Search

The spatiotemporal structure of the human microbiome1,2, proteome3 and metabolome4,5 reflects and determines regional intestinal physiology and may have implications for disease6. Yet, little is known about the distribution of microorganisms, their environment and their biochemical activity in the gut because of reliance on stool samples and limited access to only some regions of the gut using endoscopy in fasting or sedated individuals7. To address these deficiencies, we developed an ingestible device that collects samples from multiple regions of the human intestinal tract during normal digestion. Collection of 240 intestinal samples from 15 healthy individuals using the device and subsequent multi-omics analyses identified significant differences between bacteria, phages, host proteins and metabolites in the intestines versus stool. Certain microbial taxa were differentially enriched and prophage induction was more prevalent in the intestines than in stool. The host proteome and bile acid profiles varied along the intestines and were highly distinct from those of stool. Correlations between gradients in bile acid concentrations and microbial abundance predicted species that altered the bile acid pool through deconjugation. Furthermore, microbially conjugated bile acid concentrations exhibited amino acid-dependent trends that were not apparent in stool. Overall, non-invasive, longitudinal profiling of microorganisms, proteins and bile acids along the intestinal tract under physiological conditions can help elucidate the roles of the gut microbiome and metabolome in human physiology and disease.

Committees from the American Political Science Association (APSA) on the status of graduate students in political science conducted digital surveys in 2018, 2020, and 2022. Distributed using listservs from APSA, the surveys asked about a range of realities facing graduate students including employment opportunities, industry or academic support, and overall well-being. Analysis of the data pre-, during-, and post-pandemic revealed high anxiety in 2018 as part of students’ experience looking for jobs. By 2020 and 2022, anxiety worsened, such that the well-being of graduate students in political science should be addressed. We recommend a change in the structure of graduate academic programs to include stronger institutional support and an emphasis on alternative paths for work that does not entail teaching at an academic institution.

Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Abbott Introduction Novel catheter ablation technologies (e.g. RF with contiguous lesions) for pulmonary vein isolation (PVI) achieve high (80-85%) arrhythmia freedom rates at 12 months in both paroxysmal and persistent AF. However, success rates are importantly reduced (45-50%) in persistent AF patients presenting atrial cardiomyopathy with additional low voltage areas in the left atrial body. Aim SOLVE-AF study is a prospective randomized multicenter study, in which the standard approach "circumferential PVI" is compared to "additional ablation of low voltage areas and ablation of slow conducting "atrial late potentials (ALPs)" during sinus rhythm (SR)". Methods 320 patients with persistent AF will be included. Patients undergo left atrial high definition voltage mapping in SR. 160 patients with low voltage areas (5cm2) within the LA body will be randomized to "circumferential-PVI" vs. "additional low-voltage-guided ablation". The remaining 160 without low voltage substrate (registry group) will undergo "circumferential-PVI". Arrhythmia recurrences (defined as AF/AT >30 sec) will be assessed at 6 and 12 months (7-day-Holter and event-recorder) following ablation therapy (top panel). Results Currently, 120 patients have been included into the registry group and 120 patients with low voltage substrate have been randomized. Results of the SOLVE-AF-pilot study including a total of 210 patients (110 registry patients without LA-LVS and 100 patients with LA-LVS who were assigned to PVI-only versus additional substrate-based ablation) at the University-Heart-Center-FR-BK favor "PVI plus substrate-based ablation" in those patients who do present significant low voltage areas (see KM-curve bottom panel). Conclusions Results from the pilot trial suggests improved arrhythmia freedom rate with PVI plus additional substrate-based ablation during sinus rhythm. Final results of the prospective randomized multi-center trial SOLVE-AF are expected in June 2024.

Funding Acknowledgements Type of funding sources: None. Introduction / Aims This study sought to develop and validate diagnostic models to identify individuals with atrial fibrillation (AF) using amplified p-wave analysis or neural-network-trained p-wave-analysis during sinus rhythm (SR). Methods 1492 patients (491 healthy controls, 499 with paroxysmal AF and 502 with persistent AF) underwent digital 12-lead-ECG recording during sinus rhythm. The patient cohort was divided into training and validation set in a 3:2 ratio. P-wave indices including duration of standard p-wave (standard PWD; 10mm/mV, 25mm/sec, see ECG in the left panel), amplified digital p-wave (APWD, 60-100mm/mV, 175mm/sec; see ECG in the middle panel) and advanced inter-atrial block (aIAB) along with the parameters body surface area (BSA) and LA diameter (LAD) were used to develop diagnostic models using logistic regression. Each model was developed from the training set and further tested in both training and validation sets for its diagnostic performance in identifying individuals with AF. A neural-network was trained to identify the p-wave and its features (duration, morphology) to differentiate between individuals with known versus those without AF. Results Compared to standard PWD (Reference model, AUC=0.637 and 0.632, for training and validation set, respectively), APWD (Basic model) importantly improved the accuracy to identify individuals with AF (AUC=0.86 and 0.866). The ECG-based model combining APWD, aIAB and body surface area (BSA) further improved the diagnostic performance for AF (AUC=0.892 and 0.885). The integrated model, which further combined left atrial diameter (LAD) with parameters of the ECG-based model, achieved the highest diagnostic performance (AUC=0.916 and 0.902). Notably, the neural network-based p-wave-analysis identified AF patients with high accuracy during sinus rhythm (AUC: 0.85; sensitivity: 77%; specificity: 78%). Conclusions Both, the analysis of amplified p-wave and a neural-network-based automatic p-wave analysis during sinus rhythm allow identification of individuals with atrial fibrillation. The current diagnostic models provide a new basis for identifying individuals at high risk for AF, who would most benefit from AF screening.

Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Medtronic Background Atrial cardiomyopathy (ACM) is associated with an increased risk for new-onset atrial fibrillation (AF), progression from paroxysmal to persistent AF-forms and higher arrhythmia recurrence rates after PVI. Therefore, the current ESC guidelines on AF recommend to characterize the underlying ACM to better inform and treat AF patients. Over the past decade, various diagnostic tools were established to diagnose an ACM by analyzing left atrial (LA) structure, and LA electrical and mechanical function. Aim To compare head-to-head electroanatomical mapping (EAM) to assess LA low-voltage substrate (LVS), late gadolinium enhancement (LGE)-MRI to analyse LGE-extent, body surface electrocardiograpghic imaging (ECGI) to measure total atrial conduction time (TACT), digital ECG to analyse amplified p-wave duration (aPWD), and TTE to quantify LA emptying fraction (LA-EF) and LA strain (LAS) regarding ACM diagnosis and outcome prediction after PVI in a homogenous study population. Methods Thirty-six ablation-naive patients (65±9years, 86% male) with persistent AF undergoing PVI were electrically cardioverted prior to PVI and all analyses were performed in sinus rhythm. LGE-MRI, ECGI using a 252-electrode-array, digital ECG and TTE were conducted one day prior to PVI. Subsequently, a high-density LA voltage map (2124±490 sites) was acquired followed by circumferential PVI. MRI-post-processing-analyses were performed by two independent expert laboratories (Marrek for Utah and Adas3D medical for the image-intensity-ratio(IIR)-method). Analysis of aPWD and LAS during reservoir (LASr), conduit (LAScd) and contraction phase (LASct) were performed automatically. Arrhythmia recurrence was recorded within 12 months. Relevant ACM was defined as presence of a LA-LVS≥2cm2 at 0.5mV, a LGE-extent≥20% using the Utah method, a LA-EF Results A LGE-extent of ≥12% using an IIR cut-off of 1.20, a TACT≥148ms and an automatically measured aPWD≥140ms predicted a relevant ACM as defined in EAM with a sensitivity of 76% and a specificity of 60% for LGE IIR 1.20, a sensitivity of 95% and a specificity of 93% for TACT, and a sensitivity of 86% and a specificity of 80% for aPWD, respectively. Arrhythmia recurrence was significantly higher in patients with a LA-LVS≥2cm2 at 0.5mV, a LGE-extent≥12% at 1.20IIR, a TACT≥148ms, an aPWD≥140ms, a LA-EF Conclusion ACM can be diagnosed using EAM, LGE-MRI, ECGI, ECG and TTE and is associated with an increased arrhythmia recurrence rate after PVI. However, only measurement of aPWD in digital ECG, and LA-EF and LAS in TTE are easy, cost-effective, non-invasive methods without any risk for complications.

SUMMARY This manuscript reports a three-year follow-up of a case of gingival conditioning with a provisional composite veneer prior to diastema closure and tooth recontouring with direct composites. This conservative treatment resulted in a natural and harmonious smile.

The objective of this study was to examine differences in parenting, psychological well-being, and economic outcomes between fathers receiving two different programs offered by FathersFamilies Support Center for economically disadvantaged fathers: (a) Family Formation (FF), a 6-week/240-h program focused on economic stability/mobility, responsible fatherhood, and healthy relationships, with case management and legal services; (b) Economic Stability (ES), a 4-week/80-h program focused only on economic stability with limited case management and legal services. A randomized controlled trial (RCT) was used to compare fathers in FF (n = 350) vs. ES (n = 342). Surveys were administered at enrollment and 3- and 12-months postintervention. Linear and generalized linear mixed models were used to assess changes in program outcomes over time and across study groups. Four hundred and eighty-two fathers responded to either follow-up survey (251 FF, 231 ES). Nearly all (98%) were non-white (93% Black, 5% other/mixed race) and were on average 34 years old. Approximately 46% attended ≥75% of program sessions (FF 48% vs. ES 44%). Both FF and ES groups experienced improvements in parenting, psychological well-being, and financial outcomes after the programs, but changes in outcomes over time did not differ significantly by program. The lack of difference in outcomes between fathers in FF and ES groups could be due to a similar core focus on employment-related curriculum for both groups. Gaining financial stability could have contributed to positive improvements in other fatherhood domains. Implications for future research and practice are discussed herein.El objetivo de este estudio fue analizar las diferencias en la crianza, el bienestar psicológico y los resultados económicos entre padres que recibían dos programas diferentes ofrecidos por el Centro de Apoyo a los Padres y las Familias (FathersFamiliares Support Center) para padres desfavorecidos económicamente: (a) Formación de una Familia (Family Formation, FF), un programa de 6 semanas/240 horas centrado en la estabilidad/movilidad económica, la paternidad responsable y las relaciones saludables, con gestión de casos y servicios legales; (b) Estabilidad Económica (Economic Stability, ES), un programa de 4 semanas/80 horas centrado solamente en la estabilidad económica con poca gestión de casos y servicios legales. Se usó un ensayo controlado aleatorizado para comparar a los padres de FF (n=350) con los de ES (n=342). Se realizaron encuestas en la inscripción y a los 3 y a los 12 meses posteriores a la intervención. Se usaron modelos lineales y modelos mixtos lineales generalizados para evaluar los cambios en los resultados de los programas con el tiempo y entre los grupos de estudio. 482 padres respondieron a cada encuesta de seguimiento (251 FF, 231 ES). Casi todos (el 98 %) eran de color (el 93 % negros, el 5 % de otra raza o de raza mestiza) y tenían, en promedio, 34 años. Aproximadamente el 46 % asistió a más del 75 % de las sesiones de los programas (el 48 % de FF frente al 44 % de ES). Tanto el grupo de FF como el de ES tuvieron mejoras en la crianza, en el bienestar psicológico y en los resultados económicos después de los programas, pero los cambios en los resultados con el tiempo no variaron significativamente por programa. La falta de diferencia en los resultados entre los padres del grupo de FF y los del grupo de ES podría deberse a un enfoque principal similar en un currículo relacionado con el empleo para ambos grupos. La adquisición de estabilidad económica podría haber contribuido a mejoras positivas en otras áreas de la paternidad. Se comentan las consecuencias para la futura investigación y la práctica.本研究旨在研究那些接受了“父亲与家庭支持中心”为经济困难的父亲提供的两种不同计划的父亲在养育子女、心理健康和经济成果方面的差异：(a) 家庭组建（FF），一个为期6周/240小时的项目，侧重于经济稳定/流动性、负责任的父亲、健康的关系，并提供个案管理和法律服务；(b) 经济稳定（ES），一个为期4周/80小时的项目，仅侧重于经济稳定，提供有限的个案管理和法律服务。一个随机对照试验（RCT）被用来比较参加FF（n=350）和ES（n=342）的父亲。调查是在入学时和干预后3个月和12个月进行的。线性和广义线性混合模型被用来评估项目结果随时间和不同研究组的变化。482名父亲都回应了随后的调查（251名FF，231名ES）。几乎所有的人（98%）都是非白人（93%为黑人，5%为其他/混合种族），平均年龄为34岁。大约46%的人参加了≥75%的项目会议（FF 48% vs ES 44%）。FF组和ES组在项目结束后，在养育子女、心理健康和财务状况方面都有所改善，但随着时间的推移，结果的变化并没有因项目而有明显的不同。FF组和ES组的父亲在结果上没有差异，这可能是由于两组在就业相关课程上的核心重点相似。获得经济稳定可能有助于其他父亲领域的积极改善。本文讨论了对未来研究和实践的影响。.

Introduction/objectives We assess the impact of switching versus staying on the same tofacitinib dose on efficacy and safety in patients with rheumatoid arthritis (RA). Methods ORAL Sequel was an open-label, long-term extension study of patients with RA receiving tofacitinib 5 or 10 mg BID for up to 9.5 years. Tofacitinib doses could be switched during the study at investigator discretion. In this post hoc analysis, data from ORAL Sequel were stratified into four groups: 5 → 10 mg BID (Dose-up); 5 mg BID (Stay-on 5); 10 → 5 mg BID (Dose-down); and 10 mg BID (Stay-on 10). Efficacy assessments over 12 months included: change from baseline in 4-component Disease Activity Score in 28 joints, erythrocyte sedimentation rate (DAS28), and DAS28 minimum clinically important difference, remission, and low disease activity (LDA) rates. Safety was assessed for the study duration. Results Generally, DAS28 improvements and minimum clinically important difference rates were significantly greater (p Conclusion In patients with RA receiving open-label tofacitinib, this analysis found that some benefited from increasing dose from 5 to 10 mg BID and did not find that reducing dose from 10 to 5 mg BID affected efficacy or that dose switching in either direction affected safety. Study registration ClinicalTrials.gov number NCT00413699. Registered December 20, 2006. https://clinicaltrials.gov/ct2/show/NCT00413699 Key Points• This post hoc analysis of data from the long-term extension study, ORAL Sequel, assessed the impact of dose switching between tofacitinib 5 and 10 mg twice daily (BID), at the investigator’s discretion, on efficacy and safety in patients with rheumatoid arthritis (RA).• Dosing up from tofacitinib 5 to 10 mg BID was associated with improved efficacy up to 12 months versus staying on 5 mg BID, and dosing down from 10 to 5 mg BID was not generally associated with a significant loss of efficacy.• Safety outcomes were generally consistent across dose groups and did not change markedly after switching dose in either direction.• These findings can help to inform physicians on what may be expected in terms of efficacy and safety when adjusting tofacitinib dose according to clinical need. The recommended tofacitinib dosage for the treatment of RA in most jurisdictions is 5 mg BID.

Background: Comparative safety assessments are important for informed treatment decisions. Recently, serious infections related to tofacitinib (TOF) have raised considerable interest. This study aims to compare the risk for serious infections in patients with rheumatoid arthritis (RA) upon receiving TOF versus biologic disease-modifying antirheumatic drugs (bDMARDs) by age at treatment initiation. Methods: We identified adult RA patients exposed to TOF or bDMARDs using data collected by the Swiss registry for inflammatory rheumatic diseases (SCQM) from 2015 to 2018. The event of interest was the first non-fatal serious infection (SI) during drug exposure. Missing or incomplete event dates were imputed as either the lower (left) or upper (right) limit of the interval in which the event must have occurred. Separate analyses were done with the left and right imputed dates and interpreted together. The comparative risk (hazard ratio, HR) of TOF versus bDMARDs was estimated as a function of age using Cox proportional hazards regression adjusted for several possible confounders or predictors. Results: 1687 patients provided time at risk for a first SI during study participation and drug exposure for a total of 2238 different treatment courses, 345 for TOF and 1893 for bDMARDs. Exact dates were missing from 21% of the SIs, with 44 (left imputation) or 43 (right imputation), respectively, identified as first SIs (12/12 on TOF versus 32/31 on bDMARDs). Left and right imputation produced similar results. For ages >= 69 years, HRs were >1 with both imputations. Indicatively, for right imputation, at 69 and 76 years, the HRs (95% confidence intervals) were, respectively: 2.05 (1.04, 4.05; increased), and 2.87 (1.27, 6.52; clinically relevantly increased). For ages < 65 years, the data were insufficient to draw conclusions one way or another. Conclusions: Our results suggest that we should expect an increased risk for SIs upon treatment with TOF compared to bDMARDs in older patients (aged ≥ 69 years). Our study thus supports a cautious use of TOF in these patients. Further research is needed to assess whether the comparative risk is age dependent and, if so, whether it is relevantly increased in older as opposed to younger patients.

Objectives RA patients who fail to respond to MTX can receive biologic dMARDs (bDMARDs). The Torque Teno Virus (TTV) is a potential novel candidate for monitoring of immunosuppression. We explore TTV in these patients and its association with clinical response to bDMARDs. Methods The BioBio Study is a multicentre randomized open-label trial, including RA patients with insufficient response to MTX. Patients were randomized to either TNFi (infliximab, INF), anti-IL-6 (tocilizumab, TCZ), CTLA4-Ig (abatacept, ABA) or anti-CD20 (rituximab, RTX) in addition to MTX. PCR was used to quantify TTV in the peripheral blood. Results TTV was measured in 95 patients (INF, n = 23; TCZ, n = 22; ABA, n = 27; RTX; n = 23). TTV increased by a median of 4.5 × 104 copies/ml [c/ml; interquartile range (IQR) 0–7.5 × 105] after 3 months. TTV levels at month 3 were associated with the Simplified Disease Activity Index (SDAI) (P = 0.03) and the Clinical Disease Activity Index (CDAI) response (P = 0.026) at month 6. A TTV cut-off level of 1.2 × 106 c/ml at month 3 had a positive likelihood ratio of 2.7 for prediction of an 85% reduction in SDAI at month 6. Conclusion Our data suggest that TTV levels increase upon TNF, CD20 and costimulation blockade and are associated with the clinical response to bDMARDs in RA patients. Trial registration ClinicalTrials.gov; https://clinicaltrials.gov; NCT01638715

BACKGROUND HIV-exposed uninfected (HEU) individuals are predisposed to adverse health outcomes, which in part may stem from the influence of an altered intrauterine milieu on fetal programming. The placenta serves as a readout for the effects of the maternal environment on the developing fetus and may itself contribute to the pathogenesis of disease. SETTING US academic health system. METHODS We leveraged a previously established registry-based cohort of HEU adolescents and young adults to identify 26 subjects for whom placental histopathology was available. We further obtained placental tissue from 29 HIV-unexposed pregnancies for comparison. We examined differences in placental histopathology between the groups and related villous vascularity in the HEU group to prenatal maternal characteristics and long-term health outcomes. RESULTS Placentas from HEU pregnancies demonstrated a higher blood vessel count per villus as compared with controls (5.9 ± 1.0 vs. 5.4 ± 0.8; P = 0.05), which was independent of maternal prenatal age, race, body mass index, smoking status, hemoglobin, and gestational age. Furthermore, within the HEU group, lower CD4+ T-cell count during pregnancy was associated with greater placental vascularity (r = -0.44; P = 0.03). No significant relationships were observed between placental blood vessel count per villus and body mass index z-score or reactive airway disease among HEU individuals later in life. CONCLUSIONS Placentas from HEU pregnancies demonstrated increased villous vascularity compared with HIV-unexposed controls in proportion to the severity of maternal immune dysfunction. Further studies are needed to examine intrauterine exposure to hypoxia as a potential mechanism of fetal programming in HIV.

Schools provide essential functions for children with intellectual and developmental disabilities (IDD), but their vulnerability to infection with SARS-CoV-2 are a barrier to in-person learning. This qualitative study aimed to understand how weekly SARS-CoV-2 screening testing of students and staff could best facilitate in-school learning during the pandemic.Thirty-one focus groups were held with school staff and parents of children with IDD to examine the perceptions of COVID-19 during the 2020-2021 school year. Responses were analyzed using a directed thematic content analysis approach.Five principal themes were identified: risks of returning to in-person learning; facilitators and barriers to participation in SARS-CoV-2 screening testing; messaging strategies; and preferred messengers.Staff and families agreed that saliva-based SARS-CoV-2 screening testing helps increase comfort with in-person learning. Screening testing increased family and school staff comfort with in-person learning particularly because many students with special needs cannot adhere to public health guidelines.To keep children with IDD in school during the pandemic, families found SARS-CoV-2 screening testing important, particularly for students that cannot adhere to mitigation guidelines.

A hallmark of surgical training is resident involvement in operative procedures. While resident-assisted surgeries have been deemed generally safe, few studies have rigorously isolated the impact of resident post-graduate year (PGY) level on post-operative outcomes in a neurosurgical patient population. The objective of this study is to evaluate the relationship between resident training level and outcomes following single-level, posterior-only lumbar fusion, after matching on key patient demographic/clinical characteristics and attending surgeon.This coarsened-exact matching (CEM) study analyzed 2338 consecutive adult patients who underwent single-level lumbar fusion with a resident assistant surgeon at a multi-hospital university health system from 2013 to 2019. Primary outcomes were 30-day and 90-day readmissions, Emergency Department (ED) visits, reoperations, surgical complications, and mortality. First, univariate logistic regression examined the relationship between PGY level and outcomes. Then, CEM was used to control for key patient characteristics - such as race and comorbid status - and supervising attending surgeon, between the most junior (PGY-2)-assisted cases and the most senior (PGY-7)-assisted cases, thereby isolating the relationship between training level and outcomes.Among all patients, resident training level was not associated with risk of adverse post-surgical outcomes. Similarly, between exact-matched cohorts of PGY-2- and PGY-7-assisted cases, no significant differences in adverse events or discharge disposition were observed. Patients with the most senior resident assistant surgeons demonstrated longer length of stay (mean 100.5 vs. 93.8 h, p = 0.022) and longer duration of surgery (mean 173.5 vs. 159.8 min, p = 0.036).Training level of the resident assistant surgeon did not impact adverse outcomes provided to patients in the setting of single-level, posterior-only lumbar fusion. These findings suggest that attending surgeons appropriately manage cases with resident surgeons at different levels of training.

Background Relevant atrial cardiomyopathy (ACM), defined as a left atrial (LA) low-voltage area ≥ 2 cm2 at 0.5 mV threshold on endocardial contact mapping, is associated with new-onset atrial fibrillation (AF), higher arrhythmia recurrence rates after pulmonary vein isolation (PVI), and an increased risk of stroke. The current study aimed to assess two non-invasive echocardiographic parameters, LA emptying fraction (EF) and LA longitudinal strain (LAS, during reservoir (LASr), conduit (LAScd) and contraction phase (LASct)) for the diagnosis of ACM and prediction of arrhythmia outcome after PVI. Methods We prospectively enrolled 60 consecutive, ablation-naive patients (age 66 ± 9 years, 80% males) with persistent AF. In 30 patients (derivation cohort), LA-EF and LAS cut-off values for the presence of relevant ACM (high-density endocardial contact mapping in sinus rhythm prior to PVI at 3000 ± 1249 sites) were established in sinus rhythm and tested in a validation cohort (n = 30). Arrhythmia recurrence within 12 months was documented using 72-h Holter electrocardiograms. Results An LA-EF of Conclusion The echocardiographic parameters LA-EF and LAS allow accurate, non-invasive diagnosis of ACM and prediction of arrhythmia recurrence after PVI. Graphic abstract

Zusammenfassung. Es gibt zahlreiche neurobiologische, klinische und epidemiologische Belege dafür, dass die Phänomene der Angst- und der Schmerzempfindung eng miteinander interagieren. Beide Systeme gehen mit Stressaktivierungsvorgängen einher, und beide Systeme werden ihrerseits durch Langzeitstress moduliert. Die Koppelung von Schmerz, Angst und Stress erklärt auch die hohe Komorbidität von Schmerz- und Angsterkrankungen. Diese Zusammenhänge sollen auffordern, die individuelle Patientenrealität in ihrer integrativen Gesamtheit zu erfassen, in der sich nozizeptive, affektive und vegetative Symptome oftmals bedingen und verstärken.

Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Medtronic Background/Introduction Atrial cardiomyopathy (ACM) is associated with the progression from paroxysmal through persistent to permanent atrial fibrillation (AF) and increased arrhythmia recurrence rates after pulmonary vein isolation (PVI). Purpose We compare the most common left atrial (LA) late gadolinium enhancement magnetic resonance imaging (LGE-MRI)-methods (Utah-method and image-intensity-ratio (IIR)-methods) and endocardial voltage mapping for ACM-detection and outcome prediction after PVI for AF. Methods In this prospective study, 37 ablation-naive patients (66±9 years, 84% male) with persistent AF were included and electrically cardioverted into sinus rhythm. Subsequently, they underwent LA-LGE-MRI and high-definition voltage and activation mapping (2129±484 sites) in sinus rhythm prior to PVI. MRI-post-processing-analyses were performed by two independent expert laboratories (Marrek for the Utah segmentation as describers of this methodology and Adas 3D medical as developers of the Adas software for the IIR-methods) which were blinded to any clinical data. Arrhythmia recurrence was recorded within 12 months following PVI. Results The global ACM-extent was highly variable: median LA low-voltage substrate (LA-LVS) was 12.9% at The highest regional matching between LA-LVS Arrhythmia recurrence occurred in 15 (41%) patients. Freedom from arrhythmia was significantly lower in those with relevant LA-LVS (≥2cm2 at 0.5mV) but not in those with relevant LGE (Utah-stages III&IV): 43% versus 81%, p=0.009 and 50% versus 67%, p=0.338, respectively. Furthermore, relevant LA-LVS was the only predictor for arrhythmia recurrence in multivariate regression analysis. Conclusion The different LA-LGE-MRI methods have large dicrepancies regarding extent and distribution of ACM and are different to the extent and regional distribution of LA-LVS as assessed in endocardial high-definition voltage mapping in sinus rhythm. Further improvements of the LA-LGE-MRI-methods are required to enable correct diagnosis of ACM and for future evaluation of MRI-guided ablation protocols.

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): We gratefully acknowledge financial support by Deutsche Forschungsgemeinschaft (DFG) through DO637/22-3 and by the Ministerium für Wissenschaft, Forschung und Kunst Baden-Württemberg through the Research Seed Capital (RiSC) program. Introduction One treatment option for patients suffering from atrial fibrillation (AF) is to isolate the pulmonary veins, which has a very high success rate in paroxysmal AF patients. However, in patients with persistent AF, the success rate can be as low as 30%. One reason is that the additional arrhythmogenic substrate in the atria is responsible for maintaining the arrhythmia. These areas can be identified by locating low voltage areas Purpose To study the differences between mapping in SR and AF in different atrial regions and identify if regional thresholds can improve the cross-rhythm correlation. Methods Twenty-eight persistent AF patients underwent high-density voltage mapping during both SR and AF. The electro-anatomical mapping was performed using the CARTO-3 software and a 20-pole Lasso-Nav catheter (electrode size 1mm, spacing 2-6-2mm). A mean left atrial geometry was derived for the cohort and the patient’s voltage values were projected onto this mean anatomical model. The mean voltage across all patients at each mapping site was calculated for both rhythms, then the difference between them was determined. Additionally, the geometry was split into six anatomical regions: left atrial appendage (LAA), anterior, posterior, and lateral wall, roof, and septum. The optimal AF threshold was identified for each region, which correlated to low voltage areas during SR Results The highest voltages were found in the left atrial appendage, with the anterior wall presenting the lowest voltages during both rhythms. Across the entire atria, the voltage values were lower, differing between 0-1.2 mV, when mapping during AF than SR. However, the difference between rhythms differed across the atria with the lowest agreement between SR and AF voltages observed at the roof and the posterior wall. The difference in voltage between the two rhythms was highly significant (p Applying regional thresholds had little effect on the cross-rhythm classification agreement at the anterior wall. However, decreasing the threshold by 0.05 mV improved the accuracy on the posterior wall by 10%. Increasing the threshold at the lateral wall improved the accuracy by 5%. Conclusion A universal threshold for mapping during AF is sufficient for most regions with a limited reduction in the accuracy compared to SR low voltage

The frequently occurring T cell mediated rejection (TCMR) is a risk factor for allograft failure. Immunosuppressive therapy fails to reverse almost 40% of TCMRs occurring in human kidney allografts. A better understanding of the molecular mechanisms of TCMR and precision therapeutics may improve allograft longevity. We investigated adaptive immune landscape of TCMR by genome wide RNA sequencing of 34 prototypic kidney allograft biopsies from 34 adult recipients of human kidney allografts. Sixteen of the 34 biopsies were categorized as Banff TCMR and the remaining 18 as Banff Normal biopsies. Computational analysis identified higher intragraft abundance of the gene sets for key players of adaptive immune system in TCMR. TCMR allografts were characterized by, i) increased antigen processing and presentation and T cell receptor signaling, ii) increased memory T cells, Tregs, Th1, Th2 and Th17 subsets, iii) increased aerobic glycolysis of lymphocytes and reduced metabolic activity of graft parenchymal cells, iv) increased T cell inhibitory receptors and exhaustion markers, v) increased apoptosis and necroptosis, and vi) increased extracellular matrix remodeling, all in comparison to Normal biopsies. Our genome-wide transcriptomics provides an atlas of adaptive immune landscape of TCMR in human kidney allografts, help deduce molecular mechanisms and prioritization of therapeutic targets.

Funding Acknowledgements Type of funding sources: None. Introduction When aiming to stratify heart failure patients for mortality risk, exercise stress testing has proven to be relevant in specific populations of heart failure patients, but is not universally applied. Analysis of left ventricular systolic function (LVEF) remains the cornerstone for stratifying heart failure patients for prognosis and clinical treatment. The aim of the present study is to investigate the prognostic capabilities of invasive exercise testing in a real-world cohort of suspected heart failure patients in whom non-cardiac causes of dyspnea were excluded. Methods We retrospectively analyzed survival of patients who underwent right heart catheterization at rest and during exercise between 2007 to 2017 for dyspnea and expected heart failure. Pulmonary capillary wedge pressure (PCWP) at rest and the PCWP response to exercise, expressed as the ratio of PCWP at peak exercise to workload normalized to body weight [PCWL (mmHg/W/kg)], were determined. Mortality data was deducted from the official German death registry. Results A total of 682 patients [aged 64.1 ± 12 years, 269 (39.2%) women] were included. Based on LVEF, 515 patients (76.4%) had sustained LVEF ≥50%, 71 patients (10.5%) had heart failure with mildly-impaired LVEF (40-49%) and 88 patients (13.1%) had heart failure with reduced LVEF (≤40%). Absolute LVEF was not associated with all-cause mortality (HR 0.995; 95% CI 0.99-1.00; p=0.231). While increases in PCWP at rest an PCWL during exercise were both associated with death, the discriminative properties of pressure measurements derived during exercise were superior in ROC-analysis (AUC 0.637 for PCWP and AUC 0.728 for PCWL, p Discussion: In patients with clinical heart failure, invasive exercise testing improves the prediction of mortality. Subjects with a normal response to exercise have a relatively low mortality irrespective of systolic function.

Explosive volcanic eruptions can produce vast amounts of volcanic ash made up mainly of fragments of magmatic glass, country rock and minerals

Background/Aims Previous research has suggested that switching between b/tsDMARDs with different mode of action may be more effective than switching agents within the same mechanism of action. Limited data exists about the impact of an inadequate response to a previous JAK-inhibitor (JAKi) on subsequent JAKi effectiveness. Methods This is a nested study within the Swiss Clinical Quality Management (SCQM) registry of RA patients. All patients initiating baricitinib treatment courses (BARI) between 01-09-2017 and 01-06-2020, with at least one follow-up visit, were included. We compared the time to treatment discontinuation, as a measure of drug effectiveness, of BARI with a previous history of an inadequate response (IR) to tofacitinib (“BARI-post-TOFA”) or without (“BARI-initial”). Tofacitinib IR was defined as previous tofacitinib treatment discontinuation for adverse events or for ineffectiveness. Baseline characteristics were compared using t-tests or χ2. We used Kaplan-Meier curve to display crude time to discontinuation and a Cox model to estimate adjusted hazard ratio (HR). Cox model was adjusted for potential confounding factors: age, BMI, concomitant csDMARD, concomitant steroid usage, baseline CDAI, disease duration, smoking status, line of therapy, gender and seropositivity to RF/ACPA. Results Of the 273 included BARI, 72 were initiated in patients with a history of a previous tofacitinib IR (Table 1). No differences were found between the “BARI-post-TOFA” and the “BARI-initial” groups in terms of time-to-discontinuation, as demonstrated by both the unadjusted Kaplan-Meier survival analysis (Log-rank p = 0.44) and the fully adjusted Cox analysis (Hazard Ratio BARI-post-TOFA vs BARI-initial = 0.76 (95% IC [0.42 - 1.34]; p = 0.34). Other covariates significantly associated with drug maintenance were active smoking (p = 0.03) and CDAI score (p < 0.01). Conclusion In this preliminary analysis, a history of prior tofacitinib IR did not appear to significantly impact subsequent drug maintenance of baricitinib. Disclosure B.T.P. Gilbert: Other; Invited speaker for Lilly Symposium SGR Congress Lausanne (2021). D.S. Courvoisier: None. D. Mongin: None. K. Lauper: None. V.A. Guimaraes: Other; Clinical Research Scientist Immunology at Eli Lilly (Suisse) S.A. R.B. Mueller: None. A. Finckh: Grants/research support; Invited speaker and consultant for Eli Lilly. Has received research grant from Eli Lilly.