackgroundThe successive outbreaks of large-scale infectious diseases due to virus infection have been a major threat to human health in recent decades. Herpes simplex virus I (HSV-1) is a widely-disseminated DNA virus that infects the central nervous system to cause herpes labialis, keratitis and herpes simplex virus encephalitis (HSE), resulting in recurrent lifelong clinical or subclinical episodes. Luteolin is a plant flavone that has been extensively used in the treatment of various human diseases, including carcinogenesis, inflammation and chronic degenerative diseases. PurposeThe aim of this study was to investigate the antiviral molecular mechanism of luteolin against HSV-1 infection in vitro and in vivo. MethodsThe antiviral effect of luteolin in cell lines was examined by viral plaque assay, RT-qPCR, Western blot and time-of-addition assay. The interaction between luteolin and cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) was evaluated by molecular modeling and semi-denaturing detergent agarose gel electrophoresis. The efficacy of luteolin on HSE was evaluated in the HSE mouse model by analyzing weight loss, neurodegenerative symptoms and histopathological scores. Cytokine expression and protein levels were examined by RT-qPCR, Western blot and ELISA. ResultsLuteolin inhibited the early process of HSV-1 infection, without affecting the infection of acyclovir-resistant HSV-1 strains. In addition, luteolin enhanced antiviral type I interferon production and activated the cytoplasmic DNA-sensing cGAS-stimulator of interferon gene (STING) pathway. Luteolin directly bound the active substrate binding site and promoted the oligomerization of cGAS. Luteolin also inhibited HSE-related weight loss, neurodegeneration and neuroinflammation in mice caused by HSV-1 infection. Furthermore, luteolin enhanced type I interferon expression and stimulated the cGAS-STING signaling pathway in vivo. ConclusionLuteolin inhibited the post-entry process of HSV-1 by activating the cGAS-STING pathway to promote antiviral interferon production. These results provided the rationale for luteolin as a potent cGAS activator and antiviral agent.

Immune surveillance and humoral immune responses in kidney transplantation - A look back at T follicular helper cells.

T follicular helper cells comprise a specialized, heterogeneous subset of immune-competent T helper cells capable of influencing B cell responses in lymphoid tissues. In physiology, for example in response to microbial challenges or vaccination, this interaction chiefly results in the production of protecting antibodies and humoral memory. In the context of kidney transplantation, however, immune surveillance provided by T follicular helper cells can take a life of its own despite matching of human leukocyte antigens and employing the latest immunosuppressive regiments. This puts kidney transplant recipients at risk of subclinical and clinical rejection episodes with a potential risk for allograft loss. In this review, the current understanding of immune surveillance provided by T follicular helper cells is briefly described in physiological responses to contrast those pathological responses observed after kidney transplantation. Sensitization of T follicular helper cells with the subsequent emergence of detectable donor-specific human leukocyte antigen antibodies, non-human leukocyte antigen antibodies their implication for kidney transplantation and lessons learnt from other transplantation "settings" with special attention to antibody-mediated rejection will be addressed.

#3154 MALIGNANT HYPERCALCEMIA IN A CASE OF SMALL BOWEL GASTROINTESTINAL STROMAL TUMOUR

Abstract Background and Aims Malignant hypercalcemia is the most common cause of hypercalcemia, occurring in 30% of cancer patients and rendering a poor prognosis. Most cases have a humoral cause, the majority mediated by parathyroid hormone related peptide (PTHrP), rarely by 1,25-dihydroxyvitamin D3 (1,25(OH)2D) and very rarely by parathyroid hormone (PTH) ectopic production; other cases are due to local osteolysis. In the literature, there are only 5 reported cases of hypercalcemia associated to gastrointestinal stromal tumour (GIST), only 2 of them due to 1,25(OH)2D overproduction. Method Case report. Results Sixty-two years-old male with small bowel GIST diagnosed in 2014, subjected to enterectomy and on tyrosine kinase inhibitor (TKI) since 2017. TKI was changed from imatinib to sunitinib 25mg since August 2020 to the present date due to disease progression with liver metastasis. In March 2022, a PET scan showed no bone or soft tissue metastasis and there was a finding of right ureteral lithiasis with asymptomatic mild pyelocaliceal dilation. The patient had also subclinical hypothyroidism and several episodes of acute kidney injury (AKI) associated with hypercalcemia and hyperphosphatemia managed in outpatient clinic. He did not take any other medication besides the TKI. In April 2022, symptoms of disequilibrium, confusion, asthenia, and anorexia drove the patient to the Oncology Department. At physical examination the patient had an ECOG 3, was disoriented, cachectic and dehydrated, with no other noticeable findings. Blood lab tests showed a serum creatinine (sCr) of 2,86 mg/dL (baseline 1,10 mg/dL, estimated glomerular filtration rate of 72 mL/min/1,73 m2), a corrected serum total calcium (sCa) of 16,6 mg/dL and a normal serum phosphate of 4,0 mg/dL. The patient was admitted in the oncology ward with the collaboration of the nephrology department and was started on fluid therapy with 3000–4000cc NaCl 0,9%/day for a target urinary output of 75–200 mL/h. Hypercalcemia work-up showed low PTH of 8,8 pg/dL (reference range: 12–65 pg/dL). Measurement of PTHrP and 1,25(OH)2D were requested but took longer. After 3 days, despite the improvement of both sCr (2,23 mg/dL) and sCa (13,6 mg/dL), zoledronic acid was started. Results revealed an increased 1,25(OH)2D of 309 pg/dL (reference range: 10,9-79,3 pg/dL) and negative PTHrP. At the 6th day, a clear improvement of analytical (sCr 1,60 mg/dL; sCa 11,9 mg/dL) and clinical status, so the patient was discharged. The diagnosis was GIST 1,25(OH)2D overproduction causing malignant hypercalcemia and prednisolone on 20mg id was started. In June 2022, the patient had tumour progression, presenting lethargic, disoriented, and dehydrated; blood lab results showed AKI (sCr 1,97 mg/dL) and worsening hypercalcemia (sCa 14,7 mg/dL). He was admitted for fluid therapy and bisphosphonates but, even though there was a recovery of the hypercalcemia and renal function, the patient's clinical status got worse and he had a fatal outcome in the following days. Conclusion Malignant hypercalcemia caused by GIST 1,25(OH)2D overproduction is a rare condition. The work-up of an oncological patient with ureteral lithiasis and recurrent hypercalcemia should prompt us to a more in-depth investigation.

Prolonged electrocardiographic monitorization with a wearable system after an embolic stroke of undetermined source

Abstract Funding Acknowledgements Type of funding sources: None. Background Embolic cerebrovascular events that remain of unknown etiology after careful diagnostic evaluation are known as Embolic Strokes of Undetermined Source (ESUS). Subclinical atrial fibrillation (AF) is an important cause of ESUS. Purpose Our aims were to analyze the global diagnostic yield of a prolonged cardiac monitoring wearable system (PCMw) after an ESUS to detect AF and factors associated with it, including the time frame from the ESUS event to PCMw initiation. Methods We retrospectively analyzed 200 ECG recordings (3-leads, 30 days duration) by means of a PCMw in patients with an ESUS to detect AF lasting longer than 30 seconds, between 2017-2021. Results AF was detected in 21 patients (10,5 %). Patients with AF had more left atrial enlargement (OR=4,22 [1.59-6.85]; p=0.01) and atrial arrythmias in the initial 24-h Holter during hospitalization (OR=5,73 [2.03-16,49]; p=0.001). The detection of AF was significatively higher if the PCMw was worn within the first 30 days after the ESUS compared to beyond 30 days (17% vs 10,3%; p=0,002). Conclusion PCMw represents a feasible non-invasive device that could reliably detect subclinical AF episodes after an ESUS. Diagnostic yield was significatively higher when used within the first 30 days after the event, especially in selected patients.

232.10: Dynamic of Donor Derived Cell-Free DNA and Blood Gene Expression After Pancreas Transplantation

Introduction: Donor-derived cell-free DNA (dd-cfDNA) is a noninvasive test that had demonstrated high predictive performance for acute rejection in solid organ transplant. However, combining dd-cfDNA with a gene expression profile assay could improve the diagnostic of subclinical acute rejection episodes. We aimed at evaluating the combination of these two molecular diagnostic methods in pancreas transplantation. Materials and Methods: We conducted a prospective longitudinal study including all pancreas transplant recipients from our center from January 2017 to December 2018. Plasma samples were collected before transplant (D0), and at 1h, 24h and 7 days (D7) post-transplant, and at time of pancreas biopsy – either surveillance at 3 weeks (B3) and 12 months (B12), or per clinical indication. Biopsies were classified according to the Banff criteria. Dd-cfDNA percentage (%) was assessed using Eurofins Genoma AlloNext® by Next Generation Sequencing (NGS). Gene expression profiles, measured at the time of pancreas biopsy, were analysed with TruGraf®, a Blood Gene Expression Test of Eurofins_Transplant Genomics that uses a PCR-based assay to analyse gene expression from peripheral blood and assign a result of either “TX” (normal, no rejection) or “not-“TX (rejection). Results: A total of 77 patients were included (SPK n=65; PAK n=12). Dd-cfDNA increased significantly at 1h and 24h after transplantation compared to baseline (D0), most likely reflecting ischemia/reperfusion damage. No correlation with either donor demographics nor cold ischemia time was identified (p>0.05). In 52 cases a biopsy-related sample was obtained (Banff criteria: No rejection n=33; Indeterminate n=5; TCMR grade 1-3 n=15; ABMR n=4). In patients with stable graft function (no rejection during the first 12months) dd-cfDNA decreased by D7 and remained low at B3 and B12 (D0 (0.27±0.14), 1h (4.30±2.53), 24h (2.41±1.79), D7 (0.65±0.47), B3 (0.47±0.28) and B12 (0.61±1.31)) Figure 1. However, in patients with biopsy proven acute rejection (TCMR; 1.74±2.08 or ABMR; 4.42±2.93; p<0.01) % dd-cfDNA increased compared with no proven acute rejection biopsies (N-BPAR; 0.45±0.77). Furthermore, a 1% threshold had a positive predictive value to detect 86% rejection, whereas the negative predictive value was 69%. In the gene expression study 75 patients with biopsy-related sample were included: N-BPAR=41; TCMR=23; ABMR=3 and undetermined=8. The study is currently ongoing. We expect to have more conclusive datain the coming months. Conclusion: We describe the first dd-cfDNA dynamic analysis in pancreas transplant recipients, validating its application for longitudinal monitoring in clinical practice. Combining these results with gene expression profile assay may improve the performance for the diagnosis of subclinical rejection.

The role of urinary N-acetyl-β-D-glucosaminidase in early detection of acute kidney injury among pediatric patients with neoplastic disorders in a retrospective study

BackgroundThe 1-year cumulative incidence of AKI reportedly is high (52%) in pediatric neoplastic disorders. About half of these events occur within 2 weeks. However, subclinical AKI episodes may remain unrecognized by the conventional creatinine-based approaches. We investigated the diagnostic value of urinary N-acetyl-β-D-glucosaminidase (uNAG) as an early marker of acute kidney injury (AKI).MethodsIn our retrospective study, 33 children with neoplastic disorders were inculded who had serial uNAG tests (at least 5 samples/patient) with a total of 367 uNAG measurements. Renal function was determined by cystatin-C and creatinine based GFR, and relative increase of uNAG index (uNAGRI). We focused on detecting both clinical and subclinical AKI episodes (according to Biomarker-Guided Risk Assessment using pRIFLE criteria and /or elevated uNAG levels) and the incidence of chronic kidney damage.ResultsSixty episodes in 26 patients, with positivity at least in one parameter of kidney panel, were identified during the observation period. We detected 18/60 clinical and 12/60 subclinical renal episodes. In 27/60 episodes only uNAG values was elevated with no therapeutic consequence at presentation. Two patients were detected with decreased initial creatinine levels with 3 „silent” AKI.In 13 patients, modest elevation of uNAG persisted suggesting mild, reversible tubular damage, while chronic tubuloglomerular injury occurred in 5 patients.Based on ROC analysis for the occurence of AKI, uNAGRI significantly indicated the presence of AKI, the sensitivity and specificity are higher than the changes of GFRCreat. Serial uNAG measurements are recommended for the reduction of the great amount of false positive uNAG results, often due to overhydratation.ConclusionUse of Biomarker-guided Risk Assessment for AKI identified 1.5 × more clinical and subclinical AKI episodes than with creatinine alone in our pediatric cancer patients. Based on the ROC curve for the occurence of AKI, uNAGRI has relatively high sensitivity and specificity comparable to changes of GFRCysC. The advantage of serial uNAG measurements is to decrease the number of false positive results.Trial registrationThe consent to participate is not applicable because it was not reqired for ethical approval and it is a retrospectiv study.

Atrial Fibrillation is Not A Dead Horse

Prevalence and incidence of Atrial Fibrillation (AF) is high in western countries. It is apparently lower in developing countries, because of unrecognition, undertreatment and related complications and mortality. Studies in subjects wearing cardiac implantable electronic devices showed a wide burden of AF, ranging from subclinical episodes to permanent AF. The aim of our study was to identify haematological and haemodynamic differences between Paroxysmal Atrial Tachyarrhythmias (PAT) compared to Non-Paroxysmal AF (NPAF), detected by 24 hours Holter ECG, and predictive negative factors associated with increased risk of evolution from paroxysmal to persistent or permanent AF. Our data highlight the dynamic nature of PAT and NPAF. PAT in young subjects is a red flag, requiring at least changes in lifestyle and further diagnostic examinations to avoid progression to irreversible pathological myocardial electrical and structural remodeling. Comorbidities, scarce compliance, or inappropriate treatments account for high incidence of acute cerebrovascular events with disabling outcomes in elderly patients. Further studies are needed on genetic susceptibility and vulnerability. Educational campaign is the most effective, long- term strategy. Personalized approach and therapeutical scheme are recommended based on patient compliance and actual risk. A holistic approach to patient is the pillar for any clinical decision and practice.

Clinical Value of Surveillance Biopsies in Pediatric Liver Transplantation.

Although pediatric liver transplantation (LT) results in excellent long-term outcomes, a high incidence of early acute cellular rejection and late graft fibrosis persists. Routine measurement of allograft enzymes may not reliably detect rejection episodes, identify candidates for immunosuppression minimization, or indicate allograft fibrosis. Surveillance biopsies (SBs) can provide valuable information in this regard, but their role in pediatric LT is not fully established. A retrospective cohort of 236 pediatric LT recipients from a high-volume center was studied to characterize the risks and benefits of SB versus for-cause biopsies (FCBs). The study population was 47.1% male and 54.7% Hispanic, and 31% received living donor grafts. Our data suggest that patients in the SB group had better transplant outcomes (rejection-free, graft, and patient survival) compared with patients who had FCBs or who never underwent biopsy. Among 817 biopsies obtained from 236 patients, 150 (18.4%) were SBs. Only 6 patients had a biopsy-related complication, and none were observed in the SB subset. Graft biochemical blood tests did not accurately predict rejection severity on biopsy, with aspartate aminotransferase area under the receiver operating characteristic curve (AUROC) 0.66, alanine aminotransferase AUROC 0.65 (very poor predictions), and gamma-glutamyltransferase AUROC 0.58 (no prediction). SBs identified subclinical rejection in 18.6% of biopsies, whereas 63.3% of SBs had evidence of fibrosis. SBs prompted changes in immunosuppression including dose reduction. Our experience suggests that SB in pediatric LT is safe, offers valuable information about subclinical rejection episodes, and can guide management of immunosuppression, including minimization. Improved outcomes with SB were likely multifactorial, potentially relating to a more favorable early posttransplant course and possible effect of management optimization through SB. Further multicenter studies are needed to examine the role of SBs on long-term outcomes in pediatric LT.

606 Predictive value of left atrial and left ventricular strain for the detection of atrial fibrillation in patients with cryptogenic stroke

Abstract Aims Cryptogenic stroke (CS) is associated with high rate of recurrences and adverse outcomes at long-term follow-up, especially in light of its unknown etiology that often leads to ineffective secondary prevention. In such scenario, asymptomatic misdiagnosed atrial fibrillation (AF) episodes could play an important pathophysiological role. Some studies have pointed left atrial (LA) and left ventricular (LV) systolic and diastolic dysfunction as surrogate markers of AF. The aim of this study was to evaluate the relationship between echocardiographic parameters of LA and LV function, and the occurrence of AF revealed by continuous electrocardiogram (ECG) monitoring in a cohort of CS patients. Methods and results This is a single-centre prospective cohort study. Seventy-two CS patients with continuous ECG monitoring with insertable cardiac monitor (ICM) underwent transthoracic echocardiography (TTE). TTE was focused on LA and LV function, including both standard and longitudinal strain-derived parameters. All detected AF episodes lasting more than 2 min were considered. Patients with and without AF were homogeneous in all baseline characteristics, except for CHA2DS2-VASc score, which was significantly higher in AF group, and prevalence of hypercholesterolaemia, that was significantly higher in no-AF group. ICM revealed AF in 23 patients (32%), on average 196 days after ICM implantation. Among echocardiographic parameters, LV ejection fraction (LVEF, P = 0.007), LA end systolic area (LAES area, P = 0.006), LA volume index (LAVI, P = 0.008), total LA emptying fraction (LATEF, P = 0.013), E velocity (P = 0.042), pulmonary veins AR duration (P = 0.01), septal and median TDI E/e′ (respectively, P = 0.045 and P = 0.039), peak atrial longitudinal strain (PALS) in 4-chamber and in 2-chamber view (respectively, P &amp;lt; 0.001 and P = 0.011), peak atrial contraction strain (PACS, P &amp;lt; 0.001), LA conduit strain (P = 0.005), and LV longitudinal strain (LVLS, P = 0.001) were significantly associated to the occurrence of AF, suggesting worst atrial function in AF group. Furthermore, multivariable regression analysis revealed that PACS and LV strain were the only echocardiographic parameters independently associated with AF [confidence interval (CI) 95%: 0.48–0.90, P = 0.005 and CI 95%: 0.46–0.95, P = 0.041 respectively]. Conclusions In a cohort of CS patients, continuous ECG monitoring with ICM revealed subclinical AF episodes in about one-third of patients. In such population, LA and LV strain analysis add predictive value for occurrence of AF over clinical and morpho-functional echocardiographic parameters. Impaired booster pump strain and LVLS strain are strong and independent predictors of AF.

Toll-Like Receptors and Mannose Binding Lectin Gene Polymorphisms Associated with Cryptosporidial Diarrhea in Children in Southern India.

ABSTRACT.In low-resource settings, Cryptosporidium spp. is a common cause of diarrheal disease in children under the age of 3 years. In addition to diarrhea, these children also experience subclinical episodes that have been shown to affect growth and cognitive function. In this study, we screened polymorphisms in the promoter and exon1 regions of the mannose binding lectin 2 (MBL2) gene, as well as single nucleotide polymorphisms (SNPs) described in toll-like receptors (TLR) TLR1, TLR2, TLR4, and TLR9 and TIR domain-containing adaptor protein (TIRAP) genes among children with cryptosporidial diarrhea (cases) and children who only experienced asymptomatic (subclinical) cryptosporidiosis (controls). Among the polymorphisms screened, the variant allele B at codon 54 (rs1800450) of the MBL2 gene was associated with susceptibility to cryptosporidial diarrhea (odds ratio [OR] = 2.2, 95% confidence interval [CI] 1.1–4.5). When plasma MBL levels were compared, 72% of cases were found to be deficient compared with 32% among controls (OR = 5.09). Among TLR polymorphisms screened, multivariate analysis showed that heterozygous genotypes of TLR4 896A/G (rs4986790, OR = 0.33, 95% CI: 0.11–0.98) and TIRAP 539 C/T (rs8177374, OR = 0.19, 95% CI: 0.06–0.64) SNPs were associated with protection from cryptosporidial diarrhea. Although not statistically significant, these findings suggest that polymorphisms of MBL2 and TLR genes influence susceptibility to symptomatic cryptosporidial diarrhea even in settings with high exposure levels. Further studies to validate these findings in a larger cohort and to understand the role of these polymorphisms in mediating innate and adaptive immune responses to cryptosporidial infection are necessary.

Optimizing indices of atrial fibrillation susceptibility and burden to evaluate atrial fibrillation severity, risk and outcomes

Atrial fibrillation (AF) has heterogeneous patterns of presentation concerning symptoms, duration of episodes, AF burden, and the tendency to progress towards the terminal step of permanent AF. AF is associated with a risk of stroke/thromboembolism traditionally considered dependent on patient-level risk factors rather than AF type, AF burden, or other characterizations. However, the time spent in AF appears related to an incremental risk of stroke, as suggested by the higher risk of stroke in patients with clinical AF vs. subclinical episodes and in patients with non-paroxysmal AF vs. paroxysmal AF. In patients with device-detected atrial tachyarrhythmias, AF burden is a dynamic process with potential transitions from a lower to a higher maximum daily arrhythmia burden, thus justifying monitoring its temporal evolution. In clinical terms, the appearance of the first episode of AF, the characterization of the arrhythmia in a specific AF type, the progression of AF, and the response to rhythm control therapies, as well as the clinical outcomes, are all conditioned by underlying heart disease, risk factors, and comorbidities. Improved understanding is needed on how to monitor and modulate the effect of factors that condition AF susceptibility and modulate AF-associated outcomes. The increasing use of wearables and apps in practice and clinical research may be useful to predict and quantify AF burden and assess AF susceptibility at the individual patient level. This may help us reveal why AF stops and starts again, or why AF episodes, or burden, cluster. Additionally, whether the distribution of burden is associated with variations in the propensity to thrombosis or other clinical adverse events. Combining the improved methods for data analysis, clinical and translational science could be the basis for the early identification of the subset of patients at risk of progressing to a longer duration/higher burden of AF and the associated adverse outcomes.

A Prospective Controlled Trial to Evaluate Safety and Efficacy of in vitro Expanded Recipient Regulatory T Cell Therapy and Tocilizumab Together With Donor Bone Marrow Infusion in HLA-Mismatched Living Donor Kidney Transplant Recipients (Trex001).

Background: The induction of donor-specific immunological tolerance could improve outcome after kidney transplantation. However, no tolerance protocol is available for routine clinical use. Chimerism-based regimens hold promise, but their widespread application is impeded in part by unresolved safety issues. This study tests the hypothesis that therapy with polyclonal recipient regulatory T cells (Tregs) and anti-IL6R (tocilizumab) leads to transient chimerism and achieves pro-tolerogenic immunomodulation in kidney transplant recipients also receiving donor bone marrow (BM) without myelosuppressive conditioning of the recipient.Methods/design: A prospective, open-label, controlled, single-center, phase I/IIa academic study is performed in HLA-mismatched living donor kidney transplant recipients.Study group: Recipients of the study group receive in vitro expanded recipient Tregs and a donor bone marrow cell infusion within 3 days after transplantation and tocilizumab for the first 3 weeks post-transplant. In addition they are treated with thymoglobulin, belatacept, sirolimus, and steroids as immunosuppression. Starting 6 months post-transplant, sirolimus and steroids are withdrawn in a step-wise manner in stable patients.Control group: Recipients of the control group are treated with thymoglobulin, belatacept, sirolimus, and steroids as immunosuppression. Co-primary endpoints of safety (impaired graft function [eGFR <35 mL/min/1.73 m2], graft-vs.-host disease or patient death by 12 months) and efficacy (total leukocyte donor chimerism within 28 days post-transplant) are assessed. Secondary endpoints include frequency of biopsy-proven acute rejection episodes and subclinical rejection episodes on surveillance biopsies, assessment of kidney graft function, and the evaluation whether the study protocol leads to detectable changes in the immune system indicative of pro-tolerogenic immune modulation.Discussion: The results of this trial will provide evidence whether treatment with recipient Tregs and donor BM is feasible, safe and efficacious in leading to transient chimerism. If successful, this combination cell therapy has the potential to become a novel treatment option for immunomodulation in organ transplantation without the toxicities associated with myelosuppressive recipient conditioning.Trial registration: European Clinical Trials Database EudraCT Nr 2018-003142-16 and clinicaltrials.gov NCT03867617.

Incidence and predictors of atrial fibrillation episodes as detected by implantable loop recorder in patients at risk: From the LOOP study

Recent studies have suggested a high prevalence of subclinical atrial fibrillation (AF) in various patient populations, and interest in AF screening has increased. However, knowledge about episode duration is scarce, and risk factors for short or long subclinical AF episodes have yet to be recognized. The aim of the study was to assess AF by long-term continuous screening and to investigate predictors of episodes lasting ≥6 minutes, ≥5.5 hours, or ≥24 hours, respectively. A total of 597 patients aged ≥70 years and diagnosed with ≥1 of hypertension, diabetes, previous stroke, or heart failure were recruited from the general population to receive implantable loop recorder with remote monitoring. Exclusion criteria included history of AF or cardiac implantable electronic device. AF episodes were adjudicated by senior cardiologists. During 40 (37; 42) months of continuous monitoring, AF was detected in 209 (35%) of the patients. The cumulative incidences at 3 years were 33.8% (30.2%-37.8%), 16.1% (13.4%-19.4%), and 5.7% (4.1%-7.9%) for AF episodes lasting ≥6 minutes, ≥5.5 hours, and ≥24 hours, respectively. Slower resting sinus rate and higher body mass index, N-terminal prohormone of brain natriuretic peptide, and troponin T at baseline were independently associated with AF detection. Addition of these markers to a model of sex, age, and comorbidities improved prediction of AF episodes ≥24 hours (time-dependent area under the receiver operating characteristic curve 79% vs 65%, P = .037). A considerable burden of previously unknown AF was detected when long-term monitoring was applied in at-risk patients. Biomarkers were associated with AF incidence and improved prediction of long AF episodes.