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Funding Acknowledgements Type of funding sources: None. Background The recent PARTITA trial showed a net clinical benefit of early ventricular tachycardia (VT) ablation in patients with implantable cardioverter defibrillator (ICD) experiencing appropriate shocks. The PARTITA trial analysis, however, was performed in transvenous ICD recipients and data regarding its generalizability in subcutaneous ICD (S-ICD) recipients are lacking. Purpose To test whether VT ablation after an ICD shock or a hospitalization for slow VT impacts long-term clinical outcomes in S-ICD recipients. Methods All patients experiencing an ICD shock or a hospitalization for slow VT (index event) in the multicenter, international, physician-initiated, real-world iSUSI (International SubcutaneouS Implantable Cardioverter Defibrillator) registry were included in the study. Time zero was set as time of first ICD shock / slow VT hospitalization. Patients were stratified based on performance of VT ablation after the index event (VTA+ vs VTA- cohorts). The primary outcome was a combination of device-related appropriate shocks, slow VTs, and cardiovascular mortality during follow-up. Secondary outcomes were device-related appropriate shocks, slow VTs and cardiovascular mortality, taken individually. Results Among 1701 patients enrolled in the iSUSI registry, n=211 were included in this study (n=178 experiencing appropriate shocks; n=33 with slow VTs). After the index event, n=58 (27.5%) underwent VT ablation (VTA+ cohort). No significant differences regarding baseline characteristics between VTA+ and VTA- cohorts were observed: mean age 47.3±16.0 years (VTA+) vs 47.9±17.0 years (VTA-), p=0.799; males 82.8% (VTA+) vs 82.4% (VTA-), p=0.945; mean LVEF 43.8±13.2% (VTA+) vs 42.3±15.5% (VTA-), p=0.530; underlying ischemic cardiomyopathy 31.0% (VTA+) vs 32.7% (VTA-), p=0.8.19; primary prevention implant 36.2% (VTA+) vs 43.4% (VTA-), p=0.434; median number of shocks at index time n=2 [1-4] (VTA+) vs n=2 [1-3] (VTA-), p=0.590. Over a median follow-up of 17.3 [10.4–34.8] months, the combined primary outcome was experienced by 46 (21.8%) patients (Figure 1). VT ablation performance was associated with significantly lower event rates (8.6% vs 26.8%; HR 0.215 [CI 0.100–0.637]; p=0.004), although only a trend towards significance of cardiovascular mortality was observed (HR 0.168 [CI 0.020–1.252]; p=0.081). Among VT ablation, LVEF and ischemic cardiomyopathy, which resulted significantly associated with the primary combined outcome at univariate analysis, only VT ablation remained significantly associated with the outcome of interest at multivariate analysis (HR 0.264 [CI 0.104-0.672], p=0.005) (Figure 1). Survival analysis plotted using Kaplan Meier curves has been reported in Figure 2. Conclusions In a real world registry of S-ICD recipients, VT ablation post ICD shocks or hospitalizations for slow VTs was associated with a combined improved arrhythmic and mortality outcome at long-term follow-up.

Funding Acknowledgements Type of funding sources: None. Background transvenous (TV) pacemakers are negatively associated with local and systemic device-related infections, often requiring transvenous lead extraction (TLE). Moreover, patients reimplanted with a TV device following TLE, exhibit substantial mortality and reinfection rates during the subsequent follow-up (FU). In this setting, leadless pacemakers (LPMs) are appealing as a first choice for TLE patients requiring a pacemaker reimplantation. To date, limited data on real-world safety and efficacy of LPMs in patients who underwent TLE are available. Purpose The present study aims to assess long-term safety and efficacy of LPM implantation in patients who previously underwent TLE of a transvenous pacemaker, compared to LPM de novo implant patients. Methods Consecutive patients who underwent LPM implantation in 12 centers joining the International LEAdless PacemakEr (i-LEAPER) registry were enrolled. Patients receiving LPM following TLE (n=184) were compared with patients with de novo implant (n=995). The primary endpoint was LPM-related major complications rate at implant and during FU. Additionally, differences in electrical performance were assessed between the two groups. Completion of 12-months FU was obtained in all patients. Results 1179 patients were enrolled in this study and followed for a median of 12 [IQR 11-14] months. Baseline clinical characteristics resulted balanced among the two groups, apart from a higher prevalence of heart failure among recipients of LPM following TLE (16.8% vs. 9.4%, p=0.013). As reported in the Table, LPM related major complications and all-cause mortality did not differ among the two groups (1.6% TLE group vs. 2.2% de novo group, p=0.785, and 5.4% TLE group vs. 7.8% de novo group, p=0.288, respectively). Pacing threshold (PT) resulted higher in the TLE group throughout the FU (Figure-Panel A). Higher PTs were recorded in LPMs implanted at same location from where the previous transvenous lead was removed, as far as 12-months postimplant (Figure-Panel B), with a higher proportion of patients with high PT (>1 to 2V @0.24ms) in the first group at implant, 1-month, and 12-month FU (Figure-Panel C). Conclusion In this real-world registry, LPMs showed a satisfactory safety and efficacy profile after TLE. In the post-TLE cohort, better electrical parameters were obtained when LPMs were implanted at a different location from where the previous transvenous lead was extracted.

Background Transvenous (TV) pacemakers are a well established treatment of bradyarrhythmias yet their complications, namely bleeding, infection and pneumothorax, still pose challenges to modern cardiology. This applies particularly to the older patient subgroup requiring single-chamber pacing due to comorbid atrial fibrillation (AF). Furthermore, conditions such as superior venous access issues, high infectious, or bleeding risk may complicate or preclude transvenous lead implantation. While VVIR leadless (LL) pacemakers aim to tackle these shortcomings, a comparison with contemporary single-chamber TV cohorts is currently lacking thus hindering a clear definition of the scope of LL pacing in clinical practice. Purpose To prospectively analyse survival and complication rates in leadless versus transvenous single-chamber pacemaker recipients. Methods This is a prospective analysis of 344 consecutive patients who received single-chamber TV or LL pacemakers between June 2015 and May 2021 in two tertiary cardiology centres. Indications for single-chamber pacing were “slow” AF, atrio-ventricular block with comorbid AF (either permanent or accepted as “destination rhythm”) or with sinus rhythm in bedridden cognitively impaired patients. LL indications were ongoing or expected chronic haemodialysis (6.9%), superior venous access issues such as occlusion (11.1%) or need for its preservation (9.7%), active lifestyle with low amount of pacing expected (22.2%), frailty causing high bleeding and infectious risk (23.6%), as well as recent valvular endocarditis (2.8%) or implantable electronic device infection requiring extraction (5.6%). Results 72 patients (20.9%) received LL and 272 (79.1%) TV single-chamber pacemakers. In keeping with LL indications, diabetes and ongoing haemodialysis were more prevalent in the LL population. No significant difference in overall complication rate was observed between LL and TV patients (5.6% vs. 5.1%, p=0.33) apart from haematomas, which occurred more frequently in the LL population. Only 1 haematoma in the TV group required surgical reintervention. TV recipients survival was lower with greater cardiovascular mortality, likely due to selection of significantly older patients. Conclusions Given the limited complication rate observed in this contemporary single-chamber TV cohort and low life expectancy of this particular population, extending LL indications to all VVIR candidates is unlikely to provide a clearcut survival advantage. Considering the higher costs of LL technology, these data prompt a careful selection of those cases where LL approach does indeed provide an advantage. In addition to the setting of vascular access issues and high bleeding or infectious risk, these may include patients with sufficient life expectancy where lead-related risks may indeed adversely affect prognosis. Based on our patient selection criteria, LL might account for approximately 20% of VVIR pacing recipients. Funding Acknowledgement Type of funding sources: None.

Embaràs i malaltia cardíaca; Resultats de l’embaràs; Transposició de les grans artèries Embarazo y enfermedad cardíaca; Resultados del embarazo; Transposición de las grandes arterias Pregnancy and cardiac disease; Pregnancy outcomes, Transposition of the great arteries Background In the past 3 decades, the arterial switch procedure has replaced the atrial switch procedure as treatment of choice for transposition of the great arteries. Although survival is superior after the arterial switch procedure, data on pregnancy outcomes are scarce and transposition of the great arteries after arterial switch is not yet included in the modified World Health Organization classification of maternal cardiovascular risk. Methods and Results The ROPAC (Registry of Pregnancy and Cardiac disease) is an international prospective registry of pregnant women with cardiac disease, part of the European Society of Cardiology EURObservational Research Programme. Pregnancy outcomes in all women after an arterial switch procedure for transposition of the great arteries are described. The primary end point was a major adverse cardiovascular event, defined as combined end point of maternal death, supraventricular or ventricular arrhythmias requiring treatment, heart failure, aortic dissection, endocarditis, ischemic coronary events, and thromboembolic events. Altogether, 41 pregnant women (mean age, 26.7±3.9 years) were included, and there was no maternal mortality. A major adverse cardiovascular event occurred in 2 women (4.9%): heart failure in one (2.4%) and ventricular tachycardia in another (2.4%). One woman experienced fetal loss, whereas no neonatal mortality was observed. Conclusions Women after an arterial switch procedure for transposition of the great arteries tolerate pregnancy well, with a favorable maternal and fetal outcome. During counseling, most women should be reassured that the risk of pregnancy is low. Classification as modified World Health Organization risk class II seems appropriate. Funding from “Zabawas Foundation” and “De Hoop Foundation” in addition to the support from EURObservational Research Programme (EORP) is greatly acknowledged. Since the start of EORP, the following companies have supported the program: Abbott Vascular Int (2011–2021), Amgen Cardiovascular (2009–2018), AstraZeneca (2014–2021), Bayer AG (2009–2018), Boehringer Ingelheim (2009–2019), Boston Scientific (2009–2012), The Bristol Myers Squibb and Pfizer Alliance (2011–2019), Daiichi Sankyo Europe GmbH (2011–2020), The Alliance Daiichi Sankyo Europe GmbH and Eli Lilly and Company (2014–2017), Edwards (2016–2019), Gedeon Richter Plc (2014–2016), Menarini Int Op (2009–2012), MSD‐Merck & Co (2011–2014), Novartis Pharma AG (2014–2020), ResMed (2014–2016), Sanofi (2009–2011), SERVIER (2009–2021), and Vifor (2019–2022).

Funding Acknowledgements Type of funding sources: None. Background Leadless pacing has evolved as a safe and effective treatment option in selected patients. With the updated generation that allows sensing of atrial contraction, atrioventricular synchronized pacing is now possible in a VDD mode. Previous retrospective analyses have demonstrated that echocardiographic parameters may be helpful in selecting patients with a higher chance of good atrioventricular synchronous pacing behaviour. Purpose Analysis of the early experience with the second generation of leadless pacemaker and the role of ECG parameters to predict a good atrial contraction signal (so-called A4 amplitude) in patients who underwent leadless pacemaker implantation in four tertiary centres. Methods and Results In this retrospective analysis, a total of 136 patients were included. Mean age was 78.0 (64.7 - 84.2 years) years with 48.9 % being male. Coronary artery disease was the leading underlying heart disease with 27.1 % affected patients. 61.7 % of the population suffered from sinus rhythm with complete or intermittent atrioventricular block. The majority of devices were implanted at the mid-septal (61.2 %) or high-septal (25.6 %) right ventricle, respectively. Electrical parameters were optimal at implant (Table 1) and remained stable over time (Table 1). In addition, A4 signal amplitude remained stable too during follow-up compared to the value early after implantation (Table 1). From this entire cohort, patients with an ECG available at implant and those in which the device was working predominantly in the VDD mode were selected for further analyses (62 patients). PR interval measured from the ECG prior to implantation did not correlate with the A4 signal amplitude (Figure 1A; P = NS). Next, P wave amplitudes were measured in all 12 ECG leads. There was a correlation between P wave amplitude from lead V2 with the A4 amplitude (Figure 1B; P = 0.034, R2 = 0.09), whereas the other right-sided ECG leads (V1/aVR), either alone or in combination, did not correlate with the A4 signal amplitude (P = NS). Conclusions In our cohort of patients with the second generation of leadless pacemakers, offering VDD pacing, good electrical parameters can be achieved as it has been observed with the first generation. Also the A4 signal amplitude as a marker for atrial contraction remains stable over time. In regard to ECG parameters measured prior to device implantation, only the P wave amplitude in lead V2 correlated with a amplitude of the A4 signal.

Funding Acknowledgements Type of funding sources: None. Background The subcutaneous implantable cardioverter defibrillator (S-ICD) has become an alternative to transvenous ICDs (tv-ICD), especially in young patients without a need for pacing. One of the current limitations of the S-ICD is the relatively large size of the generator compared to tv-ICDs. There is little evidence whether the size of the current S-ICD generator is associated with an elevated risk of device-related complications in patients with a low body mass index (BMI). Purpose To compare the device-related complications and long-term outcomes in a large real world cohort of S-ICD recipients in patients with a BMI 18 kg/m2. Methods The iSuSI registry is a European, multi-center, open-label, independent, and physician-initiated observational registry. A total of twenty-two Public and Private Healthcare Institutions from 4 different countries in Europe were involved in the registry. All consecutive patients meeting current guideline indications for ICD implantation and undergoing implantation of a S-ICD device (Boston Scientific, Marlborough, Massachusetts, USA) at 21 European institutions enrolled in the registry were used for the current analysis. Patients were classified into two cohorts, depending on the BMI at the time of device implantations: BMI < 18 kg/m2 versus > 18 kg/m2. Results Out of a total of 1497 pts, 58 pts (3.9%) had a BMI < 18 kg/m2. Patients with BMI Over a median follow up time of 22.4 [11.6–36.8] months, both overall device-related complications (5.2% vs 7.4%) and rates of inappropriate shocks (12.0% vs 8.8%) resulted comparable between the two groups (p =0.517 and p=0.385, respectively). Figure1 reports Kaplan-Meier curves reporting the combined incidence of device-related complications and inappropriate shocks in the two groups (log-rank p = 0.576). Conclusion No difference in device-related complications and long-term outcomes after S-ICD implantation were observed in patients with BMI Figure 1: Kaplan-Meier-survival curve for the combined endpoint of inappropriate shocks (IAS) and device-related complications (DRC)

Funding Acknowledgements Type of funding sources: None. Background Young patients often represent the most suitable candidates for an entirely subcutaenous implantable cardioverter defibrillator (S-ICD) system, since they have to face a lifetime of device therapy and they rarely have a pre-existing or concurrent pacing or cardiac resynchronization therapy (CRT) indication. Moreover, S-ICD offers lower rate and a safer management of lead and major procedure-related complications. To date, a few limited case series and experiences with S-ICD in teenagers and young adults have shown that the S-ICD system is safe and feasible in this population, with a rate of inappropriate shocks (IS) comparable to transvenous (TV) ICD, but focused analysis on a large scale are currently lacking in this setting. Purpose The aim of the current study was to compare the age-related differences observed in patient selection, baseline characteristics, and device long-term associated outcomes in a large real world cohort of S-ICD recipients. The primary outcome of the study was defined as the comparisons of the IS rate observed during the entirety of follow up in the teenagers/young adult vs the adult populations. Rate of complications, freedom from sustained ventricular arrhythmic events, overall and cardiovascular mortality were also assessed in the two cohorts and assessed as secondary outcomes. Methods All S-ICD recipients in the ELISIR project were enrolled in the current study. Patients were classified into teenagers + young adults (≤ 30 years old) vs adults (> 30 years old), depending from patient age at device implantation (Figure 1). Rates of device-related complications and IS were compared between the cohorts. Results A total of 1349 patients were extracted from the ELISIR project. Teenagers and young adults represented 12.4% of the registry (n=56 teenagers; n=112 young adults). Patients were followed-up for a median of 23.1 [12.6–37.9] months. Overall, 117 (8.7%) patients experienced inappropriate S-ICD shocks and 100 (7.4%) device related complications were observed, with no age-related differences. IS resulted more frequent in the teenager and young adult cohort (14.3% vs 7.9%; p=0.006). Figure 2 reports Kaplan Meier curves for the occurrence of IS. At univariate analysis, young age was associated with IS, but after correcting for differences in arrhythmic substrate, this association resulted non-significant (aHR: 1.428 [0.883–2.331]; p=0.146). The use of SMART pass algorithm was instead associated to a strong reduction in IS (aHR 0.367 [0.245–0.548]; p Conclusion The use of S-ICD in teenagers/young adults resulted safe and effective. Indeed, the rate of complications between teenagers/young adults and adults was not significantly different. Although a higher rate of IS was observed in the teenagers/young adults, when accounting for differences in baseline substrate and comorbidities, young age did not result associated with an increased risk of IS.

Background Data on patients with heart failure (HF) with a subcutaneous implantable cardioverter defibrillator (S–ICD) are scarce. Objective Aim of this study was to assess clinical outcomes of the S–ICD in HF patients in a real–world analysis from the largest European retrospective S–ICD registry (ELISIR). Methods All consecutive patients undergoing S–ICD implantation at several European institutions were used for the current analysis. The population was classified into two groups: the HF (classified as HF with reduced and mid–range ejection fraction – HFrEF and HFmrEF) vs the no–HF cohort. The primary outcome of the study was the inappropriate shock (IS) rate across the two cohorts. As secondary outcomes, appropriate shocks, cardiovascular mortality and device–related complications during follow–up were assessed Results A total of 1409 patients from the ELISIR registry were included; HF patients represented 57.3% of the entire cohort (n = 701, 86.9% HFrEF; n = 106,13.1% HFmrEF). Over a median follow–up of approximately 2 years, a total of 133 inappropriate shocks were observed in the entire cohort, without significant differences among the two groups (9.2% vs 9.8%, p = 0.689). 133 complex ventricular arrhythmias were adequately recognized and treated, with similar rates of appropriate shocks (9.2% vs 9.8%, p = 0.689). Inappropriate and effective shocks–free survival has been represented in Figure 1 (Kaplan–Meier estimates). At multivariate analysis (Figure 2), age (HR = 0.974 [0.955–0.992], p = 0.005), LVEF (HR = 0.954 [0.926–0.984], p = 0.003), arrhythmogenic right ventricular cardiomyopathy – ARVC (HR = 3.364 [1.206–9.384], p = 0.020) and smart pass + (HR = 0.321 [0.184–0.560], p Conclusion The use of S–ICD in HF patients did not result in a higher rate of inappropriate shocks when compared to no–HF patients, even when stratifying for LVEF. Only age, LVEF, ARVC e Smart Pass algorithm were predictors of the primary outcome at multivariate analysis. Despite a lower overall rate of complications in the entire cohort, HF patients experienced device–related complications more frequently.

Background Stroke prophylaxis in very high risk (CHA2DS2–VASc ≥ 5) patients with atrial fibrillation (AF) is one of the major challenges faced by physicians. Specifically, initiating direct oral anticoagulants (DOACs) in these patients poses a therapeutic conundrum due to the concomitant high risk of bleeding. Left atrial appendage occlusion (LAAO) might be a potential alternative for thromboembolic (TE) prevention; however, there are no studies comparing these two strategies in very high–risk patients. Objective To evaluate the efficacy of LAAO versus DOACs in AF patients at very high TE risk. Methods Data were extracted from two prospective databases including 1053 Watchman and 1328 DOAC patients. Watchman patients with a CHA2DS2–VASc ≥ 5 accounted for 26.3% (n = 277). In order to attenuate the imbalance in covariates, a 1:1 propensity score matching technique was used (co–variates: age, sex, CHA2DS2–VASc and HAS–BLED scores). This method resulted in 554 matched patients (277 patients per group; mean age: 79±7y; 57.4% F; CHA2DS2–VASc: 5.8±0.9). The primary endpoint was a composite of cardiovascular (CV) death, TE events (Stroke/TIA/peripheral embolism) and clinically significant bleeding. The annual TE and major bleeding risks were estimated based on the CHA2DS2–VASc score and compared with the annualized observed risk. Results After a mean follow–up of 26±7 months, total events were 55 (9.4 event rates per 100 patient–years) in LAAO group vs. 78 (14.9 event rates per 100 patient–years) in DOAC group. DOACs had a significantly higher risk of the primary endpoint (hazard ratio [HR]: 1.30; 95% confidence interval [CI]: 1.08 to 1.56; p = 0.03). TE events (HR: 1.15; 95% CI: 0.84 to 1.57; p = 0.63) and CV death (HR: 1.13; 95% CI: 0.84 to 1.54; p = 0.63) did not differ between groups. Major bleeding events were significantly lower in LAAO patients (HR: 0.75; 95% CI: 0.51 to 0.82; p = 0.04). The unadjusted estimated risk of TE events was 12.3% with LAAO and 12.4% with DOACs. The annualized incidence of TE was 3.2% with LAAO and 4.1% with DOACs, which led to a risk reduction of 74% and 67%, respectively. Conclusion In a large cohort of AF patients at very high TE risk (CHA2DS2–VASc ≥ 5), LAAO showed similar stroke prevention but a significantly lower risk of major bleeding than DOACs during a > 2year follow–up.

Background The subcutaneous implantable cardioverter defibrillator (S–ICD) has become an alternative to transvenous ICDs (TV–ICD) in patients who do not need pacing. To date, there is little evidence directly comparing the rates of inappropriate shocks (IAS) in young vs old S–ICD recipients. Purpose Aim of our study was to assess differences in device–related complications and inappropriate shocks (IS) between teenagers/young adults and adult recipients of a subcutabeous implantable cardioverter defibrillator (S–ICD) device. Methods Two propensity–matched cohorts of teenagers + young adults (≤ 30–year–old) and adults (> 30–year–old) were retrieved from the ELISIR registry. The primary outcome was the comparison of the inappropriate shock (IAS) rate; complications, freedom from sustained ventricular arrhythmic events, overall and cardiovascular mortality were deemed secondary outcomes. Results A total of 1491 patients were extracted from the ELISIR project. Teenagers + young adults represented 11.0% of the entire cohort. Two propensity–matched groups of 161 patients each were used for the analysis (Figure 1); median follow–up was 23.1 [13.2–40.5] months. 15.2% patients experienced inappropriate S–ICD shocks and 9.3% device related complications were observed with no age–related differences in IAS (16.1% vs 14.3%; p = 0.642) and complication rates (9.9% vs 8.7%; p = 0.701); Figure 2 shows a survival analysis from inappropriate shocks in the teen–ager/young adult cohort (red) and in the adult cohort (blue). At univariate analysis, young age was not associated with increased rates of IAS (HR 1.204 [0.675–2.148]: p = 0.529). At multivariate analysis (Figure 3), the use of SMART pass algorithm was associated to a strong reduction in IAS (aHR 0.292 [0.161–0.525]; p Conclusion In a large multicentered European registry of patients with S–ICD, 11.0% of all recipients were teenagers or young adults. The use of S–ICD in teenagers/young adults resulted safe and effective, and the rates of complications and IAS between teenagers/young adults and adults were not significantly different. The only predictor of increased IAS was a diagnosis of ARVC.

Background One of the current limitations of the S–ICD is the relatively large size of the generator compared to the TV (transvenous) ICD. There is little evidence whether the size of the current S–ICD generator is associated with an elevated risk of device–related complications in patients with a low body mass index (BMI). Purpose Aim of this study was to compare the device–related complications and long–term outcomes in a large real world cohort of S–ICD recipients in patients with a BMI 18 kg/m2. Methods All consecutive patients meeting current guideline indications for ICD implantation and undergoing implantation of a S–ICD device (Boston Scientific, Marlborough, Massachusetts, USA) at 21 European institutions enrolled in the extended ELISIR registry were used for the current analysis. Patients were classified into two cohorts, depending on the BMI at the time of device implantations: BMI < 18 kg/m2 versus > 18 kg/m2. Results Out of a total of 1497 pts, 58 pts (3.9%) had a BMI < 18 kg/m2. Patients with BMI Conclusion No differences in device–related complications and long–term outcomes after S–ICD implantation were observed in patients with BMI

Description The 2020 Match has recently concluded. While the results give us some information about where the medical field is headed, the decision by the NBME and FSMB to change USMLE Step 1 score reporting to only a pass/fail outcome will also impact how residency programs navigate the NRMP in the years ahead.

We demonstrate an electrokinetically pumped sheath flow nanospray interface for capillary electrophoresis coupled to negative mode electrospray mass spectrometry. In this interface, application of an electric field generates electro-osmotic flow at the interior of a glass emitter that is pulled to a 10–20 micrometer inner diameter orifice. Electro-osmotic flow pumps liquid around the distal tip of the separation capillary, ensheathing analyte into the electrospray electrolyte. In negative ion mode, negative potential applied to an untreated glass emitter drives sheath flow away from the emitter orifice, decreasing the stability and efficiency of the spray. In this manuscript, we treat a portion of the interior of the electrospray emitter with 3-aminopropyltrimethoxysilane, which grafts primary amines to the interior. The amines take on a positive charge, which reverses electro-osmosis and generates stable sheath flow to the emitter orifice under negative potential. Negative mode operation is demonstrated by analyzing a metabolite extract from stage 1 Xenopus laevis embryos. Production of the treated emitters was quite reproducible. We evaluated the performance of three emitters using a set of amino acids; the relative standard deviation in peak intensity was 7% for the most intense component.

Introduction The screening of carotid and/or ileo-femoral subclinical atherosclerosis using vascular ultrasound could be a cost-effective tool in the reclassification of cardiovascular risk in primary cardiovascular prevention. But until today we don't have evidence indicating which atherosclerotic load indicator variable (such as plaque area, number of atherosclerotic plaques or affected territories) has the most predictive power for future cardiovascular events. Objectives a. Evaluate the prevalence of carotid and ileo-femoral subclinical atherosclerosis (SubAth). b. Evaluate the predictive power of each atherosclerotic load indicator variable for cardiovascular events (CVE). c. to compare those methods with Framingham Score for prediction of CVE. Material and methods We retrospectively evaluated patients from our registry called CARFARE (CARDIOMETABOLIC RISK FACTORS REGISTRY) conducted in the context of a cardiovascular primary prevention program (n=6108). In this analysis we included only those patients who completed a follow up ≥24 months from the first vascular evaluation. Exclusion criteria: 65 years old, BMI>40 kg/m2, previous cardiovascular and/or cerebrovascular event, chronic stable angina. We used Framingham score for the cardiovascular risk assessment. We evaluated the following atherosclerotic load variables using high resolution vascular ultrasonography (Mannheim Consensus): carotid plaques area (AR-C), ileo-femoral plaques area (AR-IF), and total (carotid+ileo-femoral, AR-TOT), number of affected territories (N-TER). Primary composite endpoints (P-CVE): myocardial infarction, stroke, hospitalization due to angina or acute heart failure. For prediction power analysis we used ROC curves and logistic regressions (unadjusted and adjusted by age, sex, BMI, major cardiovascular risk factors and treatment). Results We included 1431 patients (55.0±9.78 y.o., 38% women, follow-up period of 789±23 days). The total P-CVE rate was 3.77% during this period (54 events). The overall prevalence of atherosclerosis in this population was 60.7%. The AUC of the ROC curves for P-CVE prediction was 0.648, for Framingham 0.706, for AR-C 0.726, for AR-IF 0.746, for AR-TOT and 0.79 for N-TER (graph). The AUC of AR-TOT and N-TER were significantly higher than the AUC of the Framingham score (p=0.017 and p=0.0004, respectively) for prediction of P-CVE. The dichotomization criteria according to ROC were: AR-C>5.80 mm2, AR-IF>23.0 mm2, AR-TOT>43.9 mm2, and N-TER>1. In the logistic regressions adjusted for prediction of P-CVE the OR were: Framingham 1.05 (95% CI: 1.02–1.07), AR-C 4.00 (95% CI: 1.89–8.47), AR-IF 4.01 (95% CI: 2.02–8.32), AR-TOT 4.35 (95% CI: 2.13- 8.91) and N-TER 6.95 (95% CI: 3.05–15.8). Comparison of ROC curves for CVE Conclusions The carotid/ileo-femoral SubAth scan was a more potent predictor of cardiovascular events than the Framingham score, particularly those variables that indicate extension of multiterritorial affection like AR-TOT or N-TER.

Climate change is one of the greatest public health threats of the twenty-first century. Recent surveys of veterinary students and practicing veterinarians have highlighted their concerns about the impacts of climate change on animal health and a strong desire to be knowledgeable about the practice and promotion of environmental sustainability within clinical practice. Most American Veterinary Medical Association (AVMA)–accredited veterinary schools have a veterinary teaching hospital (VTH) where veterinary students receive their core clinical education. Given this, VTHs may provide opportunities for students to learn how veterinary clinics can decrease their environmental footprint and actions they could incorporate into their future clinical work. To assess the feasibility of and support for introducing environmentally sustainable practices into VTHs, we distributed an anonymous online survey to all AVMA-accredited veterinary schools with an associated VTH. Responses were received from 843 individuals representing 23 VTHs in 7 countries. While the overwhelming majority of responding personnel believe this is an important topic, there is little evidence that sustainable behaviors are being practiced or showcased within VTHs. Respondents were most interested in working to increase recycling and reduce general waste and energy consumption within their hospitals. In addition to a lack of educational resources, funding was a commonly identified barrier to incorporating more environmentally sustainable practices. These results add to the growing evidence that enhanced incorporation of sustainability into veterinary medical education at all stages is needed and that VTHs provide a unique opportunity to lead by example.

Cryphaea consimilis (Cryphaeaceae, Bryophyta), new record for Argentina. Cryphaea consimilis Mont. (Cryphaeaceae, Bryophyta) is recordered for the first time for Argentina, extending its distribution within the subantarctic forests. A brief description, discussion, distribution map and illustration of the species are provided. A lectotype for this species is here designated.

Nucleotides are among the most frequently used chemical building blocks in the research, development and manufacture of drug substances. They are composed of three highly polar subunit molecules (a nucleobase, a sugar, and at least one phosphate group), which makes their separation and analysis very challenging by conventional liquid chromatography techniques. Herein, we describe a simple, efficient, and cost-effective ion-exchange chromatography (IEC) method for the separation and purification of over 20 nucleotides. This method combines the use of a Tosoh TSKgel SuperQ-5P W resin in conjunction with a fully aqueous eluent profile (ammonium bicarbonate-based) that allows for a straightforward scale-up transition and convenient drying process with minimal environmental impact. This generic method was optimized using chromatography simulation software (ACD Labs/LC Simulator) and successfully applied to the preparative purification of multicomponent nucleotide mixtures using readily available Fast Protein Liquid Chromatography (FPLC) instrumentation. These IEC method conditions can be effectively applied as the starting point for method development and isolation of other highly polar nucleotide species beyond those investigated in this study.

Supercritical fluid chromatography (SFC) has become the fastest growing analytical tool for chiral and achiral small-molecule pharmaceutical separations. The benefits from savings in cost (as a result of lower solvent and energy consumption), and time have made SFC a proven effective tool for solving many analytical problems for small-molecules over the years. There is, however, a gap in the application of SFC for larger biomolecules, proteins and peptides. There has been a notable increase of protein- and peptide-based drug therapies that contain a higher-order structure important to their efficacy. These studies leverage the use of size exclusion chromatography coupled with hydrogen-deuterium exchange (SEC-HDX) methodology and circular dichroism (CD) spectroscopy to probe global conformational structures of model peptides and proteins following purification by preparative SFC. It was demonstrated that bradykinin and insulin can be used in SFC purification, and moreover, insulin was able to recover its original higher-order structure when compared to pre-purification insulin by three orthogonal techniques: 1) calculated percent alpha-helicity based on CD spectra, 2) alpha-helix - temperature hysteresis analysis by CD and 3) SEC-HDX-MS at different temperatures. However, it was shown that the higher order structures of the other three model proteins used in the study (ubiquitin, cytochrome C, and apomyoglobin) were significantly modified during SFC purification and were unable to re-fold to their original conformations. The present workflow was applied successfully to several peptide therapeutic programs at our comp any and in addition can be applied for small proteins.

Misfolding of therapeutic peptides and proteins can lead to numerous issues, ranging in severity, including loss of function, aggregation, immunogenicity, and cytotoxicity. A primary component of protein folding is secondary structure, including α-helices and β-sheets. Many native peptides and proteins are predominately α-helical therefore, it is of critical importance to develop robust and reliable analytical tools to investigate protein higher order structure, including the percentage of α-helix under various conditions, to evaluate protein folding and prevent the negative effects of misfolding. However, given the complexity of protein folding and higher order structure, it is unlikely that one technique will provide a comprehensive analysis. To bridge this gap, this study presents the combination of two orthogonal techniques – circular dichroism (CD) and size-exclusion chromatography-hydrogen-deuterium exchange-mass spectrometry (SEC-HDX-MS) to investigate global peptide and protein conformations. Also, the incorporation of trifluoroethanol (TFE), a known stabilizer of α-helical structures, into the analyses, aims to enhance the discrimination power of these two techniques by increasing the alpha helical stability range of study. CD data was used to estimate the percent of α-helix content and its thermal stability while online SEC-HDX-MS screening compared global conformational changes of each peptide based on a difference in the number of deuterons exchanged to protons, ΔHDX. The workflow described in this report can be very beneficial in pharmaceutical development. The model peptides were chosen to demonstrate the workflow with commercially available compounds. The goal of this study was to show a proof-of-concept for direct correlation of these methodologies and to estimate the percentage of α-helix content at a particular ΔHDX, which is indicative of the state of protein folding.

While capillary zone electrophoresis (CZE) has been used to produce very rapid and efficient separations, coupling these high-speed separations with mass spectrometry (MS) has been challenging. Now, with much faster and sensitive mass spectrometers, it is possible to take full advantage of the CZE speed and reconstruct the fast migrating peaks. Here are three high-speed CZE-MS analyses via an electrokinetically pumped sheath-flow interface. The first separation demonstrates CZE-ESI-MS of an amino acid mixture with a two-minute separation, >50,000 theoretical plates, low micromolar concentration detection limits, and subfemtomole mass detection limits (LTQ XL mass spectrometer). The second separation with our recently improved third-generation CE-MS interface illustrates a 20 amino acid separation in ~7 minutes with an average over 200,000 plate counts, and results in almost-baseline resolution of structural isomers, leucine and isoleucine. The third separation is of a BSA digest with a reproducible CZE separation and mass spectrometry detection in two minutes. CZE-MS/MS analysis of the BSA digest identified 31 peptides, produced 52% sequence coverage, and generated a peak capacity of ~40 across the one-minute separation window (Q-Exactive mass spectrometer).

There is a need for low cost, sensitive and chemical specific detectors for routine characterization of biomolecules. In this study, we utilize sheath-flow surface-enhanced Raman scattering (SERS) to analyze a mixture of eight biologically-active peptides separated by capillary zone electrophoresis (CZE). Analysis of the SERS electropherogram resulting from online detection resolves the characteristic Raman bands attributed to the amino acid constituents of each peptide, which enables identification. The detection limit by SERS was found to be 10−8 M. Our results suggest that the structural information obtained from the detected vibrational modes provides complementary characterization to other chemically specific detectors like mass spectrometry and improved chemical identification over other commonly used optical-based post-chromatographic detection methods. In addition, the sheath-flow SERS detection results in band narrowing in the observed electropherogram that enables distinction of closely migrating species. The results presented here indicate that online SERS detection can provide fast, robust, reproducible, and chemical specific detection to facilitate the characterization of peptides.

Se describe Thamniopsis flexifolium, una nueva especie para las Yungas en el noroeste de la Argentina que sedistingue de sus congéneres por las plantas rojizas a púrpuras, los dientes del margen foliar grandes y agudos, ylas células de la lámina de paredes lateralmente engrosadas, a veces proradas. Se registra además un nuevo taxónpara el país: Lepidopilum muelleri. Se incluyen descripciones, distribuciones, ilustraciones, comentarios de lasnovedades taxonómicas y una clave para las especies de la familia Pilotrichaceae del noroeste de Argentina. Thamniopsis flexifolium is a new species from Yungas in the Northwest of Argentina. It is distinguished from congeners by the reddish purple plants, large teeth and sharp leaf margin and the cells of the sheet laterally thickened walls, sometimes prorate. Further, Lepidopilum muelleri is a new record for the country. Descriptions, distributions, illustrations, discussions to the taxa and the key are included for the species of the family Pilotrichaceae of the northwest of Argentina. Fil: Colotti, María T.. Universidad Nacional de Tucumán. Facultad de Ciencias Naturales e Instituto Miguel Lillo; Argentina Fil: Suarez, Guillermo Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico - Tucumán. Unidad Ejecutora Lillo; Argentina. Universidad Nacional de Tucumán. Facultad de Ciencias Naturales e Instituto Miguel Lillo; Argentina Fil: Schiavone, Maria M.. Universidad Nacional de Tucumán. Facultad de Ciencias Naturales e Instituto Miguel Lillo; Argentina

The role of apoptosis in the persistence of hepatitis C virus (HCV) infection is controversial. Moreover, conflicting data on the modulation of this process by HCV proteins have been provided. We evaluated the susceptibility of peripheral lymphocytes from patients with chronic hepatitis C to apoptosis both spontaneous and after incubation with a chimeric Cucumber mosaic virus (CMV) carrying 180 copies of the synthetic R9 mimotope obtained from more than 200 hypervariable region-1 sequences of HCV. Resting T lymphocytes were found to be sensitized to apoptosis as a result of chronic HCV infection. The plant virus-derived vector R9-CMV displayed a strong pro-apoptotic effect associated with activation of both caspase-8 and -9, indicating the involvement of both extrinsic and intrinsic apoptotic pathways. A parallel R9-CMV-mediated activation of endoplasmic reticulum-stress was suggested by the significant induction of BiP/GRP78, GADD153 and caspase-12. These data contribute to define the complex HCV/host interaction, and open new prospects for developing a plant-derived antigen-presenting system to strengthen host defences against persistent pathogens.

Four fusicoccane-type diterpenoids (1−4), including the new 1 and 2; four pinguisane-type sesquiterpenoids (5−8); and two aromadendrane-type sesquiterpenoids (9 and 10) were isolated from an Argentine collection of the endemic liverwort Porella chilensis. The biofilm formation of the human pathogen Pseudomonas aeruginosa was inhibited by compounds 3 (53 and 47%), 9 (45 and 41%), and 10 (48 and 37%) at 50 and 5 μg/mL, respectively. Compounds 3, 9, and 10 also produced a slight decrease in bacterial growth and interfere with the process of quorum sensing at the same doses. Fil: Gilabert Valero, José Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto de Química del Noroeste. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Química del Noroeste; Argentina Fil: Ramos Vernieri, Alberto Nicolás. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Schiavone, Maria Magdalena. Universidad Nacional de Tucumán. Facultad de Ciencias Naturales e Instituto Miguel Lillo; Argentina Fil: Arena, Mario Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto de Química del Noroeste. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Química del Noroeste; Argentina Fil: Bardon, Alicia del Valle. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto de Química del Noroeste. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Química del Noroeste; Argentina

Fil: Suarez, Guillermo Martin. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - Tucuman; Argentina. Fundacion Miguel Lillo; Argentina

Globulinella halloyi is described from Volcan Socompa in Salta Province of Argentina. It is readily distinguished from congeners by the following combination of character states: robust plants, with costa dorsally and ventrally toothed and with two stereid bands in transverse section, and elongate propagula ca. 200 µm long. A description and ilustrations of the new species are provided. A table of morphological characters compares the three species of Globulinella.

Emtricitabine (FTC) is a synthetic nucleoside analogue of cytosine, which is intracellularly phosforylated to form the active form emtricitabine 5'triphosphate (E5TP). E5TP inhibits both HIV and Hepatitis B reverse transcriptase. Clinical trials have shown FTC to be active as part of highly active anti-retroviral therapy in naive HIV-positive patients. FTC may be dosed once daily and in vitro is less associated with the M184V mutation, which is classically associated with failure of treatment with lamivudine. In clinical practice, toxicity with FTC is unusual. The most common treatment-related adverse events are diarrhoea, headache, nausea, dizziness, abdominal pain, aesthenia and rash. Skin discolouration, which is typically reported as hyperpigmentation and usually affecting either the palms of the hands or the soles of the feet, is reported on under 2% of individuals and is almost exclusive to patients of African origin.