Preemptive Intervention Research Articles

Evaluation of Atrial Fibrillation Risk and Outcome after Allogeneic Transplantation Using an Artificial Intelligence ECG Algorithm and Echocardiographic Parameters in an MDS Cohort

Introduction Atrial fibrillation/flutter (Afib) contributes independently to the hematopoietic cell transplant comorbidity index (HCTCI) and is a known complication of allogeneic hematopoietic transplantation (AlloHCT) which has been linked to inferior outcomes, particularly in older patients. An electrocardiogram (ECG)-based artificial intelligence (AI) algorithm to predict Afib and cardiac contractile dysfunction risk has been validated (Lancet 394:861, 2019). We hypothesized that assessment of pre-transplant Afib risk using the AI algorithm may predict future development of Afib and help identify patients at higher risk for this complication. Methods 191 consecutive MDS patients undergoing AlloHCT with curative intent using myeloablative (28.3%) or reduced intensity conditioning (62.3%) in the Mayo Clinic Comprehensive Cancer Center (Rochester, Jacksonville, Phoenix) between November 2015 and January 2022 were included in this retrospective analysis. Primary outcome was Afib within 100 days and 365 days of transplantation, and we also assessed the outcomes of Death and Relapse. Revised IPSS (IPSS-R) and HCTCI scores were included for all patients. Elevated Afib risk score using the AI algorithm was calculated from pre-transplant ECG, performed during vital organ testing at AlloHCT clearance. In addition to left ventricular (LV) ejection fraction (EF) we evaluated detailed echocardiographic (Echo) parameters including LV volume and mass indices, left atrial volume index (LAVI), maximum trans mitral flow velocities during LV filling (E velocity) and during the diastolic phase due to atrial contraction (A velocity), the velocity of the annulus away from the apex during the protodiastolic phase (e' velocity), E/A and E/e' ratios, the presence of valvular disease, and right ventricular systolic pressure (RVSP). We performed an analysis using a Cox proportional hazards regression models (adjusting for age and sex) to evaluate associations with Afib risk, Relapse, and Overall Survival. Results The median age was 64 years (18-75), 58.6% were male, 6.9% non-white race, and 3.7% Hispanic/Latino ethnicity. Most patients had an HCTCI score of 0-3 (76.3%). GVHD prophylaxis was predominantly with calcineurin inhibitor-based regimes plus/minus methotrexate or mycophenolate mofetil (83.8%). 5.2% of patients had a history of Afib before transplant. Non-relapse mortality was 7.9% at 100 days, and 18.3% at 365 days. N=25 patients (13.1%) developed Afib within 100 days, and n=28 (14.7%) within 1-year after AlloHCT. On multivariable analysis, Age [Hazard Ratio (HR) 2.83, 95% Confidence Interval (CI) 1.36-5.89, p=0.0055] and Echo parameters [including LAVI (HR 2.10, CI 1.23-3.58, p=0.0067), E velocity (HR 3.28, CI 1.29-8.80, p=0.013), E/A ratio (HR 3.74, CI 1.75-7.97, p=0.0006), E/e ' ratio (HR 1.81, CI 1.07-3.07, p=0.026) and RVSP (HR 1.68, CI 1.04-2.70, p=0.032)] were significantly associated with Afib risk; elevated AI risk score was significant in the univariate model (HR 2.74, CI 1.15-6.53, p=0.023) but was borderline in the multivariate model (HR 2.34, CI 0.98-5.60, p=0.056) ( Table 1). Based on previous observations we evaluated the association of AI and Echo parameters with Relapse and Death after AlloHCT ( Table 1). Age (HR 1.32, CI 1.01-1.71, p=0.041) and IPSS-R (HR 1.20, CI 1.08-1.33, p=0.0009) were significantly associated with Death after AlloHCT, while HCTCI (HR 1.10, CI 1.00-1.22, p=0.052) and higher LV EF (HR 0.63, CI 0.38-1.06, p=0.084) were borderline. For Relapse, only IPSS-R (HR 1.52, CI 1.31-1.75, p=1.22E-08) was significant, while increase Echo E velocity was of borderline significance (HR 0.45, CI 0.20-1.02, p=0.057). Conclusions Afib is a common post-AlloHCT complication and is more frequent with increasing Age. Echo parameters (specifically E/A ratio) predict significantly higher Afib risk, while the baseline ECG AI algorithm was of borderline significance. The selection of patients with lower HCTCI scores, and the low background prevalence of Afib in this cohort (i.e., selection of patients with lower baseline cardiac morbidity) are possible explanations for non-significance of the AI algorithm. As anticipated Age and IPSS-R are the greatest predictors of Death after AlloHCT, although the suggestion of an association with baseline Echo parameters highlights the importance of identifying those who may benefit from preemptive Cardiology intervention.

Infusion Reactions with Alternative Therapies during the National Shortage of Iron Dextran

Introduction The national shortage of intravenous iron dextran has required patients to receive more alternative iron infusions, such as iron sucrose and sodium ferric gluconate/sucrose, since January 2023. While prior studies have evaluated rates of infusion reactions among some commonly used intravenous iron formulations, data is lacking among differing doses of iron formulations and especially in the setting of this iron dextran shortage. Clinicians at our institution generally observed more adverse reactions with alternative iron infusions during the national shortage of iron dextran compared to prior. Our study examines the infusion reactions of various iron therapies at differing doses and actions providers and patients took thereafter to assess the impact of the iron dextran national shortage on patients. Methods Patients were included who received iron infusions in three Henry Ford Hospital clinics in metropolitan Detroit, Michigan, from July 2022-June 2023 with the national iron dextran shortage impacting the health system since January 2023. Age, race, sex, reason for iron infusion, iron infusion formulation received, time of infusion, and dosing schedule of infusion were recorded for all participants. We assessed the symptoms experienced and actions taken for patients who had an infusion reaction. The number and type of infusion reactions between different iron infusion formulations and doses were then compared. Results Of the 880 unique patients assessed, 496 (56.4%) received iron dextran, iron sucrose, or sodium ferric gluconate/sucrose between July 2022 and December 2022 prior to the national iron dextran shortage and 384 (43.6%) patients had iron infusions between January 2023 and June 2023 during the shortage. Iron dextran accounted for most of the infusions (n= 356, 71.8%) prior to the shortage whereas iron sucrose was the majority (n=312, 81.3%) during the shortage. Prior to the national shortage, 30 iron infusions reactions occurred, with 18 (60%) associated with iron dextran, 9 (30%) with iron sucrose, and 3 (16.7%) with sodium ferric gluconate/sucrose. During the shortage, 44 reactions occurred, with 1 (2.27%) associated with iron dextran, 41 (93.1%) with iron sucrose, and 2 (4.54%) with sodium ferric gluconate/sucrose. The most reactions (n=41, 55.4%) occurred with iron sucrose at a dose of 500mg across the whole study period. Less reactions (n=9, 12.2%) were reported for iron sucrose at progressively lower doses, comparable to reactions with iron dextran at doses greater than 1000mg (n=8, 10.8%) and at lower doses of iron dextran (n=10, 13.5%). The most common reaction across all infusion types was nausea, vomiting, and/or diarrhea. After an iron infusion reaction, the infusion plan was then most commonly discontinued, with patients either switching to alternative iron infusion formulations, continuing the same infusion type with medications for symptoms, or continuing the same infusion type with lower dose and increased frequency. Conclusion More iron infusion reactions occurred after the national shortage of iron dextran since January 2023 in the setting of more frequent use of alternative iron therapies. The most common infusion formulation associated with a reaction was iron sucrose at its higher recommended dose of 500mg, compared with iron dextran and sodium ferric gluconate/sucrose. Providers should be aware of these associated adverse reactions with the different doses of alternative formulations when recommending infusions for patients, and the need for preemptive intervention.

Chidamide-Based Pre-Emptive Treatment for High-Risk AML Patients after Hematopoietic Stem Cell Transplantation: A Real-World Experience from Chinese Single-Center

Background: The treatment of relapsed or refractory acute myeloid leukemia ( AML) remains challenging. Measurable residual disease (MRD) persistence at transplantation or post-transplantation has been identified as the strongest risk factor for relapse and poor outcomes for patients with hematological malignancies (HMs). Chidamide, a novel oral histone deacetylase inhibitor, has shown potential therapeutic effects in various types of HMs by inducing cell apoptosis and regulating immunity. This study aimed to evaluate the efficacy and safety of Chidamide-based prophylactic or pre-emptive treatment for patients who are MRD positive before or who have sustained MRD positive after transplantation. Aim: The rate of 6 months of conversion to MRD- and relapse-free survival of high-risk AML after Chidamide-based treatment. Methods: From December 2020 to July 2023, 50 patients with high-risk HMs received chidamide-based therapy after allo-HSCT. 39 patients were diagnosed with AML ( 4 secondary AML), 2 with myelodysplastic syndromes, 6 with acute lymphoid leukemia, and 3 with mixed-phenotype acute leukemia. 46 patients (92%) with relapsed/refractory status or detectable MRD (MRD+) at transplantation or after allo-HSCT received chidamide as pre-emptive, and the remaining 4 high-risk patients with MRD− conducted as prophylactic intervention. Patients with detectable MRD before transplantation and those who remained positive for MRD after transplantation were defined as very high-risk AML (VHR-AML). Chidamide was administered at a dose of 5 mg per day orally, 6 times per week, lasting at least 1 year after engraftment. Additional agents included hypomethylating agents (HMAs), donor lymphocyte infusion (DLI) or tyrosine kinase inhibitor (TKI) in patients with Philadelphia chromosome-positive. In this study, 28 patients received chidamide monotherapy, 13 received chidamide combined with HMAs, and 9 cases with other therapy. Results: The median age of all patients was 38 years old (range 17-67), comprising 24 males and 26 females. Up to 1st July 2023, with a median follow-up period of 376 days (25-984d), the overall rate of MRD negative showed 64%. The rate of MRD- survival, Relapse-free survival (RFS) and overall survival (OS) were 56%, 66% and 76%, respectively. The 6 months MRD negative rate, RFS and OS rate were 86%, 82%, 86% and 88%, which maintained at 82%, 82% and 86% with 12 months follow-up, respectively. In 46 cases of the pre-emptive intervention arm, the overall MRD- rate was 61.7%. Among them, 83.3% of patients (20/24) who received chidamide monotherapy exhibited a much higher conversion to MRD− than those combined with HMAs (7/13, 53.8%) or other drugs (2/9, 22.2%) (P=0.004). In 4 cases who received chidamide monotherapy as prophylactic intervention, 3 patients sustained MRD negativity up to the last follow-up, except for one patient diagnosed with MPAL(B+M) relapsed after 1 year of HSCT with taking chidamide for 6 months. A total of 30 patients (including 25 AML) with VHR diseases remained in a status of MRD+ or non-remission after transplantation. Eighteen patients (60%) achieved MRD− and sustained for a median of 251 days (range 31-531 d). VHR-AML patients account for 94.4% (17/18) of MRD- responders(Figure 1A). Similarly, the results showed a higher rate of conversion from MRD+ to MRD− in chidamide monotherapy than the combination groups (Chidamide monotherapy, 81.8%; Chidamide + HMA, 63.6% and Chidamide + others, 25%, P=0.042,Figure 1B). It highlighted that treatment with chidamide resulted in increased MRD− response, especially for AML. On the contrary, of 7 patients with B-cell malignancy, including 5 B-ALL and 2 MPAL (B + M) patients, only 2 (28.6%) patients converted to MRD−. Reversible grade 3/4 neutropenia occurred in 38% of patients, and thrombocytopenia was observed in 24% during the first four treatment cycles. Five patients experienced grade 1/2 non-hematological adverse events, such as fatigue, gastrointestinal reaction, pneumonia and infection. No new-onset GvHD was reported in patients without a prior history of GvHD during chidamide treatment. Conclusion: The chidamide-based regimen is safe and effective in pre-emptive treatment for patients with high-risk relapsed AML after transplantation. Whether as a monotherapy or combined with HMA, chidamide shows significant efficacy in eliminating MRD, warranting further clinical research.

Robotic tomographic ultrasound and artificial intelligence for management of haemodialysis arteriovenous fistulae.

Arteriovenous fistulae (AVF) and Arteriovenous Grafts (AVG) may present a problematic vascular access for renal replacement therapy (RRT), reliant on recurrent specialist nurse and medical evaluation. Dysfunctional accesses are frequently referred 'out of the dialysis clinic' for specialist sonographic examination, with associated delays potentiating loss of vascular access viability and/or need for emergency intervention. Definitive anatomical and functional diagnostics based in the dialysis unit may help to solve these delays and associated complications. This publication reports a novel vascular access monitoring concept, Robotic Tomographic Ultrasound (RTU). Robotic Tomographic Ultrasound incorporates a semi-autonomous, robotic vascular ultrasound system and purpose designed analysis software that can be deployed at the point of care. Three-dimensional scan data, as well as conventional B-Mode and Doppler data are obtained by the system and transferred to a cloud based reporting and analysis software. Scans are remotely annotated and interpreted by a sonographer, with diagnostic data presented securely to clinicians on their preferred web based application/web connected device. Software developed specifically for pre AVF mapping, maturation and monitoring protocols, analyse the data and then present interpreted results to all caring clinicians to assist with decision making. Vascular access planning can be determined with high confidence with data from the Map module. Maturation data can be presented in line with institutional requirements to the dialysis nurse, facilitating precocious needle access. Robotic Tomographic Ultrasound is a novel approach to vascular access management that may reduce the risk of loss of functional access by regular monitoring with the system; automated alerts guiding clinicians to the need for pre-emptive intervention, and the potential to increase longevity of the vascular access.

Results of a hemodialysis vascular access routine ultrasound surveillance protocol and frequency of surveillance guided pre-emptive access maintenance interventions

Background: To evaluate the implementation of routine surveillance using ultrasound on hemodialysis vascular access (VA) outcomes and determine the number and frequency of corrective, surveillance-guided procedures performed. Methods: Multicenter, prospective, observational study that includes consecutive hemodialysis patients receiving therapy from native arteriovenous fistulae (AVF) or grafts (AVG). Participants were assigned to a routine VA Color Doppler ultrasound surveillance (DUS) protocol from January 2019 to December 2021. Patients were referred for corrective procedures (endovascular or surgical) based on clinical or DUS findings (pre-emptive procedures; PEP). Primary endpoint was the estimation of primary unassisted (PUP) and secondary patency (SP) rates. Secondary endpoints were the determination of the number and frequency of PEP and VA survival rates. Results: In total, 223 patients with 243 VA (192 AVF and 51 AVG) were included. Access PUP and SP rates were 83% and 93% at 12 months, 75% and 88% at 24 months, and 72% and 83% at 36 months follow-up. Autologous fistulae PUP and SP were 89% and 96% at 12 months, 81% and 93% at 24 months, and 80% and 89% at 36 months, respectively. Graft PUP and SP were 56% and 80% at 12 months, 44% and 65% at 24 months, and 39% and 54% at 36 months, respectively. In total, 56 corrective procedures (38/56 PEP; 65.5%) were performed (0.13 procedures/year), of which 34 were in AVF patients (0.09 procedures/year) and 22 in AVG patients (0.40 procedures/year). Overall, 33 VA losses occurred (0.06 failures/year), 17 in AVF (0.04 failures/year), and 16 in AVG patients (0.20 failures/year). Conclusion: The use of DUS resulted in the timely diagnosis of dysfunction, satisfactory overall VA survival, and patency rates, with a low PEP frequency. Randomized controlled trials are required to establish the value of DUS surveillance on access patency and whether DUS-guided interventions could improve VA outcomes.

Abstract 219: Prediction of Shock-Refractory Ventricular Fibrillation Amidst Continuous Chest Compressions During Out-of-Hospital Cardiac Arrest Resuscitation

Background: Shock-refractory (SR) ventricular fibrillation (VF) patients (requiring ≥ 3 shocks) have relatively poor outcomes. Prediction of SR-VF may enable preemptive interventions targeted to improve SR-VF outcomes, such as earlier antiarrhythmics, alternative shock delivery strategies, or early transport for hospital-based interventions. We recently demonstrated prediction of SR-VF in the context of current practice whereby chest compressions (CCs) are interrupted for electrocardiogram (ECG) analysis prior to the initial shock. However, since pausing CCs is detrimental to outcome, ideally next-generation defibrillator algorithms will analyze during uninterrupted CCs, precluding CC interruption for SR-VF prediction. Aim: We designed a machine learning algorithm to predict SR-VF based on ECGs surrounding the first shock during CCs. Methods: We performed a retrospective study of adult out-of-hospital VF cardiac arrests treated by paramedics from 2008-2020 in King County WA. From each patient we collected a pair of 3-s VF ECG segments during uninterrupted CCs prior to and 1 minute following the first shock. Patients were randomized into 80%/20% groups for training/test. A random forest classifier was trained to predict SR-VF using dimensionally-reduced ECG scalograms. Performance was assessed by area under the receiver operating characteristic curve (AUC) and sensitivity for >90% specificity. Results: Of 940 included patients, 584 (62%) had SR-VF, median age was 62, 206 (22%) were female, and 429 (46%) survived to hospital discharge. AUC for predicting SR-VF was 0.80 (95% CI: 0.72-0.85) in 188 test patients (Figure), with specificity of 92% and sensitivity of 52%. Conclusion: Automated SR-VF prediction during ongoing CCs is possible using the ECG surrounding the initial shock. Early identification of SR-VF during CCs could prompt preemptive, patient-specific treatments without compromising CPR, potentially improving resuscitation outcome.

Characterizing the pre-clinical phase of inflammatory bowel disease

Understanding the biological changes that precede a diagnosis of inflammatory bowel disease (IBD) could facilitate pre-emptive interventions, including risk factor modification, but this pre-clinical phase of disease remains poorly characterized. Using measurements from 17 hematological and biochemical parameters taken up to 10 years before diagnosis in over 20,000 IBD patients and population controls, we address this at massive scale. We observe widespread significant changes in multiple biochemical and hematological parameters that occur up to 8 years before diagnosis of Crohn's disease (CD) and up to 3 years before diagnosis of ulcerative colitis. These changes far exceed previous expectations regarding the length of this pre-diagnosticphase, revealing an opportunity for earlier intervention, especially in CD. In summary, using a nationwide, case-control dataset-obtained from the Danish registers-we provide a comprehensive characterization of the hematological and biochemical changes that occur in the pre-clinical phase of IBD.

Evaluation of Public Health Mass Campaign: Hesitancy and Event Ratios Method

Several public health interventions administer drugs and vaccines to large number of people for preemptive or reactive intervention. These vaccines and drugs were developed in very narrow conditions in clinical trials and we therefore have to continuously monitor the efficacy in the field. This paper proposes a method to evaluate the efficacy in the field using data collected from the intervention coverage survey and surveillance. The design is closely related to cohort prospective studies except that the sample size is not fixed upfront and the measure of association not affected by the population denominator. It uses two new terms: hesitancy ratio denoted β, which is the ratio of the target that does to receive the intervention to the target that received it; event ratio is denoted by α is the ratio of health event or disease being prevented absolute incidence in the intervention group to that is in control group. It further shows that risk ratio (RR) can be calculated from these two parameters by taking their products. i.e. RR = α β. This method is therefore called Hesitancy and Event Ratios (HER) Method. We can conclude that this method is scientifically sound and can be used in the evaluation of public health intervention in the field. We recommend that this method be included in routine monitoring of programs for efficacy evaluation.

Novel Approaches to Treatment of Acute Myeloid Leukemia Relapse Post Allogeneic Stem Cell Transplantation.

The management of patients with acute myeloid leukemia (AML) relapsed post allogeneic hematopoietic stem cell transplantation (HSCT) remains a clinical challenge. Intensive treatment approaches are limited by severe toxicities in the early post-transplantation period. Therefore, hypomethylating agents (HMAs) have become the standard therapeutic approach due to favorable tolerability. Moreover, HMAs serve as a backbone for additional anti-leukemic agents. Despite discordant results, the addition of donor lymphocytes infusions (DLI) generally granted improved outcomes with manageable GvHD incidence. The recent introduction of novel targeted drugs in AML gives the opportunity to add a third element to salvage regimens. Those patients harboring targetable mutations might benefit from IDH1/2 inhibitors Ivosidenib and Enasidenib as well as FLT3 inhibitors Sorafenib and Gilteritinib in combination with HMA and DLI. Conversely, patients lacking targetable mutations actually benefit from the addition of Venetoclax. A second HSCT remains a valid option, especially for fit patients and for those who achieve a complete disease response with salvage regimens. Overall, across studies, higher response rates and longer survival were observed in cases of pre-emptive intervention for molecular relapse. Future perspectives currently rely on the development of adoptive immunotherapeutic strategies mainly represented by CAR-T cells.

Analysis of the risk and pre-emptive control of viral outbreaks accounting for within-host dynamics: SARS-CoV-2 as a case study

In the era of living with COVID-19, the risk of localised SARS-CoV-2 outbreaks remains. Here, we develop a multiscale modelling framework for estimating the local outbreak risk for a viral disease (the probability that a major outbreak results from a single case introduced into the population), accounting for within-host viral dynamics. Compared to population-level models previously used to estimate outbreak risks, our approach enables more detailed analysis of how the risk can be mitigated through pre-emptive interventions such as antigen testing. Considering SARS-CoV-2 as a case study, we quantify the within-host dynamics using data from individuals with omicron variant infections. We demonstrate that regular antigen testing reduces, but may not eliminate, the outbreak risk, depending on characteristics of local transmission. In our baseline analysis, daily antigen testing reduces the outbreak risk by 45% compared to a scenario without antigen testing. Additionally, we show that accounting for heterogeneity in within-host dynamics between individuals affects outbreak risk estimates and assessments of the impact of antigen testing. Our results therefore highlight important factors to consider when using multiscale models to design pre-emptive interventions against SARS-CoV-2 and other viruses.

PB0917 Stratification of Risk Factors of Lung Cancer-Associated Venous Thromboembolism and Determining the Critical Point for Preemptive Intervention: An Evidence Synthesis Approach

PB0917 Stratification of Risk Factors of Lung Cancer-Associated Venous Thromboembolism and Determining the Critical Point for Preemptive Intervention: An Evidence Synthesis Approach

Ön-Alıcı ve Önleyici Müdahalede Simülasyonlar

Simülasyonlar gerçek ortamların taklit edilmesi ve birebir benzerlerinin matematiksel modellerle yaratılması ile oluşturulan dijital ortamlardır. Bu dijital ortamlara gerçek dünyanın verileri yüklenerek yaşanabilecek tüm olasılıkların hesaplanabilmesi mümkün olabilmektedir. Ortaya çıkan bilginin ise gerçek dünyadaki politikaları etkileyebilmesi tartışılması gereken bir konu olmaktadır. Simülasyonlar sayesinde devletlerin önemli güvenlik meselelerine dair olasılık hesaplarının yapılması artık sık sık başvurulan yöntemler haline gelmiştir. Ancak dijital alan üzerinden sağlanmaya çalışılan bu güvenlik yönteminin savunma dayanağı olarak yönlendirici olup olmayacağı ya da simülasyon verilerine dayanarak bir eylemde bulunmanın saldırı olarak yorumlanıp yorumlanamayacağı tartışılmalıdır. Bu çalışma bu sorulara yanıt aramak için ele alınmıştır. Kavramsal çerçeve ön-alıcı ve önleyici müdahale kavramlarıdır. Bu çerçevede simülasyon verilerinin müdahale ederken bir savunma dayanağı olarak kullanılmasının ön-alıcı mı yoksa önleyici mi olduğu tartışılmaktadır. Simülasyon verileri ve yapay zekâ analizlerinin düşman tanımlaması ve saldırganlık göstergelerinin hesaplamalarında meşru bir hukuksal dayanak olup olamaması uluslararası iş birliğinin şekli ve uluslararası aktörlerin kabul edilir seçenekleri meşrulaştırma süreçlerine göre değişmektedir.

Limits to inoculating against the risk of fake news: a replication study in Singapore during COVID-19

The COVID-19 pandemic laid bare the problem of fake news as one of the defining challenges of our time. The sudden proliferation of fake news and its direct impact on public health and safety led to increasing attention to pre-bunking interventions as a possible tool against the risks of fake news. These studies claimed that it is possible to use pre-emptive interventions such as games to induce cognitive resistance against the deception techniques deployed by fake new producers. We wanted to test if this method could be as effective in a non-Western context, and in an on-going catastrophic risk event. This paper presents the results of a replication study of Roozenbeek and van der Linden’s gaming experiment with certain modifications tailored to the case of Singapore in 2020 in the midst of the COVID-19 pandemic. We could not replicate the results of the original study. However, we found factors that could have accounted for the different results, including high levels of trust in English mainstream media and the government, and positive attitudes towards censorship. We also found that participants were most resistant against conspiratorial deception techniques but also more vulnerable to impersonation techniques. We reflect on what the results of our study say about the limitations of psychology-focused interventions and the need for a wider suite of interventions targeting different levels of analysis, including sociological factors and the risk context.

A study of genetic variants, genetic risk score and DNA methylation of PNPLA3 and TM6SF2 in alcohol liver cirrhosis.

Genetic and epigenetic factors are associated with thedevelopment of alcohol-associated liver disease (AALD). The single nucleotide polymorphisms (SNPs), rs738409 in Patatin-like phospholipase domain-containing protein (PNPLA3) and rs58542926 in Transmembrane 6 Superfamily Member 2 (TM6SF2) are strongly associated with AALD in different global populations, Hence, we analyzed the genetic risk score for these variants and deoxyribonucleic acid (DNA) methylation levels of the PNPLA3 and TM6SF2 genes among cases (alcohol liver cirrhosis) and controls (heavy drinkers without cirrhosis). We studied patients with alcohol use disorder (AUD) with cirrhosis (AUD-C + ve, n = 136) and without cirrhosis (AUD-C-ve, n = 107) drawn from the clinical services of St. John's Medical College Hospital (SJMCH) (Gastroenterology and Psychiatry) and Centre for Addiction Medicine (CAM),National Institute of Mental Health and Neurosciences, (NIMHANS). Genotype data was generated for rs738409 (PNPLA3) and rs58542926 (TM6SF2) and used to calculate unweighted genetic risk score (uGRS) and weighted genetic risk scores (wGRS). DNA methylation levels were estimated by pyrosequencing at PNPLA3 and TM6SF2 loci. Overall we observed a significantly higher genetic risk score (weighted genetic risk score, wGRS) in individuals with alcohol use disorder compared to control population (p = < 0.01). Further, uGRS and wGRS were associated with thediagnosis of cirrhosis, even after correcting for age of onset, quantity and frequency of drinking. We also found hypomethylation at CpG2 of TM6SF2 gene in AUD-C + ve compared to AUD-C-ve (P = 0.02). We found that a genetic risk score based on SNPs in the PNPLA3 and TM6SF2 genes was significantly associated with cirrhosis in patients with AUD, suggesting a potential utility in identifying patients at risk and providing pre-emptive interventions. These may include interventions that aim to alter DNA methylation, which may be one of the mechanisms through which elevated genetic risk may influence thedevelopment of cirrhosis.

FLT3 inhibitors as MRD-guided salvage treatment for molecular failure in FLT3 mutated AML

Patients with FLT3-mutated AML have a high relapse rate and suboptimal outcomes. Many have co-mutations suitable for measurable residual disease (MRD) monitoring by RT-qPCR and those destined to relapse can be identified by high or rising levels of MRD, called molecular failure. This provides a window for pre-emptive intervention, but there is little evidence to guide treatment. The use of FLT3 inhibitors (FLT3i) appears attractive but their use has not yet been evaluated. We identified 56 patients treated with FLT3i at molecular failure. The FLT3 mutation was an ITD in 52, TKD in 7 and both in 3. Over half of patients had previously received midostaurin. Molecular failure occurred at a median 9.2 months from diagnosis and was treated with gilteritinib (n = 38), quizartinib (n = 7) or sorafenib (n = 11). 60% achieved a molecular response, with 45% reaching MRD negativity. Haematological toxicity was low, and 22 patients were bridged directly to allogeneic transplant with another 6 to donor lymphocyte infusion. 2-year overall survival was 80% (95%CI 69–93) and molecular event-free survival 56% (95%CI 44–72). High-sensitivity next-generation sequencing for FLT3-ITD at molecular failure identified patients more likely to benefit. FLT3i monotherapy for molecular failure is a promising strategy which merits evaluation in prospective studies.

Efficacy and Safety of Plerixafor Combined with G-CSF for Autologous Peripheral Blood Hematopoietic Stem Cell Mobilization in Lymphoma Patients

To investigate the efficacy and safety of plerixafor combined with granulocyte colony-stimulating factor (G-CSF) in mobilizing peripheral blood hematopoietic stem cells in patients with lymphoma. The clinical data of lymphoma patients who received autologous hematopoietic stem cell mobilization using plerixafor combined with G-CSF from January 2019 to December 2021 were retrospectively analyzed. The patients received 3 kinds of mobilization regimens: front-line steady-state mobilization, preemptive intervention, and recuse mobilization. The acquisition success rate, excellent rate of collection, and incidence of treatment-related adverse reaction were counted. The influence of sex, age, disease remission status, bone marrow involvement at diagnosis, chemotherapy lines, number of chemotherapy, platelet count and number of CD34+ cells on the day before acquisition in peripheral blood on the collection results were analyzed to identify the risk factors associated with poor stem cell collection. A total of 43 patients with lymphoma were enrolled, including 7 cases who received front-line steady-state mobilization, 19 cases who received preemptive intervention, and 17 cases who received recuse mobilization. The overall acquisition success rate was 58.1% (25/43) after use of plerixafor combined with G-CSF, and acquisition success rate of front-line steady-state mobilization, preemptive intervention, and recuse mobilization was 100%, 57.9%(11/19), and 41.2%(7/17), respectively. The excellent rate of collection was 18.6%(8/43). A total of 15 patients experienced mild to moderate treatment-related adverse reactions. The number of CD34+ cells < 5 cells/μl in peripheral blood on the day before collection was an independent risk factor affecting stem cell collection. Plerixafor combined with G-CSF is a safe and effective mobilization regimen for patients with lymphoma. The number of CD34+ cells in peripheral blood on the day before collection is an predictable index for the evaluation of stem cell collection.

Inoculation Reduces Misinformation: Experimental Evidence from Multidimensional Interventions in Brazil

Abstract Misinformation is widely seen as a threat to democracy that should be promptly addressed by scholars, journalists, and policymakers. However, some of the debated solutions are either controversial (internet platform regulation) or may be difficult and costly to implement in many settings (fact-checking corrections). This study investigates the effectiveness of preemptive interventions, a type of solution that has received considerably less attention in this debate. Studies show that interventions through awareness and media literacy campaigns can inoculate citizens against misinformation, but these interventions are restricted to a few contexts and settings. Our paper uses two field experiments, one of which was conducted in partnership with Brazil’s main newspaper, to investigate the effectiveness of multidimensional interventions against misinformation in São Paulo. The findings show that preemptive interventions can indeed reduce rumor acceptance and provide insights into the strategies to combat misinformation in democracies.

Measurable residual disease study through three different methods can anticipate relapse and guide early interventions in childhood acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is the most common cancer among children. Measurable residual disease (MRD, previously named minimal residual disease) study can guide therapy adjustments or preemptive interventions that might avoid hematological relapse. Clinical decision making and patient outcome were evaluated in 80 real-life childhood ALL patients, according to the results observed in 544 bone marrow samples analyzed with three MRD methods: multiparametric flow cytometry (MFC), fluorescent in-situ hybridization (FISH) on B or T-purified lymphocytes and patient-specific nested reverse transcription polymerase chain reaction (RT-PCR). Estimated 5year overall survival and event-free survival were 94% and 84.1%, respectively. A total of 12 relapses in 7 patients were associated with positive MRD detection with at least one of the three methods: MFC (p < 0.00001), FISH (p < 0.00001) and RT-PCR (p = 0.013). MRD assessment allowed the anticipation of relapse and adapted early interventions with different approaches including chemotherapy intensification, blinatumomab, HSCT and targeted therapy to halt relapse in five patients, although two of them relapsed afterwards. MFC, FISH and RT-PCR are complementary methods for MRD monitoring in pediatric ALL. Although, our data clearly show that MDR positive detection is associated with relapse, continuation of standard treatment, intensification or other early interventions were able to halt relapse in patients with different risks and genetic background. More sensitive and specific methods are warranted to enhance this approach. However, whether early treatment of MRD can improve overall survival in patients with childhood ALL needs to be evaluated in adequately controlled clinical trials.

#3179 PREDICTORS OF VASCULAR ACCESS THROMBOSIS IN MAINTENANCE HEMODIALYSIS PATIENTS – QA, KT/V AND CONVECTIVE VOLUME

Abstract Background and Aims Vascular access (VA) is vital for hemodialysis (HD) treatments and should allow to achieve the recommended dose of dialysis. Thrombosis is the primary cause of VA failure in grafts (AVG) and fistulas (AVF) and should be avoided as it can lead to significant patient morbidity and mortality. However, despite its importance, predictors of VA thrombosis are not completely established. Even if large randomized controlled trials are lacking to clearly identify the ideal surveillance strategies and benefits of surveillance, evidence suggests that when combined with preemptive interventions, prospective monitoring and surveillance and early detection of dysfunctional VA may reduce the thrombosis rate and improve its long-term patency. Several monitoring and surveillance techniques of VA can be used, from unexplained drop in dialysis adequacy (Kt/V and convective volume) to the noninvasive estimation of VA blood flow (Qa). The aim of this study was to assess whether these parameters can predict VA thrombosis. Method We retrospectively evaluated all episodes of VA thrombosis admitted in our Vascular Access Centre (VAC) between July 2019 and December 2022. Patient's demographics, VA characteristics and data from dialysis sessions were collected. Descriptive statistics were calculated and expressed as mean (standard deviation) or median (IQR) or count (%), as adequate. Values were compared using Mann-Whitney for independent samples and Pearson chi-squared test with 95% confidence intervals (CI). The predictors of VA thrombosis studied were Qa, Kt/V and convective volume (CV), in the case of the patients on hemodiafiltration. Qa was measured using the thermodilution method called blood temperature monitoring (BTM®), and Kt/V and CV with Online Clearance Monitoring (OCM®). In this study, we evaluated the ratio between the last measured value of Qa prior to the thrombosis episode and the average of the previous three months (Qa trend), and the ratio between the last measured value of Kt/V and CV before the thrombosis episode and the average of the previous month (Kt/V trend and CV trend, respectively) as predictors of VA thrombosis Results From July 2019 and December 2022, we treated, in our VAC, 386 VA thrombosis episodes in 226 patients. In our study population, mean age was 71.1 (± 13.2) years, 64% were male, 31% had diabetes. The dialysis vintage was 51 (69) months and the VA vintage was 42 (62) months. 70.2% of the VA thrombosis were on AVF. Prior to thrombosis the median of Qa obtained by BTM was 650 (495) mL/min, the median of kt/v was 1.43 (0.62) and the median of CV was 22.4 (6.3). The average of the previous values for Qa, Kt/V and CV were 658 (353) ml/min, 1.53 (0.35) and 23.5 (3.9) L. The median (IQR) of Qa trend, Kt/V trend and CV trend were -8,5 (33,3) %, -6,0 (28,2) % and -2,5 (17,0)%. We found no statistical significance for Qa trend and CV trend between AVF and AVG as predictors of VA thrombosis, but the reduction in Kt/V values was significantly more pronounced in AVF (-6.8%; Q1 -30.1% to Q3 0.7%) than in AVG (-3.8%; Q1 -18.0% to Q3 + 5.0%) (p = 0.007) as predictor of thrombosis. In 68.9% of VA thrombosis, we noticed a reduction in Kt/V value before the episode (73.8% in AVF and 57.5% in AVG, p = 0.002). We found no statistically significance in the reduction of Qa and CV values between AVF and AVG thrombosis episodes. Conclusion Our study showed that Kt/V trend was a better predictor of VA thrombosis than Qa trend and CV trend, especially in AVF.

The IPTA Nashville Consensus Conference on Post-Transplant lymphoproliferative disorders after solid organ transplantation in children: III - Consensus guidelines for Epstein-Barr virus load and other biomarker monitoring.

The International Pediatric Transplant Association convened an expert consensus conference to assess current evidence and develop recommendations for various aspects of care relating to post-transplant lymphoproliferative disorders after solid organ transplantation in children. In this report from the Viral Load and Biomarker Monitoring Working Group, we reviewed the existing literature regarding the role of Epstein-Barr viral load and other biomarkers in peripheral blood for predicting the development of PTLD, for PTLD diagnosis, and for monitoring of response to treatment. Key recommendations from the group highlighted the strong recommendation for use of the term EBV DNAemia instead of "viremia" to describe EBV DNA levels in peripheral blood as well as concerns with comparison of EBV DNAemia measurement results performed at different institutions even when tests are calibrated using the WHO international standard. The working group concluded that either whole blood or plasma could be used as matrices for EBV DNA measurement; optimal specimen type may be clinical context dependent. Whole blood testing has some advantages for surveillance to inform pre-emptive interventions while plasma testing may be preferred in the setting of clinical symptoms and treatment monitoring. However, EBV DNAemia testing alone was not recommended for PTLD diagnosis. Quantitative EBV DNAemia surveillance to identify patients at risk for PTLD and to inform pre-emptive interventions in patients who are EBV seronegative pre-transplant was recommended. In contrast, with the exception of intestinal transplant recipients or those with recent primary EBV infection prior to SOT, surveillance was not recommended in pediatric SOT recipients EBV seropositive pre-transplant. Implications of viral load kinetic parameters including peak load and viral set point on pre-emptive PTLD prevention monitoring algorithms were discussed. Use of additional markers, including measurements of EBV specific cell mediated immunity was discussed but not recommended though the importance of obtaining additional data from prospective multicenter studies was highlighted as a key research priority.