Heart rate distribution in paced and non-paced patients with severe recurrent reflex syncope and tilt-induced asystole: Findings from the BIOSync CLS study

Background: Undiagnosed sinus or atrioventricular node dysfunction may bias estimation of the real efficacy of cardiac pacing in preventing vasovagal reflex syncope. We assessed this hypothesis in the BIOSync CLS trial which showed that dual-chamber pacing with closed loop stimulation (CLS) remarkably reduced recurrences of syncope. Methods and results: In the study patients aged 40 years or older with ≥2 episodes of loss of consciousness in the last year and an asystolic response to Tilt-Table test were randomized to pacing ON (DDD-CLS mode) or pacing OFF (ODO mode). We utilized the available pacemaker diagnostic data in a total of 103 patients (52 pacing ON, 51 pacing OFF) to generate cumulative distribution charts for heart rate (HR) and percentage of pacing. At 12 months, we did not find evidence of suspected sinus or atrioventricular node dysfunction. Beats were similarly distributed between groups (p = 0.96), with an average HR of 76 ± 8 bpm (pacing ON) versus 77 ± 7 bpm (pacing OFF). In the active group, the median percentage of atrial and ventricular pacing was 47% and 0%, respectively. Intolerance to high pacing rates was reported in only one patient (1.6%) and was easily resolved by reprogramming the maximum CLS pacing rate. Conclusions: We did not find evidence of suspected sinus or atrioventricular node dysfunction in the BIOSync CLS patients. The benefit of pacing should be ascribed to pacing prevention of pure vasovagal episodes. CLS algorithm modulated pacing rates over a wide frequency range, consistently competing with sinus node

Variability of cardioinhibition in vasovagal syncope:differences between subgroups during cardioinhibition and beyond

Purpose: We compared hemodynamic parameters between subjects with marked, intermediate and minimal cardioinhibition during vasovagal syncope.Methods: The study included subjects with a decrease in heart rate while experiencing a complete vasovagal syncope during tilt-table testing. The subjects were classified as having marked, intermediate or minimal cardioinhibition, based on tertile values of the decrease in heart rate. Hemodynamic parameters between these groups were compared before tilt in the supine position, shortly after tilt and during cardioinhibition. Results:A total of 149 subjects with a median age of 43 (interquartile range 24–60) years were included in the study. Among the three groups with different levels of cardioinhibition, the highest heart rate was observed in subjects with marked cardioinhibition both before and shortly after tilt and at the start of cardioinhibition. The heart rate decrease in these subjects was both larger and faster compared to subjects with minimal and intermediate cardioinhibition. Conclusion: Subjects with marked cardioinhibition have both a larger and faster decrease in heart rate compared to subjects with intermediate and minimal cardioinhibition, as early as from the start of cardioinhibition. Marked cardioinhibition is related to differences in hemodynamic profiles already present well before the start of cardioinhibition.</p

Diagnostic yield and accuracy in a tertiary referral syncope unit validating the ESC guideline on syncope:a prospective cohort study

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Reduction of blood culture contamination rate by an educational intervention

Background: Although mechanical dyssynchrony parameters derived by speckle tracking echocardiography (STE) may predict response to cardiac resynchronization therapy (CRT), comparability of parameters derived with different STE vendors is unknown. Methods: In the MARC study, echocardiographic images of heart failure patients obtained before CRT implantation were prospectively analysed with vendor specific STE software (GE EchoPac and Philips QLAB) and vendor-independent software (TomTec 2DCPA). Response was defined as change in left ventricular (LV) end-systolic volume between examination before and six-months after CRT implantation. Basic longitudinal strain and mechanical dyssynchrony parameters (septal to lateral wall delay (SL-delay), septal systolic rebound stretch (SRSsept), and systolic stretch index (SSI)) were obtained from either separate septal and lateral walls, or total LV apical four chamber. Septal strain patterns were categorized in three types. The coefficient of variation and intra-class correlation coefficient (ICC) were analysed. Dyssynchrony parameters were associated with CRT response using univariate regression analysis and C-statistics. Results: Two-hundred eleven patients were analysed. GE-cohort (n = 123): age 68 years (interquartile range (IQR): 61-73), 67% male, QRS-duration 177ms (IQR: 160-192), LV ejection fraction: 26 +/- 7%. Philips-cohort (n = 88): age 67 years (IQR: 59-74), 60% male, QRS-duration: 179 ms (IQR: 166-193), LV ejection fraction: 27 +/- 8. LV derived peak strain was comparable in the GE-(GE: -7.3 +/- 3.1%, TomTec: -6.4 +/- 2.8%, ICC: 0.723) and Philips-cohort (Philips: -7.7 +/- 2.7%, TomTec: -7.7 +/- 3.3%, ICC: 0.749). SL-delay showed low ICC values (GE vs. TomTec: 0.078 and Philips vs. TomTec: 0.025). ICC's of SRSsept and SSI were higher but only weak (GE vs. TomTec: SRSsept: 0.470, SSI: 0.467) (Philips vs. QLAB: SRSsept: 0.419, SSI: 0.421). Comparability of septal strain patterns was low (Cohen's kappa, GE vs. TomTec: 0.221 and Philips vs. TomTec: 0.279). Septal strain patterns, SRSsept and SSI were associated with changes in LV end-systolic volume for all vendors. SRSsept and SSI had relative varying C-statistic values (range: 0.530-0.705) and different cut-off values between vendors. Conclusions: Although global longitudinal strain analysis showed fair comparability, assessment of dyssynchrony parameters was vendor specific and not applicable outside the context of the implemented platform. While the standardization taskforce took an important step for global peak strain, further standardization of STE is still warranted

Gene expression profiling of epithelium-associated FcRL4(+) B cells in primary Sjogren's syndrome reveals a pathogenic signature

In primary Sjögren's syndrome (pSS), FcRL4+ B cells are present in inflamed salivary gland tissue, within or in close proximity to ductal epithelium. FcRL4 is also expressed by nearly all pSS-related mucosa-associated lymphoid tissue (MALT) B cell lymphomas, linking FcRL4 expression to lymphomagenesis. Whether glandular FcRL4+ B cells are pathogenic, how these cells originate, and how they functionally differ from FcRL4- B cells in pSS is unclear. This study aimed to investigate the phenotype and function of FcRL4+ B cells in the periphery and parotid gland tissue of patients with pSS. First, circulating FcRL4+ B cells from 44 pSS and 54 non-SS-sicca patients were analyzed by flow cytometry. Additionally, RNA sequencing of FcRL4+ B cells sorted from parotid gland cell suspensions of 6 pSS patients was performed. B cells were sorted from cell suspensions as mini bulk (5 cells/well) based on the following definitions: CD19+CD27-FcRL4- ('naive'), CD19+CD27+FcRL4- ('memory'), and CD19+FcRL4+ B cells. We found that, although FcRL4+ B cells were not enriched in blood in pSS compared with non-SS sicca patients, these cells generally exhibited a pro-inflammatory phenotype. Genes coding for CD11c (ITGAX), T-bet (TBX21), TACI (TNFRSF13B), Src tyrosine kinases and NF-κB pathway-related genes were, among others, significantly upregulated in glandular FcRL4+ B cells versus FcRL4- B cells. Pathway analysis showed upregulation of B cell activation, cell cycle and metabolic pathways. Thus, FcRL4+ B cells in pSS exhibit many characteristics of chronically activated, pro-inflammatory B cells and their gene expression profile suggests increased risk of lymphomagenesis. We postulate that these cells contribute significantly to the epithelial damage seen in the glandular tissue and that FcRL4+ B cells are an important treatment target in pSS

The Importance of Connexin 43 in Enamel Development and Mineralization

During enamel development, formation of hydroxyapatite crystals and regulation of pH in the enamel matrix require massive transport of ions. Both ameloblasts and adjacent dental epithelial cells in the stellate reticulum co-express several transmembrane cotransporters/ion-exchangers for transport of ions across plasma membranes. Gap junctions (GJs) enable intercellular exchanges of ions between neighboring cells. This suggests that the ameloblasts and other cell layers of the enamel organ, form a functional unit. During the bell stage of tooth formation, the non-ameloblast dental epithelium highly expresses the Na-K-Cl cotransporter (Nkcc1). Nkcc1-null mice are associated with enamel hypomineralization and increased expression of GJ protein connexin 43 (Cx43), suggesting that reduced ion transport in the Nkcc1-null mouse is in part compensated by increased intercellular ion transport through GJs. To understand the role of GJs in ion transport and its effect on pH regulation, we examined in a mouse strain in which Cx43 was ablated selectively in DMP1 expressing cells (Cx43flox/flox mice crossed with DMP1-8kb-Cre mice), including ameloblasts. Micro-CT analysis showed that the mineral density at late maturation stage incisal enamel of the Cx43-null mice was 10% less than in controls, whereas that in dentin was unchanged. Maturation stage ameloblasts of mice lacking the pH regulating sodium/bicarbonate transporter NBCe1 (Nbce1-null), or chloride channel Cftr (Cftr-null) were found to have increased Cx43-immunostaining. These results support the possibility that GJs in the ameloblast–papillary complex at the maturation stage contribute to ion transport by enabling passage of ions directly from cells of the papillary layer into ameloblast layer. Increasing the number of GJs may partly compensate the reduction of ion-cotransporters and ion exchangers in dental epithelium

Outcomes of a new slowly resorbable biosynthetic mesh (Phasix (TM)) in potentially contaminated incisional hernias : a prospective, multi-center, single-arm trial

Background: Resorbable biomaterials have been developed to reduce the amount of foreign material remaining in the body after hernia repair over the long-term. However, on the short-term, these resorbable materials should render acceptable results with regard to complications, infections, and reoperations to be considered for repair. Additionally, the rate of resorption should not be any faster than collagen deposition and maturation; leading to early hernia recurrence. Therefore, the objective of this study was to collect data on the short-term performance of a new resorbable biosynthetic mesh (Phasix (TM)) in patients requiring Ventral Hernia Working Group (VHWG) Grade 3 midline incisional hernia repair. Materials and methods: A prospective, multi-center, single-arm trial was conducted at surgical departments in 15 hospitals across Europe. Patients aged >= 18, scheduled to undergo elective Ventral Hernia Working Group Grade 3 hernia repair of a hernia larger than 10 cm(2) were included. Hernia repair was performed with Phasix (TM) Mesh in sublay position when achievable. The primary outcome was the rate of surgical site occurrence (SSO), including infections, that required intervention until 3 months after repair. Results: In total, 84 patients were treated with Phasix (TM) Mesh. Twenty-two patients (26.2%) developed 32 surgical site occurrences. These included 11 surgical site infections, 9 wound dehiscences, 7 seromas, 2 hematomas, 2 skin necroses, and 1 fistula. No significant differences in surgical site occurrence development were found between groups repaired with or without component separation technique, and between clean-contaminated or contaminated wound sites. At three months, there were no hernia recurrences. Conclusion: Phasix (TM) Mesh demonstrated acceptable postoperative surgical site occurrence rates in patients with a Ventral Hernia Working Group Grade 3 hernia. Longer follow-up is needed to evaluate the recurrence rate and the effects on quality of life. This study is ongoing through 24 months of follow-up

Digital consults to optimize guideline-directed therapy: design of a pragmatic multicenter randomized controlled trial

AIMS: Many heart failure (HF) patients do not receive optimal guideline-directed medical therapy (GDMT) despite clear benefit on morbidity and mortality outcomes. Digital consults (DCs) have the potential to improve efficiency on GDMT optimization to serve the growing HF population. The investigator-initiated ADMINISTER trial was designed as a pragmatic multicenter randomized controlled open-label trial to evaluate efficacy and safety of DC in patients on HF treatment. METHODS AND RESULTS: Patients (n = 150) diagnosed with HF with a reduced ejection fraction will be randomized to DC or standard care (1:1). The intervention group receives multifaceted DCs including (i) digital data sharing (e.g. exchange of pharmacotherapy use and home-measured vital signs), (ii) patient education via an e-learning, and (iii) digital guideline recommendations to treating clinicians. The consults are performed remotely unless there is an indication to perform the consult physically. The primary outcome is the GDMT prescription rate score, and secondary outcomes include time till full GDMT optimization, patient and clinician satisfaction, time spent on healthcare, and Kansas City Cardiomyopathy Questionnaire. Results will be reported in accordance to the CONSORT statement. CONCLUSIONS: The ADMINISTER trial will offer the first randomized controlled data on GDMT prescription rates, time till full GDMT optimization, time spent on healthcare, quality of life, and patient and clinician satisfaction of the multifaceted patient- and clinician-targeted DC for GDMT optimization

An evaluation of classification systems for stillbirth

<p>Abstract</p> <p>Background</p> <p>Audit and classification of stillbirths is an essential part of clinical practice and a crucial step towards stillbirth prevention. Due to the limitations of the ICD system and lack of an international approach to an acceptable solution, numerous disparate classification systems have emerged. We assessed the performance of six contemporary systems to inform the development of an internationally accepted approach.</p> <p>Methods</p> <p>We evaluated the following systems: Amended Aberdeen, Extended Wigglesworth; PSANZ-PDC, ReCoDe, Tulip and CODAC. Nine teams from 7 countries applied the classification systems to cohorts of stillbirths from their regions using 857 stillbirth cases. The main outcome measures were: the ability to retain the important information about the death using the <it>InfoKeep </it>rating; the ease of use according to the <it>Ease </it>rating (both measures used a five-point scale with a score <2 considered unsatisfactory); inter-observer agreement and the proportion of unexplained stillbirths. A randomly selected subset of 100 stillbirths was used to assess inter-observer agreement.</p> <p>Results</p> <p><it>InfoKeep </it>scores were significantly different across the classifications (<it>p </it>≤ 0.01) due to low scores for Wigglesworth and Aberdeen. CODAC received the highest mean (SD) score of 3.40 (0.73) followed by PSANZ-PDC, ReCoDe and Tulip [2.77 (1.00), 2.36 (1.21), 1.92 (1.24) respectively]. Wigglesworth and Aberdeen resulted in a high proportion of unexplained stillbirths and CODAC and Tulip the lowest. While <it>Ease </it>scores were different (<it>p </it>≤ 0.01), all systems received satisfactory scores; CODAC received the highest score. Aberdeen and Wigglesworth showed poor agreement with kappas of 0.35 and 0.25 respectively. Tulip performed best with a kappa of 0.74. The remainder had good to fair agreement.</p> <p>Conclusion</p> <p>The Extended Wigglesworth and Amended Aberdeen systems cannot be recommended for classification of stillbirths. Overall, CODAC performed best with PSANZ-PDC and ReCoDe performing well. Tulip was shown to have the best agreement and a low proportion of unexplained stillbirths. The virtues of these systems need to be considered in the development of an international solution to classification of stillbirths. Further studies are required on the performance of classification systems in the context of developing countries. Suboptimal agreement highlights the importance of instituting measures to ensure consistency for any classification system.</p