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Aims: Catheter ablation (CA) of post-ablation left atrial tachycardias (LATs) can be challenging. So far, pulsed field ablation (PFA) has not been compared to standard point-by-point radiofrequency current (RFC) energy for LAT ablation. To compare efficacy of PFA vs. RFC in patients undergoing CA for LAT., Methods and Results: Consecutive patients undergoing LAT-CA were prospectively enrolled (09/2021-02/2023). After electro-anatomical high-density mapping, ablation with either a pentaspline PFA catheter or RFC was performed. Patients were matched 1:1. Ablation was performed at the assumed critical isthmus site with additional ablation, if necessary. Right atrial tachycardia (RAT) was ablated with RFC. Acute and chronic success were assessed. Fifty-six patients (n = 28 each group, age 70 ± 9 years, 75% male) were enrolled.A total of 77 AT (n = 67 LAT, n = 10 RAT; 77% macroreentries) occurred with n = 32 LAT in the PFA group and n = 35 LAT in the RFC group. Of all LAT, 94% (PFA group) vs. 91% (RFC group) successfully terminated to sinus rhythm or another AT during ablation (P = 1.0). Procedure times were shorter (PFA: 121 ± 41 vs. RFC: 190 ± 44 min, P < 0.0001) and fluoroscopy times longer in the PFA group (PFA: 15 ± 9 vs. RFC: 11 ± 6 min, P = 0.04). There were no major complications. After one-year follow-up, estimated arrhythmia free survival was 63% (PFA group) and 87% (RFC group), [hazard ratio 2.91 (95% CI: 1.11-7.65), P = 0.0473]., Conclusion: Pulsed field ablation of post-ablation LAT using a pentaspline catheter is feasible, safe, and faster but less effective compared to standard RFC ablation after one year of follow-up. Future catheter designs and optimization of the electrical field may further improve practicability and efficacy of PFA for LAT., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background Robotic-assisted surgery continues to grow in popularity. Access during evenings and weekends for non-elective operations can be restricted out of safety concerns. We sought to analyze and compare outcomes of patients undergoing robotic cholecystectomy, a common urgent procedure for acute calculous cholecystitis, during regular hours versus evenings or weekends. Based on this comparison, we sought to determine if this restriction is justified. Methods We performed a retrospective analysis of 46 patients who underwent robotic cholecystectomy for acute calculous cholecystitis per 2018 Tokyo criteria by a single surgeon at a single institution between 2021 and 2022. Patients were grouped as undergoing "after-hours" cholecystectomy if the operation started at five pm or later, or anytime during the weekend (Saturday, Sunday). Demographic, perioperative, and outcome variables were tabulated and analyzed. For illustrative purposes, the data presented as median ± standard deviation were applicable. Results After-hours cholecystectomy occurred in 26 patients and regular-hours cholecystectomy occurred in 20 patients. There were no significant differences in perioperative variables between the two cohorts in terms of body mass index, age, gender, cirrhotic status, American Society of Anesthesiology score, white blood cell count, or neutrophil percentage. The after-hours group had more prior abdominal operations. There were no significant differences between the two groups in terms of operative time, estimated blood loss, or length of stay. There were no mortalities. There was one readmission in the after-hours cohort unrelated to the operation. Conclusion Robotic cholecystectomy can be safely performed on the weekends and evenings. Hospitals should make the robotic platform available during this time., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Shapera et al.)

Background: With the emergence of new subvariants, the disease severity of Severe Acute Respiratory Syndrome Coronavirus-2 has attenuated. This study aimed to compare the disease severity in patients hospitalized with omicron variant infection to those with influenza infection., Methods: We compared data from the multicenter observational, prospective, epidemiological "CORONA Germany" (Clinical Outcome and Risk in hospitalized COVID-19 patients) study on patients infected with Severe Acute Respiratory Syndrome Coronavirus-2 to retrospective data on influenza infection cases from November 2016 to August 2022. Severe Acute Respiratory Syndrome Coronavirus-2 cases were classified as wild-type/delta variant before January 2022, or omicron variant from January 2022 onward. The primary outcome was in-hospital mortality, adjusted for age, gender, and comorbidities., Results: The study included 35,806 patients from 53 hospitals in Germany, including 4,916 patients (13.7%) with influenza infection, 16,654 patients (46.5%) with wild-type/delta variant infection, and 14,236 patients (39.8%) with omicron variant infection. In-hospital mortality was highest in patients with wild-type/delta variant infection (16.8%), followed by patients with omicron variant infection (8.4%) and patients with influenza infection (4.7%). In the adjusted analysis, higher age was the strongest predictor for in-hospital mortality (age 80 years vs. age 50 years: OR 4.25, 95% CI 3.10-5.83). Both, patients with wild-type/delta variant infection (OR 3.54, 95% CI 3.02-4.15) and patients with omicron variant infection (OR 1.56, 95% CI 1.32-1.84) had a higher risk for in-hospital mortality than patients with influenza infection., Conclusion: After adjusting for age, gender and comorbidities, patients with wild-type/delta variant infection had the highest risk for in-hospital mortality compared to patients with influenza infection. Even for patients with omicron variant infection, the adjusted risk for in-hospital mortality was higher than for patients with influenza infection. The adjusted risk for in-hospital mortality showed a strong age dependency across all virus types and variants., Trial Registration Number: NCT04659187., Competing Interests: NG reports grants from Boston Scientific, grants from Medtronic and support from Bayer Vital outside the submitted work. MAG reports grants/speaker honoraria and consultation fees from Boston Scientific, Farapulse Inc., Biosense Webster, Abbott and Medtronic outside the submitted work. WG reports grants/speaker honoraria and consultation fees from AstraZeneca, Olympus and PulmonX outside the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials. All other authors have nothing to disclose., (Copyright: © 2023 Dickow et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Particle therapy is a noninvasive, catheter-free modality for cardiac ablation. We previously demonstrated the efficacy for creating ablation lesions in the porcine heart. Despite several earlier studies, the exact mechanism of early biophysical effects of proton and photon beam delivery on the myocardium remain incompletely resolved., Methods: Ten normal and 9 infarcted in situ porcine hearts received proton beam irradiation (40 Gy) delivered to the left ventricular myocardium with follow-up for 8 weeks. High-resolution electroanatomical mapping of the left ventricular was performed at baseline and follow-up. Bipolar voltage amplitude, conduction velocity, and connexin-43 were determined within the irradiated and nonirradiated areas., Results: The irradiated area in normal hearts showed a significant reduction of bipolar voltage amplitude (10.1±4.9 mV versus 5.7±3.2, P <0.0001) and conduction velocity (85±26 versus 55±13 cm/s, P =0.03) beginning at 4 weeks after irradiation. In infarcted myocardium after irradiation, bipolar voltage amplitude of the infarct scar (2.0±2.9 versus 0.8±0.7 mV, P =0.008) was significantly reduced as well as the conduction velocity in the infarcted heart (43.7±15.7 versus 26.3±11.4 cm/s, P =0.02). There were no significant changes in bipolar voltage amplitude and conduction velocity in nonirradiated myocardium. Myocytolysis, capillary hyperplasia, and dilation were seen in the irradiated myocardium 8 weeks after irradiation. Active caspase-3 and reduction of connexin-43 expression began in irradiated myocardium 1 week after irradiation and decreased over 8 weeks., Conclusions: Irradiation of the myocardium with proton beams reduce connexin-43 expression, conduction velocity, and bipolar conducted electrogram amplitude in a large porcine model. The changes in biomarkers preceded electrophysiological changes after proton beam therapy., Competing Interests: Disclosures Dr Packer in the past 12 months has provided consulting services for Abbott, ArtFix, Biosense Webster Inc, External Beam Ablation Med (EBAmed), Maxwell Biomed, MediaSphere Medical, LLC, MedLumics, Medtronic, St. Jude Medical, Siemens, Sanofi, Thermedical, and Wave Strategy. Dr Packer received no personal compensation for these consulting activities unless noted. Dr Packer receives research funding from the Abbott, Biosense Webster, Boston Scientific/EPT, CardioInsight, EBAmed, Medtronic Inc, Siemens, St. Jude Medical Inc, Thermedical Inc, National Institutes of Health (NIH), Robertson Foundation, Vital Project Funds Inc, Mr and Mrs J. Michael Cook/Fund. Mayo Clinic and Dr Packer have a financial interest in Analyze-AVW technology that may have been used to analyze some of the heart images in this research. In accordance with the Bayh-Dole Act, this technology has been licensed to commercial entities, and both Mayo Clinic and Dr Packer have received royalties less than $10 000, the federal threshold for significant financial interest. In addition, Mayo Clinic holds an equity position in the company to which the AVW technology has been licensed. Dr Packer and Mayo Clinic jointly have equity in a privately held company, EBAmed, and has received stock options from Neutrace, ArtFix Ltd, and Xenter Inc. Dr Packer has a licensing agreement with the American Heart Association and Medtronic Inc, for the Mayo Atrial Fibrillation Symptom Inventory (MAFSI) Survey and has contractual rights to receive future royalties under this license. Royalties from Wiley & Sons, Oxford, and St. Jude Medical. The other authors report no conflicts.

Background: A recent subanalysis of the EAST-AFNET 4 (Early Treatment of Atrial Fibrillation for Stroke Prevention Trial) suggests a stronger benefit of early rhythm control (ERC) in patients with atrial fibrillation and a high comorbidity burden when compared to patients with a lower comorbidity burden., Methods: We identified 109 739 patients with newly diagnosed atrial fibrillation in a large United States deidentified administrative claims database (OptumLabs) and 11 625 patients in the population-based UKB (UK Biobank). ERC was defined as atrial fibrillation ablation or antiarrhythmic drug therapy within the first year after atrial fibrillation diagnosis. Patients were classified as (1) ERC and high comorbidity burden (CHA 2 DS 2 -VASc score ≥4); (2) ERC and lower comorbidity burden (CHA 2 DS 2 -VASc score 2-3); (3) no ERC and high comorbidity burden; and (4) no ERC and lower comorbidity burden. Patients without an elevated comorbidity burden (CHA 2 DS 2 -VASc score 0-1) were excluded. Propensity score overlap weighting and cox proportional hazards regression were used to balance patients and compare groups for the primary composite outcome of all-cause mortality, stroke, or hospitalization with the diagnoses heart failure or myocardial infarction as well as for a primary composite safety outcome of death, stroke, and serious adverse events related to ERC., Results: In both cohorts, ERC was associated with a reduced risk for the primary composite outcome in patients with a high comorbidity burden (OptumLabs: hazard ratio, 0.83 [95% CI 0.72-0.95]; P =0.006; UKB: hazard ratio, 0.77 [95% CI, 0.63-0.94]; P =0.009). In patients with a lower comorbidity burden, the difference in outcomes was not significant (OptumLabs: hazard ratio, 0.92 [95% CI, 0.54-1.57]; P =0.767; UKB: hazard ratio, 0.94 [95% CI, 0.83-1.06]; P =0.310). The comorbidity burden interacted with ERC in the UKB (interaction- P =0.027) but not in OptumLabs (interaction- P =0.720). ERC was not associated with an increased risk for the primary safety outcome., Conclusions: ERC is safe and may be more favorable in a population-based sample of patients with high a comorbidity burden (CHA 2 DS 2 -VASc score ≥4)., Competing Interests: Disclosures Dr Kirchhof is listed as inventor on 2 patents held by University of Birmingham (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016012783). Dr Kirchhof receives research support for basic, translational, and clinical research projects from European Union, British Heart Foundation, Leducq Foundation, Medical Research Council (United Kingdom), and German Center for Cardiovascular Research, from several drug and device companies active in atrial fibrillation and has received honoraria from several such companies in the past, but not in the last 3 years. Dr Rillig received consultant fees from Medtronic, KODEX-EPD, Biosense Webster and travel grants and lecture fees from Medtronic, Cardiofocus, Biosense Webster, Abbott, Boehringer Ingelheim, Philips KODEX-EPD, Ablamap, Bayer and Novartis. Dr Noseworthy is a study investigator in an ablation trial sponsored by Medtronic. Dr Noseworthy and Mayo Clinic are involved in potential equity/royalty relationship with AliveCor. Dr Noseworthy has served on an expert advisory panel for OptumLabs. Dr Noseworthy and Mayo Clinic have filed patents related to the application of AI to the ECG for diagnosis and risk stratification. Dr Ellinor has received sponsored research support from Bayer AG and IBM Research and he has served on advisory boards or consulted for Bayer AG, MyoKardia, and Novartis. The other authors report no conflicts.

Background EAST-AFNET 4 (Early Treatment of Atrial Fibrillation for Stroke Prevention Trial) demonstrated clinical benefit of early rhythm-control therapy (ERC) in patients with new-onset atrial fibrillation (AF) and concomitant cardiovascular conditions compared with current guideline-based practice. This study aimed to evaluate the generalizability of EAST-AFNET 4 in routine practice. Methods and Results Using a US administrative database, we identified 109 739 patients with newly diagnosed AF during the enrollment period of EAST-AFNET 4. Patients were classified as either receiving ERC, using AF ablation or antiarrhythmic drug therapy, within the first year after AF diagnosis (n=27 106) or not receiving ERC (control group, n=82 633). After propensity score overlap weighting, Cox proportional hazards regression was used to compare groups for the primary composite outcome of all-cause mortality, stroke, or hospitalization with the diagnoses heart failure or myocardial infarction. Most patients (79 948 of 109 739; 72.9%) met the inclusion criteria for EAST-AFNET 4. ERC was associated with a reduced risk for the primary composite outcome (hazard ratio [HR], 0.85; 95% CI, 0.75-0.97 [ P =0.02]) with largely consistent results between eligible (HR, 0.89; 95% CI, 0.76-1.04 [ P =0.14]) or ineligible (HR, 0.77; 95% CI, 0.60-0.98 [ P =0.04]) patients for EAST-AFNET 4 trial inclusion. ERC was associated with lower risk of stroke in the overall cohort and in trial-eligible patients. Conclusions This analysis replicates the clinical benefit of ERC seen in EAST-AFNET 4. The results support adoption of ERC as part of the management of recently diagnosed AF in the United States.

Type I Interferons (IFNs), including numerous IFNα subtypes and IFNβ, are key molecules during innate and adaptive immune responses against viral infections. These cytokines exert various non-redundant biological activities, although binding to the same receptor. Persistent viral infections are often characterized by increased IFN signatures implicating a potential role of type I IFNs in disease pathogenesis. Using the well-established Friend retrovirus (FV) mouse model, we compared the therapeutic efficacy of IFNα11 and IFNβ in acute and chronic retroviral infection. We observed a strong antiviral activity of both IFNs during acute FV infection, whereas only IFNα11 and not IFNβ could also control persistent FV infection. The therapeutic treatment with IFNα11 induced the expression of antiviral IFN-stimulated genes (ISG) and improved cytotoxic T cell responses. Finally, dysfunctional CD8 + T cells solely regained cytotoxicity after IFNα11 treatment. Our data provide evidence for opposing activities of type I IFNs during chronic retroviral infections. IFNβ was shown to be involved in immune dysfunction in chronic infections, whereas IFNα11 had a strong antiviral potential and reactivated exhausted T cells during persistent retroviral infection. In contrast, during acute infection, both type I IFNs were able to efficiently suppress FV replication., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Schwerdtfeger, Dickow, Schmitz, Francois, Karakoese, Malyshkina, Knuschke, Dittmer and Sutter.)

Aims: With the implementation of saline-enhanced radiofrequency (SERF) needle-tip ablation, real-time validation of lesion formation is needed for the controllable creation of transmural lesions. The aim of the study was to analyse the ability of two-dimensional intracardiac echocardiography (2D-ICE) to guide and validate SERF ablation in real-time., Methods and Results: Fifty-six SERF energy deliveries at left ventricular sites of 11 dogs guided by 2D-ICE were analysed (power: 15-50 W; time: 25-120 s; irrigation saline: 60°C with 10 mL/min flow rate). Catheter tip/tissue orientation and lesion formation could be well detected by 2D-ICE in 49 (87.5%) energy deliveries. Gross pathology analysis confirmed excellent 2D-ICE lesion localization, the ability to detect transmural lesions (70% sensitivity, 47% specificity) and positive correlation between 2D-ICE and the corresponding gross pathology measurements of 'maximal lesion depth'; (repeated measures correlation: rrm = 0.43, P = 0.012) and 'depth at maximal lesion width' (D@MW; rrm = 0.51, P = 0.003). The median angle between SERF catheter tip and endocardium was 76° [interquartile range (IQR) 58-83°]. The more perpendicular the catheter tip/tissue orientation was the deeper D@MW (rrm = 0.32, P = 0.045). Grade 3 microbubbles on 2D-ICE during ablation, indicating inadequate catheter tip/tissue contact, was associated with smaller lesion volumes than with Grade 1 microbubbles (284.8 mm3 [IQR 151.3-343.1] vs. 2114.1 mm3 [IQR 1437.0-3026.3], P < 0.001)., Conclusion: With excellent lesion localization and a 70% detection rate of transmural lesions, 2D-ICE is well suited to validate SERF ablation lesion formation in real-time. The catheter tip/tissue angle impacts the lesion formation and through perpendicular catheter positioning, deeper intramural areas of the myocardium can be reached., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Background Atrial fibrillation (AF) is common in patients with hypertrophic cardiomyopathy (HCM) and is associated with a deterioration of clinical status. Ablation of symptomatic AF is an established therapy, but in HCM, the characteristics of recurrent atrial arrhythmias and the long-term outcome are uncertain. Methods and Results Sixty-five patients with HCM (aged 64.5±9.9 years, 42 [64.6%] men) underwent AF ablation. The ablation strategy included pulmonary vein isolation in all patients and ablation of complex fractionated atrial electrograms or subsequent atrial tachycardias (AT) if appropriate. Paroxysmal, persistent AF, and a primary AT was present in 13 (20.0%), 51 (78.5%), and 1 (1.5%) patients, respectively. Twenty-five (38.4%) patients developed AT with a total number of 54 ATs. Stable AT was observed in 15 (23.1%) and unstable AT in 10 (15.3%) patients. The mechanism was characterized as a macroreentry in 37 (68.5%), as a localized reentry in 12 (22.2%), a focal mechanism in 1 (1.9%), and not classified in 4 (7.4%) ATs. After 1.9±1.2 ablation procedures and a follow-up of 48.1±32.5 months, freedom of AF/AT recurrences was demonstrated in 60.0% of patients. No recurrences occurred in 84.6% and 52.9% of patients with paroxysmal and persistent AF, respectively ( P <0.01). Antiarrhythmic drug therapy was maintained in 24 (36.9%) patients. Conclusions AF ablation in patients with HCM is effective for long-term rhythm control, and especially patients with paroxysmal AF undergoing pulmonary vein isolation have a good clinical outcome. ATs after AF ablation are frequently observed in HCM. Freedom of atrial arrhythmia is achieved by persistent AF ablation in a reasonable number of patients even though the use of antiarrhythmic drug therapy remains high.

Background: Inability to eliminate intramural arrhythmogenic substrate may lead to recurrent ventricular tachycardia after catheter ablation. The aim of the present study was to evaluate intramural and full thickness lesion formation using a heated saline-enhanced radiofrequency (SERF) needle-tip catheter, compared with a conventional ablation catheter in normal and infarcted myocardium., Methods: Twenty-two adult mongrel dogs (30-40 kg, 15 normal and 7 myocardial infarct group) were studied. Lesions were created using the SERF catheter (40 W/50 °C) or a standard contact force (CF) catheter in both groups., Results: Comparing SERF to CF ablation, the SERF catheter produced larger lesion volumes than the standard CF catheter-even with >20 g of CF-in both normal (983.1±905.8 versus 461.9±178.3 mm 3 ; P =0.023) and infarcted left ventricular myocardium (1052.3±543.0 versus 340.3±160.5 mm 3 ; P =0.001). SERF catheter lesions were more often transmural than standard CF lesions with >20 g of CF in both groups (59.1% versus 7.7%; P <0.001 and 60.0% versus 12.5%; P =0.017, respectively). Using the SERF catheter, mean depth of ablated lesions reached 90% of the left ventricular wall in both normal and infarcted myocardium., Conclusions: The SERF catheter created more transmural and larger ablative lesions in both normal and infarcted canine myocardium. SERF ablation is a promising new approach for endocardial intramural and full thickness ablation of ventricular tachycardia substrate that is not accessible with current techniques.

Background: Phrenic nerve injury (PNI) remains one of the most frequent complications during cryoballoon-based pulmonary vein isolation (CB-PVI). Since its introduction in 2013, the use of compound motor action potential (CMAP) for the prevention of PNI during CB-PVI is increasing; however, systematic outcome data are sparse., Methods: The CMAP technique was applied in conjunction with abdominal palpation during pacing manoeuvres (10 mV, 2 ms) from the superior vena cava for 388 consecutive patients undergoing CB-PVI between January 2015 and May 2017 at our tertiary arrhythmia centre. Cryoablation was immediately terminated when CMAP amplitude was reduced by 30%., Results: Reductions in CMAP amplitude were observed in 16 (4%) of 388 patients during isolation of the right veins. Of these, 11 (69%) patients did not manifest a reduction in diaphragmatic excursions. The drop in CMAP amplitude was observed in 10 (63%) patients during ablation of the right superior pulmonary veins (PVs) and in 7 (44%) patients during ablation of the right inferior PVs. Postprocedural persistent PNI was observed in three of four patients for a duration of 6 months, with one of these patients remaining symptomatic at the 24-month follow-up. One of the four patients was lost to long-term follow-up., Conclusions: All PNIs occurred during right-sided CB-PVI and were preceded by a reduction in CMAP amplitude. Thus, the standardized use of CMAP surveillance during CB-PVI is easily applicable, reliable and compared with other studies, results in a lower number of PNIs., Competing Interests: The authors have declared that no competing interests exist.

Purpose of Review: Atrial fibrillation (AF), the most common sustained arrhythmia, is associated with high rates of morbidity and mortality. Maintenance of stable sinus rhythm (SR) is the intended treatment target in symptomatic patients, and catheter ablation aimed at isolating the pulmonary veins provides the most effective treatment option, supported by encouraging clinical outcome data. A variety of energy sources and devices have been developed and evaluated. In this review, we summarize the current state of the art of catheter ablation of AF and describe future perspectives., Recent Findings: Catheter ablation is a well-established treatment option for patients with symptomatic AF and is more successful at maintaining SR than antiarrhythmic drugs. Antral pulmonary vein isolation (PVI) as a stand-alone ablation strategy results in beneficial clinical outcomes and is therefore recommended as first-line strategy for both paroxysmal and persistent AF. While radiofrequency-based PVI in conjunction with a three-dimensional mapping system was for many years considered to be the "gold standard", the cryoballoon has emerged as the most commonly used alternative AF ablation tool, especially in patients with paroxysmal AF. Patients with persistent or long-standing persistent AF and with arrhythmia recurrence after previous PVI may benefit from additional ablation strategies, such as substrate modification of various forms or left atrial appendage isolation. New technologies and techniques, such as identification of the AF sources and magnetic resonance imaging-guided substrate modification, are on the way to further improve the success rates of catheter ablation for selected patients and might help to further reduce arrhythmia recurrence., Conclusions: Pulmonary vein isolation is the treatment of choice for symptomatic patients with paroxysmal and persistent drug-refractory AF. The reconnection of previously isolated pulmonary veins remains the major cause of AF recurrence. Novel ablation tools, such as balloon technologies or alternative energy sources, might help to overcome this limitation. Patients with non-paroxysmal AF and with AF recurrence might benefit from alternative ablation strategies. However, further studies are warranted to further improve our knowledge of the underlying mechanisms of AF and to obtain long-term clinical outcomes on new ablation techniques.

Clinical administration of Interferon α (IFNα) resulted in limited therapeutic success against some viral infections. Immune modulation of CD8 + T cell responses during IFNα therapy is believed to play a pivotal role in promoting viral clearance. However, these clinical studies primarily focused on IFNα subtype 2. To date, the immunomodulatory roles of the remaining 10-13 IFNα subtypes remains poorly understood, thereby precluding assessments of their potential for more effective treatments. Here, we report that virus-specific CD8 + T cell responses were influenced to various extents by individual IFNα subtypes. IFNα4, 6, and 9 had the strongest effects on CD8 + T cells, including antiproliferative effects, improved cytokine production and cytotoxicity. Interestingly, augmented cytokine responses were dependent on IFNα subtype stimulation of dendritic cells (DCs), while antiproliferative effects and cytotoxicity were mediated by IFNAR signaling in either CD8 + T cells or DCs. Thus, precise modulation of virus-specific CD8 + T cell responses may be feasible for specific antiviral immunotherapies through careful selection and administration of individual IFNα subtypes., (Copyright © 2019 Dickow, Francois, Kaiserling, Malyshkina, Drexler, Westendorf, Lang, Santiago, Dittmer and Sutter.)

T cell dysfunction and immunosuppression are characteristic for chronic viral infections and contribute to viral persistence. Overcoming these burdens is the goal of new therapeutic strategies to cure chronic infectious diseases. We recently described that therapeutic vaccination of chronic retrovirus infected mice with a calcium phosphate (CaP) nanoparticle (NP)-based vaccine carrier, functionalized with CpG and viral peptides is able to efficiently reactivate the CD8 + T cell response and improve the eradication of virus infected cells. However, the mechanisms underlying this effect were largely unclear. While type I interferons (IFNs I) are considered to drive T cell exhaustion by persistent immune activation during chronic viral infection, we here describe an indispensable role of IFN I induced by therapeutic vaccination to efficiently reinforce cytotoxic CD8 + T cells (CTL) and improve control of chronic retroviral infection. The induction of IFN I is CpG dependent and leads to significant IFN signaling indicated by upregulation of IFN stimulated genes. By vaccinating chronically retrovirus-infected mice lacking the IFN I receptor (IFNAR -/- ) or by blocking IFN I signaling in vivo during therapeutic vaccination, we demonstrate that IFN I signaling is necessary to drive full reactivation of CTLs. Surprisingly, we also identified an impaired suppressive capability of regulatory T cells in the presence of IFNα, which implicates an important role for vaccine-induced IFNα in the regulation of the T cell response during chronic retroviral infection. Our data suggest that inducing IFN I signaling in conjunction with the presentation of viral antigens can reactivate immune functions and reduce viral loads in chronic infections. Therefore, we propose CaP NPs as potential therapeutic tool to treat chronic infections.

Background: Current retrospective evidence suggests similar clinical and superior hemodynamic outcomes of the Sorin Freedom Solo stentless aortic valve (SFS) (LivaNova PLC, London, UK) compared to the Carpentier Edwards Perimount stented aortic valve (CEP) (Edwards Lifesciences Inc., Irvine, California, USA). To date, no reports exist describing case-matched long-term outcomes and analysis for treatment of native valve endocarditis (NVE)., Methods: From 2004 through 2014, 77 consecutive patients (study group, 59.7% male, 68.9 ± 12.5 years, logEuroSCORE II 7.6 ± 12.3%) received surgical aortic valve replacement (SAVR) with the SFS. A control group of patients after SAVR with the CEP was retrieved from our database and matched to the study group regarding 15 parameters including preoperative endocarditis. Acute perioperative outcomes and follow-up data (mean follow-up time 48.7±29.8 months, 95% complete) were retrospectively analyzed., Results: No differences in early mortality occurred during 30-day follow up (3/77; 3.9% vs. 4/77; 5.2%; p = 0.699). Echocardiographic findings revealed lower postprocedural transvalvular pressure gradients (max. 17.0 ± 8.2 vs. 24.5 ± 9.2 mmHg, p< 0.001/ mean pressure of 8.4 ± 4.1 vs. 13.1 ± 5.9 mmHg, p< 0.001) in the SFS group. Structural valve degeneration (SVD) (5.2% vs. 0%; p = 0.04) and valve explantation due to SVD or prosthetic valve endocarditis (PVE) (9.1% vs. 1.3%; p = 0.04) was more frequent in the SFS group. All-cause mortality during follow-up was 20.8% vs. 14.3% (p = 0.397). When patients were divided into subgroups of NVE and respective utilized bioprosthesis, the SFS presented impaired outcomes regarding mortality in NVE cases (p = 0.031)., Conclusions: The hemodynamic superiority of the SFS was confirmed in this comparison. However, clinical outcomes in terms of SVD and PVE rates, as well as survival after NVE, were inferior in this study. Therefore, we are reluctant to recommend utilization of the SFS for treatment of NVE.

Lipoprotein lipase (LPL) activity and free fatty acid levels were studied in freshly milked, uncooled milk from individual Danish Holstein or Jersey cows, or after storage for up to 24h at either a cooling temperature (4°C) or at the milking temperature (31°C). Upon cooling for up to 24h, LPL activity increased in the cream phase, whereas the activity in the skim milk was steady, as observed for Jersey cows, or increased, as seen for the Holsteins. Storage at 31°C decreased the LPL activity in both the cream phase and the skim milk phase. The increase in free fatty acid levels was found to depend on LPL activity, incubation temperature, substrate availability, and incubation time. Furthermore, the migration of milk proteins between the skim milk phase and the cream phase upon cooling of milk from Jersey cows or from Danish Holstein cows was studied using proteomic methods involving 2-dimensional gel electrophoresis and mass spectrometry. Proteins associated with the milk fat globules were isolated from all milk fractions and analyzed. Major changes in the distributions of proteins between the skim milk phase and the cream phase were observed after cooling at 4°C for 4h, where a total of 29 proteins between the 2 breeds was found to change their association with the milk fat globule membrane (MFGM) significantly. Among these, the MFGM proteins adipophilin, fatty acid-binding protein, and lactadherin, as well as the non-MFGM proteins β-casein, lactoferrin, and heat shock protein-71, were identified. Adipophilin, lactadherin, and lactoferrin were quantitatively more associated with the MFGM upon cold storage at 4°C, whereas β-casein, fatty acid-binding protein, and heat shock protein-71 were found to be less associated with the MFGM upon cold storage., (Copyright © 2011 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)