High-resolution HLA sequencing and hypocretin receptor 2 autoantibodies in narcolepsy type 1 and type 2.

Narcolepsy is a sleep disorder caused by an apparent degeneration of orexin/hypocretin neurons in the lateral hypothalamic area and a subsequent decrease in orexin/hypocretin levels in the cerebrospinal fluid. Narcolepsy is classified into type 1 (NT1) and type 2 (NT2). While genetic associations in the human leukocyte antigen (HLA) region and candidate autoantibodies have been investigated in NT1 to imply an autoimmune origin, less is known about the pathogenesis in NT2. Twenty-six NT1 and 15 NT2 patients were included, together with control groups of 24 idiopathic hypersomnia (IH) patients and 778 general population participants. High-resolution sequencing was used to determine the alleles, the extended haplotypes, and the genotypes of HLA-DRB3, -DRB4, -DRB5, -DRB1, -DQA1, -DQB1, -DPA1, and -DPB1. Radiobinding assay was used to determine autoantibodies against hypocretin receptor 2 (anti-HCRTR2 autoantibodies). NT1 was associated with HLA-DRB5*01:01:01, -DRB1*15:01:01, -DQA1*01:02:01, -DQB1*06:02:01, -DRB5*01:01:01, -DRB1*15:01:01, -DQA1*01:02:01, -DQB1*06:02:01 (odds ratio [OR]: 9.15; p = 8.31 × 10-4) and HLA-DRB5*01:01:01, -DRB1*15:01:01, -DQA1*01:02:01, -DQB1*06:02:01, -DRB4*01:03:01, -DRB1*04:01:01, -DQA1*03:02//03:03:01, -DQB1*03:01:01 (OR: 23.61; p = 1.58 × 10-4) genotypes. Lower orexin/hypocretin levels were reported in the NT2 subgroup (n = 5) that was associated with the extended HLA-DQB1*06:02:01 haplotype (p = .001). Anti-HCRTR2 autoantibody levels were not different between study groups (p = .8524). We confirmed the previous association of NT1 with HLA-DQB1*06:02:01 extended genotypes. A subgroup of NT2 patients with intermediate orexin/hypocretin levels and association with HLA-DQB1*06:02:01 was identified, indicating a possible overlap between the two distinct narcolepsy subtypes, NT1 and NT2. Low anti-HCRTR2 autoantibody levels suggest that these receptors might not function as autoimmune targets in either NT1 or NT2.

Home capillary sampling and screening for type 1 diabetes, celiac disease, and autoimmune thyroid disease in a Swedish general pediatric population: the TRIAD study.

Objective: To screen a general pediatric population for type 1 diabetes (T1D), celiac disease (CD), and autoimmune thyroid disease (AITD) after home capillary sampling. Methods: Swedish schoolchildren between 6-9 years and 13-16 years of age were invited to screening by taking a capillary sample at home. Samples were returned by mail and assessed for autoantibodies associated with T1D, CD, and AITD. Persistently autoantibody-positive children were referred for clinical follow-up. Results: Of 19,593 invited, 3,527 (18.0%) consented to participate and 2,315/3,527 (65.6%) returned a blood sample of sufficient volume. Hemolysis occurred in 830/2,301 (36.1%) samples. After exclusion of 42 children with previously known T1D, CD, or AITD, and two autoantibody-positive children who declined a confirmatory sample, 2,271/19,593 (11.6%) were included. 211/2,271 (9.3%) had persistent autoantibodies: 60/2,271 (2.6%) with T1D autoantibodies, 61/2,271 (2.7%) with CD autoantibodies, and 99/2,271 (4.4%) with AITD autoantibodies; 9/2,271 (0.4%) were autoantibody positive for ≥1 disease. After clinical follow-up, 3/2,271 (0.1%) were diagnosed with T1D, 26/2,271 (1.1%) with CD, and 6/2,271 (0.3%) with AITD. Children with a first-degree relative (FDR) with T1D, CD, and/or AITD, had higher occurrence of autoantibodies compared to children without an FDR (63/344, 18.3%, vs. 148/1,810, 8.2%) (p < 0.0001, OR 2.52, 95% CI 1.83-3.47), and higher occurrence of screening-detected diagnosis (14/344, 4.1%, vs. 21/1,810, 1.2%) (p < 0.0001, OR 3.61, 95% CI 1.82-7.18). Half of these children screened positive for another disease than the FDR. Conclusion: Screening for T1D, CD, and AITD by home capillary sampling in a Swedish general pediatric population detected autoimmunity in 9.3% and undiagnosed disease in 1.5%.

Childhood screening for type 1 diabetes comparing automated multiplex Antibody Detection by Agglutination-PCR (ADAP) with single plex islet autoantibody radiobinding assays.

BACKGROUND: Two or more autoantibodies against either insulin (IAA), glutamic acid decarboxylase (GADA), islet antigen-2 (IA-2A) or zinc transporter 8 (ZnT8A) denote stage 1 (normoglycemia) or stage 2 (dysglycemia) type 1 diabetes prior to stage 3 type 1 diabetes. Automated multiplex Antibody Detection by Agglutination-PCR (ADAP) assays in two laboratories were compared to single plex radiobinding assays (RBA) to define threshold levels for diagnostic specificity and sensitivity. METHODS: IAA, GADA, IA-2A and ZnT8A were analysed in 1504 (54% females) population based controls (PBC), 456 (55% females) doctor's office controls (DOC) and 535 (41% females) blood donor controls (BDC) as well as in 2300 (48% females) patients newly diagnosed (1-10 years of age) with stage 3 type 1 diabetes. The thresholds for autoantibody positivity were computed in 100 10-fold cross-validations to separate patients from controls either by maximizing the χ2-statistics (chisq) or using the 98th percentile of specificity (Spec98). Mean and 95% CI for threshold, sensitivity and specificity are presented. FINDINGS: The ADAP ROC curves of the four autoantibodies showed comparable AUC in the two ADAP laboratories and were higher than RBA. Detection of two or more autoantibodies using chisq showed 0.97 (0.95, 0.99) sensitivity and 0.94 (0.91, 0.97) specificity in ADAP compared to 0.90 (0.88, 0.95) sensitivity and 0.97 (0.94, 0.98) specificity in RBA. Using Spec98, ADAP showed 0.92 (0.89, 0.95) sensitivity and 0.99 (0.98, 1.00) specificity compared to 0.89 (0.77, 0.86) sensitivity and 1.00 (0.99, 1.00) specificity in the RBA. The diagnostic sensitivity and specificity were higher in PBC compared to DOC and BDC. INTERPRETATION: ADAP was comparable in two laboratories, both comparable to or better than RBA, to define threshold levels for two or more autoantibodies to stage type 1 diabetes. FUNDING: Supported by The Leona M. and Harry B. Helmsley Charitable Trust (grant number 2009-04078), the Swedish Foundation for Strategic Research (Dnr IRC15-0067) and the Swedish Research Council, Strategic Research Area (Dnr 2009-1039). AL was supported by the DiaUnion collaborative study, co-financed by EU Interreg ÖKS, Capital Region of Denmark, Region Skåne and the Novo Nordisk Foundation.

Multi-harmonic near-infrared-ultraviolet dual-comb spectrometer.

Dual-comb spectroscopy in the ultraviolet (UV) and visible would enable broad bandwidth electronic spectroscopy with unprecedented frequency resolution. However, there are significant challenges in generation, detection, and processing of dual-comb data that have restricted its progress in this spectral region. In this work, we leverage robust 1550 nm few-cycle pulses to generate frequency combs in the UV-visible. We combine these combs with a wavelength multiplexed dual-comb spectrometer and simultaneously retrieve 100 MHz comb-mode-resolved spectra over three distinct harmonics at 386, 500, and 760 nm. The experiments highlight the path to continuous dual-comb coverage spanning 200-750 nm, offering extensive access to electronic transitions in atoms, molecules, and solids.

The degree of permanent pacemaker dependence and clinical outcomes following transcatheter aortic valve implantation: implications for procedural technique.

Aims: Conduction abnormalities necessitating permanent pacemaker (PPM) implantation remain the most frequent complication post-transcatheter aortic valve implantation (TAVI), yet reliance on PPM function varies. We evaluated the association of right-ventricular (RV)-stimulation rate post-TAVI with 1-year major adverse cardiovascular events (MACE) (all-cause mortality and heart failure hospitalization). Methods and results: This retrospective cohort study of patients undergoing TAVI in two high-volume centers included patients with existing PPM pre-TAVI or new PPM post-TAVI. There was a bimodal distribution of RV-stimulation rates stratifying patients into two groups of either low [≤10%: 1.0 (0.0, 3.6)] or high [>10%: 96.0 (54.0, 99.9)] RV-stimulation rate post-TAVI. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated comparing MACE in patients with high vs. low RV-stimulation rates post-TAVI. Of 4659 patients, 408 patients (8.6%) had an existing PPM pre-TAVI and 361 patients (7.7%) underwent PPM implantation post-TAVI. Mean age was 82.3 ± 8.1 years, 39% were women. A high RV-stimulation rate (>10%) development post-TAVI is associated with a two-fold increased risk for MACE [1.97 (1.20, 3.25), P = 0.008]. Valve implantation depth was an independent predictor of high RV-stimulation rate [odds ratio (95% CI): 1.58 (1.21, 2.06), P=<0.001] and itself associated with MACE [1.27 (1.00, 1.59), P = 0.047]. Conclusion: Greater RV-stimulation rates post-TAVI correlate with increased 1-year MACE in patients with new PPM post-TAVI or in those with existing PPM but low RV-stimulation rates pre-TAVI. A shallower valve implantation depth reduces the risk of greater RV-stimulation rates post-TAVI, correlating with improved patient outcomes. These data highlight the importance of a meticulous implant technique even in TAVI recipients with pre-existing PPMs.

Prevalence of Thyroid Peroxidase and Thyroglobulin Autoantibodies in the Swedish Population.

Autoimmune thyroid disease (AITD) may be detected prior to clinical symptoms through the presence of autoantibodies against thyroid peroxidase (TPOab), thyroglobulin (TGab), or both.The present study aimed to develop a novel radiobinding assay (RBA) for TPOab and to determine the prevalence of TPOab and TGab in the Swedish population.Patient samples from 27 newly diagnosed Graves' disease patients in longitudinal follow-up and 124 AITD autoantibody-positive children in prospective follow-up for increased risk of type 1 diabetes were included to validate the novel RBA for TPO. The results of RBA were compared with those obtained by commercial radioimmunoassay (RIA) and electrochemiluminescence (ECL). Furthermore, 476 serum samples from adult blood donors and 297 from 13-year-old school children were analyzed for the presence of TPOab and TGab.Receiver operating characteristics analysis for the novel TPOab resulted in an area under curve (AUC) value of 0.82 (p<0.0001), a sensitivity of 77.8%, and a specificity of 91.9% in adult blood donors, and an AUC value of 0.70 (p<0.0001), a sensitivity of 53.2% and a specificity of 95.3% in the 13-year-old school children, respectively. TPOab levels in RBA correlated with both ECL (r=0.8950, p<0.0001) and RIA (r=0.9295, p<0.0001). The prevalence of TPOab and TGab was 6.3% and 7.6% in adult blood donors and 2.9 and 3.7% in 13-year-old school children.In conclusion, a novel RBA for the determination of TPOab was developed and validated with current methodologies. This study also reports an increasing prevalence of thyroid autoantibodies from adolescence to adulthood.

Virtual reality-assisted distraction during transcatheter aortic valve implantation under local anaesthesia: A randomised study.

BACKGROUND: A minimal approach, using local anaesthesia alone, has been advocated to promote faster transcatheter aortic valve replacement (TAVR) procedures in intermediate-risk patients. Pre- and periprocedural anxiety and pain remain a concern. Virtual reality (VR) is a form of non-pharmacological distraction that can potentially modulate pain and anxiety. This randomised study explored whether VR reduces pain and anxiety during TAVR without sedation and compared the effects of VR with those of standard care. METHODS AND RESULTS: Between June 2022 and March 2023, 207 patients underwent transfemoral TAVR (TF-TAVR). Of these, 117 (56.5%) patients were willing to participate in the study and met the educational background and mental status criteria for assessment. Fifty-nine patients underwent TF-TAVR with VR glasses (VR group). Fifty-eight patients underwent standard TF-TAVR without VR (control group; CG). Post-interventional anxiety scores (STAI-S) (31.5 ± 13.4 vs. 38.5 ± 19.2, p = 0.02) and the perceived duration of the procedure (60.1 ± 32.3 vs. 73.0 ± 32.4, p = 0.04) were lower in the VR than in the CG. Procedure time, pain, and anxiety scores (visual analogue scale) were similar between the groups. The complication rate was low and not associated with VR. Post-interventional delirium occurred in nine patients, and was similar between the groups (VR: 4 [6.8%] vs. CG: 5 [8.6%], p = 0.71). No periprocedural strokes were observed. CONCLUSION: VR for TAVR is feasible and safe and expands the non-drug spectrum of therapy for anxiety and pain in patients undergoing TAVR with a minimalistic approach.

Percutaneous left atrial appendage closure for stroke prevention in patients with chronic renal disease.

Introduction: Atrial fibrillation (AF) is the most common cardiac arrhythmia in the general population. Atrial fibrillation is associated with an increased risk of thromboembolic events, particularly stroke. Chronic kidney disease (CKD) is associated with a higher prevalence of AF and is an independent risk factor of increased mortality and stroke in AF patients. Left atrial appendage closure (LAAC) for stroke prevention plays an important role in the treatment of patients with AF and increased bleeding risk. The impact of CKD on outcomes after LAAC has not been deeply investigated. We assessed whether percutaneous LAAC is safe and feasible in CKD patients. Material and methods: Ninety-seven patients (mean age: 73.9 ±8.5 years) with AF and contraindications for oral anticoagulation (OAC) or complications under OAC underwent LAAC with the Amplatzer Cardiac Plug and the Amplatzer Amulet Occluder in an open-label observational single-center study. We classified patients as having normal to mild (KDOQI stage I-II) or moderate to severe (KDOQI stage III-V) CKD. Results: Patients with moderate to severe CKD (n = 49) had increased CHA2DS2-VASc and HAS-BLED scores and were at higher thromboembolic and bleeding risk (CHA2DS2-VASc: 4.08 ±0.79, HAS-BLED: 4.76 ±0.69) than patients with mild to moderate CKD (n = 48, CHA2DS2-VASc: 3.69 ±1.1, HAS-BLED: 4.06 ±0.66; p < 0.001 for both). In both groups, procedural and occlusion success was similar (97.9% vs. 95.9%; p = 0.479). Follow-up of 6 months and from 12 to 36 months revealed effective stroke prevention and no bleeding complication in both groups. Conclusions: In spite of a higher thromboembolic and bleeding risk in patients with severe CKD, LAAC is a safe and feasible option for stroke prevention.

Broadband 1-GHz mid-infrared frequency comb.

Mid-infrared (MIR) spectrometers are invaluable tools for molecular fingerprinting and hyper-spectral imaging. Among the available spectroscopic approaches, GHz MIR dual-comb absorption spectrometers have the potential to simultaneously combine the high-speed, high spectral resolution, and broad optical bandwidth needed to accurately study complex, transient events in chemistry, combustion, and microscopy. However, such a spectrometer has not yet been demonstrated due to the lack of GHz MIR frequency combs with broad and full spectral coverage. Here, we introduce the first broadband MIR frequency comb laser platform at 1 GHz repetition rate that achieves spectral coverage from 3 to 13 µm. This frequency comb is based on a commercially available 1.56 µm mode-locked laser, robust all-fiber Er amplifiers and intra-pulse difference frequency generation (IP-DFG) of few-cycle pulses in χ(2) nonlinear crystals. When used in a dual comb spectroscopy (DCS) configuration, this source will simultaneously enable measurements with µs time resolution, 1 GHz (0.03 cm-1) spectral point spacing and a full bandwidth of >5 THz (>166 cm-1) anywhere within the MIR atmospheric windows. This represents a unique spectroscopic resource for characterizing fast and non-repetitive events that are currently inaccessible with other sources.

High-resolution HLA class II sequencing of Swedish multiple sclerosis patients.

Multiple sclerosis (MS) is a chronic neurological disease believed to be caused by autoimmune pathogenesis. The aetiology is likely explained by a complex interplay between inherited and environmental factors. Genetic investigations into MS have been conducted for over 50 years, yielding >100 associations to date. Globally, the strongest linkage is with the human leukocyte antigen (HLA) HLA-DRB5*01:01:01-DRB1*15:01:01-DQA1*01:02:01-DQB1*06:02:01 haplotype. Here, high-resolution sequencing of HLA was used to determine the alleles of DRB3, DRB4, DRB5, DRB1, DQA1, DQB1, DPA1 and DPB1 as well as their extended haplotypes and genotypes in 100 Swedish MS patients. Results were compared to 636 population controls. The heterogeneity in HLA associations with MS was demonstrated; among 100 patients, 69 extended HLA-DR-DQ genotypes were found. Three extended HLA-DR-DQ genotypes were found to be correlated to MS; HLA-DRB5*01:01:01-DRB1*15:01:01-DQA1*01:02:01-DQB1*06:02:01 haplotype together with (A) HLA-DRB4*01:01:01//DRB4*01:01:01:01-DRB1*07:01:01-DQA1*02:01//02:01:01-DQB1*02:02:01, (B) HLA-DRBX*null-DRB1*08:01:01-DQA1*04:01:01-DQB1*04:02:01, and (C) HLA-DRB3*01:01:02-DRB1*03:01:01-DQA1*05:01:01-DQB1*02:01:01. At the allelic level, HLA-DRB3*01:01:02 was considered protective against MS. However, when combined with HLA-DRB3*01:01:02-DRB1*03:01:01-DQA1*05:01:01-DQB1*02:01:01, this extended haplotype was considered a predisposing risk factor. This highlights the limitations as included with investigations of single alleles relative to those of extended haplotypes/genotypes. In conclusion, with 69 genotypes presented among 100 patients, high-resolution sequencing was conducted to underscore the wide polymorphisms present among MS patients. Additional studies in larger cohorts will be of importance to define MS among the patient group not associated with HLA-DRB5*01:01:01-DRB1*15:01:01-DQA1*01:02:01-DQB1*06:02:01.

Genetic Variants Associated with Neuropeptide Y Autoantibody Levels in Newly Diagnosed Individuals with Type 1 Diabetes.

(1) Autoantibodies to the leucine variant of neuropeptide Y (NPY-LA) have been found in individuals with type 1 diabetes (T1D). We investigated the association between the levels of NPY-LA and single nucleotide polymorphisms (SNP) to better understand the genetic regulatory mechanisms of autoimmunity in T1D and the functional impacts of increased NPY-LA levels. (2) NPY-LA measurements from serum and SNP genotyping were done on 560 newly diagnosed individuals with T1D. SNP imputation with the 1000 Genomes reference panel was followed by an association analysis between the SNPs and measured NPY-LA levels. Additionally, functional enrichment and pathway analyses were done. (3) Three loci (DGKH, DCAF5, and LINC02261) were associated with NPY-LA levels (p-value < 1.5 × 10−6), which indicates an association with neurologic and vascular disorders. SNPs associated with variations in expression levels were found in six genes (including DCAF5). The pathway analysis showed that NPY-LA was associated with changes in gene transcription, protein modification, immunological functions, and the MAPK pathway. (4) Conclusively, we found NPY-LA to be significantly associated with three loci (DGKH, DCAF5, and LINC02261), and based on our findings we hypothesize that the presence of NPY-LA is associated with the regulation of the immune system and possibly neurologic and vascular disorders.

Embolic Protection with the TriGuard 3 System in Nonagenarian Patients Undergoing Transcatheter Aortic Valve Replacement for Severe Aortic Stenosis.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) improves the survival and life quality of nonagenarian patients with aortic stenosis. Stroke remains one of the most worrisome complications following TAVR. Cerebral embolic protection devices (CEPDs) may reduce neurological complications after TAVR. This study evaluated the safety and efficacy of CEPDs during TAVR in nonagenarian patients. METHODS: Between January 2018 and October 2021, 869 patients underwent transfemoral TAVR (TF-TAVR) at our center. Of these, 51 (5.9%) patients were older than ninety years. In 33 consecutive nonagenarian patients, TF-TAVR was implanted without CEPDs using balloon-expandable valves (BEVs) and self-expandable valves (SEVs). Eighteen consecutive nonagenarians underwent TF-TAVR using a CEPD (CP group). Follow up period was in-hospital or 30 days after the procedure, respectively. RESULTS: Minor access site complications occurred in two patients (3.9%) and were not CEPD-associated. Postinterventional delirium occurred in nine patients (17.6%). Periprocedural minor non-disabling stroke and delirium occurred in ten patients (19.6%). Periprocedural major fatal stroke occurred in two patients in the BEV group (3.9%). Two patients in the BEV group died due to postinterventional pneumonia with sepsis. The mortality rate was 7.8%. The results did not differ between the groups. CONCLUSIONS: Age alone is no longer a contraindication for TAVR. CEPD using the Triguard 3 system in nonagenarian TAVR patients was feasible and safe and did not increase access site complications.

Multiplex agglutination-PCR (ADAP) autoantibody assays compared to radiobinding autoantibodies in type 1 diabetes and celiac disease.

Multiplex Antibody-Detection by Agglutination-PCR (ADAP) assay was compared to singleplex standard radiobinding assays (RBA) to detect autoantibodies against insulin (IAA), GAD65 (GADA), islet antigen-2 (IA-2A), ZnT8 (ZnT8A) and tissue transglutaminase (TGA). Serum samples from 273 (114F/158M), 15-73 years of age healthy controls and 227 (109F/118M) newly diagnosed type 1 diabetes children, 1-11 years of age, were analyzed in both assay systems.The original WHO standard 97/550 and in-house reference standards for RBA were compared to ADAP. The ADAP and RBA generated parallel reference standards in all assays except TGA. Lower detection limits were observed in the ADAP assay for GADA,IAA and ZnT8A, markedly for TGA, but not for IA-2A. The Receiver Operating Characteristics (ROC) curve AUC analyses for pairwise comparison of ADAP with RBA showed no difference for GADA (n.s.), ADAP greater AUC for IAA (p = 0.005), RBA greater AUC for IA-2A (p = 0.0004) and ZnT8A (p < 0.0001) while ADAP TGA had a greater AUC compared to both RBA TGA-IgG (p < 0.0001) and TGA-IgA (p < 0.0001). These data suggest that the ADAP and RBA assays are comparable with equal performance for GADA, better ADAP performance for IAA while the RBA showed better performance in both IA-2A and ZnT8A associated with greater heterogeneity in autoantibody levels. The simultaneous analysis of 5 different autoantibodies by ADAP in sample volume reduced to only 4 µL and at an increased lower detection limit in all assays except IA-2A makes the ADAP automated autoantibody assay a distinct advantage for high throughput screening.

Alternative access in high-risk patients in the era of transfemoral aortic valve replacement.

BACKGROUND: We aimed to evaluate the outcomes of transapical and transaortic transcatheter aortic valve replacement (TAVR) in high-risk patients who were not suitable for transfemoral access and had a logistic EuroSCORE-I ≥ 25% and Society of Thoracic Surgeons (STS) score >6%. 'STS/ACC TAVR In-Hospital Mortality Risk App' was evaluated. MATERIAL AND METHODS: Between January 2016 and May 2020, 126 patients at very high risk for aortic valve replacement underwent transapical (n = 121) or transaortic (n = 5) transcatheter aortic valve replacement. TAVR was performed using SAPIEN 3™ or ACURATE TA™ prosthesis. RESULTS: The logistic EuroSCORE-I was 40.6 ± 14.0%, the STS-score 7.9 ± 4.6%, and STS/ACC-score 8.4 ± 3.4%. Valve implantation was successful in all patients. Operative, in-hospital and 30-days mortality, were 0, 7.9, and 13.5%, respectively. Survival was 72% at one year and 48% at four years. Expected/observed in-hospital mortality was 1.0 for the STS-score and 1.06 for the STS/ACC-score. Renal failure, low ejection fraction, and postoperative acute kidney injury, hemorrhage, and vascular complications were identified as independent predictors for 30-day mortality. CONCLUSIONS: Transapical and transaortic TAVR in high-risk patients unsuitable for transfemoral access is still a reasonable alternative in these patients. STS and STS/ACC-score appear to be highly accurate in predicting in-hospital mortality in high-risk patients undergoing TAVR.

Early Pacemaker Implantation after Transcatheter Aortic Valve Replacement: Impact of PlasmaBlade™ for Prevention of Device-Associated Bleeding Complications.

Background and Objectives: Permanent pacemaker implantation (PPI) is frequently required following transcatheter aortic valve replacement (TAVR). Dual antiplatelet therapy (DAPT) or oral anticoagulation therapy (OAK) is often necessary in these patients since they are at higher risk of thromboembolic events due to TAVR implantation, high incidence of coronary artery diseases (CAD) with the necessity of coronary intervention, and high rate of atrial fibrillation with the need of stroke prevention. We sought to evaluate the safety, efficiency, and clinical outcomes of early PPI following TAVR using the PlasmaBlade™ (Medtronic Inc., Minneapolis, MN, USA) pulsed electron avalanche knife (PEAK) for bleeding control in patients under DAPT or OAK. Materials and Methods: This retrospective single-center study included patients who underwent PPI after transfemoral TAVR (TF) at our center between December 2015 and May 2020. All PPI were performed using the PlasmaBlade™ Device. Results: The overall PPI rate was 14.1% (83 of 587 patients; 82.5 ± 4.6 years; 45.8% male). The PPI procedures were used to treat high-grade atrioventricular block (81.9%), severe sinus node dysfunction (13.3%), and alternating bundle branch block (4.8%). At the time of the procedure, 35 (42.2%) patients received DAPT, and 48 (57.8%) patients received OAK (50% with vitamin K antagonist (VKA) and 50% with novel oral anticoagulants (NOAK)). One device-pocket hematoma treated conservatively occurred in a patient (1.2%) receiving NOAK. Two re-operations were necessary in patients due to immediate lead dislocation (2.4%). Conclusions: The results of this study illustrate that the use of PlasmaBlade™ for PPI in patients after a TAVR who require antithrombotic treatment is feasible and might result into lower rates of severe bleeding complications compared to rates reported in the literature. Use of the PlasmaBlade device may be considered in this specific group of patients because of their high risk of bleeding.

Transapical transcatheter mitral valve implantation in patients with degenerated mitral bioprostheses or failed ring annuloplasty.

BACKGROUND: We sought to evaluate the outcomes of transapical transcatheter mitral valve replacement in patients with degenerated mitral bioprostheses or failed mitral ring annuloplasty and high surgical risk for redo mitral valve procedure. METHODS: Between August 2012 and December 2020, 41 consecutive high-risk patients underwent transcatheter mitral 'valve-in-valve' (TM-ViV, n=25) or 'valve-in-ring' (TM-ViR, n=16) implantation at our institution. All procedures were performed in a hybrid operating theater using the SAPIEN XT/3™ or the DIRECT FLOW MEDICAL™ prostheses. Data was collected prospectively according to MVARC criteria. RESULTS: The logistic EuroSCORE-I was 42.3%±20.5% (mean ± SD), the Society of Thoracic Surgeons (STS) score was 11.9%±10.8%, and the STS/ACC-score was 7.6%±4.2%. Transcatheter mitral valve implantations were successful in all patients (100%). Early echocardiographic examinations showed no obstruction of the left ventricular outflow tract (LVOT), no paravalvular leakage, and only trace transvalvular leakage in eight patients. There was no operative mortality; thirty-day mortality was 9.8%. Survival was 72% at one year and 63% at three years. At two-year follow-up, transvalvular mean pressure gradients were 4.6±1.4 mmHg. CONCLUSIONS: Transapical transcatheter mitral valve-in-valve or valve-in-ring implantation represents a true minimally invasive alternative to surgical redo procedures, especially in high-risk patients with failed bioprosthetic mitral valves or annuloplasty and favorable anatomy.

Mitral surgical redo versus transapical transcatheter mitral valve implantation.

BACKGROUND: Transcatheter methods have been rapidly evolving to provide an alternative less invasive therapeutic option, mainly because redo patients often present with multiple comorbidities and high operative risk. We sought to evaluate and compare our experience with transapical transcatheter mitral valve replacement (TA-TMVR) to conventional redo mitral valve replacement in patients presenting with degenerated biological mitral valve prostheses or failed valve annuloplasty. METHODS AND MATERIAL: Between March 2012 and November 2020, 74 consecutive high-risk patients underwent surgical redo mitral valve replacement (n = 33) or TA-TMVR (n = 41) at our institution. All patients presented with a history of a surgical mitral valve procedure. All transcatheter procedures were performed using the SAPIEN XT/3™ prostheses. Data collection was prospectively according to MVARC criteria. RESULTS: The mean logistic EuroSCORE-II of the whole cohort was 19.9±16.7%, and the median STS-score was 11.1±12.5%. The mean age in the SMVR group was 63.7±12.8 years and in the TMVR group 73.6±9.7 years. Patients undergoing TA-TMVR presented with significantly higher risk scores. Echocardiography at follow up showed no obstruction of the left ventricular outflow tract, no paravalvular leakage and excellent transvalvular gradients in both groups (3.9±1.2 mmHg and 4.2±0.8 mmHg in the surgical and transcatheter arm respectively). There was no difference in postoperative major adverse events between the groups with no strokes in the whole cohort. Both methods showed similar survival rates at one year and a 30-day mortality of 15.2% and 9.8% in SAVR and TMVR group, respectively. Despite using contrast dye in the transcatheter group, the rate of postoperative acute kidney failure was similar between the groups. CONCLUSION: Despite several contraindications for surgery, we showed the non-inferiority of TA-TMVR compared to conventional surgical redo procedures in high-risk patients. With its excellent hemodynamic and similar survival rate, TA-TMVR offers a feasible alternative to the conventional surgical redo procedure in selected patients.

A/H1N1 hemagglutinin antibodies show comparable affinity in vaccine-related Narcolepsy type 1 and control and are unlikely to contribute to pathogenesis.

An increased incidence of narcolepsy type 1 (NT1) was observed in Scandinavia following the 2009-2010 influenza Pandemrix vaccination. The association between NT1 and HLA-DQB1*06:02:01 supported the view of the vaccine as an etiological agent. A/H1N1 hemagglutinin (HA) is the main antigenic determinant of the host neutralization antibody response. Using two different immunoassays, the Luciferase Immunoprecipitation System (LIPS) and Radiobinding Assay (RBA), we investigated HA antibody levels and affinity in an exploratory and in a confirmatory cohort of Swedish NT1 patients and healthy controls vaccinated with Pandemrix. HA antibodies were increased in NT1 patients compared to controls in the exploratory (LIPS p = 0.0295, RBA p = 0.0369) but not in the confirmatory cohort (LIPS p = 0.55, RBA p = 0.625). HA antibody affinity, assessed by competition with Pandemrix vaccine, was comparable between patients and controls (LIPS: 48 vs. 39 ng/ml, p = 0.81; RBA: 472 vs. 491 ng/ml, p = 0.65). The LIPS assay also detected higher HA antibody titres as associated with HLA-DQB1*06:02:01 (p = 0.02). Our study shows that following Pandemrix vaccination, HA antibodies levels and affinity were comparable NT1 patients and controls and suggests that HA antibodies are unlikely to play a role in NT1 pathogenesis.