Plant Omega-3 Fatty Acids May Lower Risk of Atrial Fibrillation in Individuals with a Low Intake of Marine Omega-3 Fatty Acids.

BACKGROUND: Omega-3 fatty acids derived from seafood acids may influence cardiac arrhythmogenesis, whereas the role of the major plant-derived omega-3 fatty acid, alpha-linolenic acid (ALA), on atrial fibrillation (AF) is largely unknown. OBJECTIVES: We aimed to investigate the association between ALA intake and risk of incident AF overall and in subjects with a low intake of marine omega-3 fatty acids. METHODS: We followed a total of 54,260 middle-aged men and women enrolled into the Danish Diet, Cancer, and Health cohort for development of AF using nationwide registries. Intake of ALA was assessed using a validated food frequency questionnaire and modeled as a restricted cubic spline. Statistical analyses were conducted using Cox proportional hazards regression. RESULTS: We identified a total of 4902 incident AF events during a median of 16.9 y of follow-up. In multivariable analyses, we observed indications of a statistically nonsignificant inverse association between ALA intake and risk of AF up to an ALA intake of 2.5 g/d, whereas no appreciable association was found for higher intakes of ALA. A statistically significant dose-dependent negative association was found between ALA intake and risk of AF in individuals consuming < 250 mg marine omega-3 fatty acids daily, whereas no association was found in those with a higher intake of marine omega-3 fatty acids. CONCLUSIONS: Intake of ALA was associated with a lower risk of AF in individuals consuming a low intake of marine omega-3 fatty acids. This finding is novel and warrants further investigation.

Development of sterile platform for quantification of extracellular analytes via single walled carbon nanotubes.

Progress has been made studying cell-cell signaling communication processes. However, due to limitations of current sensors on time and spatial resolution, the role of many extracellular analytes is still unknown. A single walled carbon nanotube (SWNT) platform was previously developed based on the avidin-biotin immobilization of SWNT to a glass substrate. The SWNT platform provides real time feedback about analyte concentration and has a high concentration of evenly distributed sensors, both of which are essential for the study of extracellular analytes. Unfortunately, this initial SWNT platform is synthesized through unsterile conditions and cannot be sterilized post-production due to the delicate nature of the sensors, making it unsuitable for in vitro work. Herein the multiple-step process for SWNT immobilization is modified and the platform's biocompatibility is assessed in terms of sterility, cytotoxicity, cell proliferation, and cell morphology through comparison with non-sensors controls. The results demonstrate the SWNT platform's sterility and lack of toxicity over 72 h. The proliferation rate and morphology profiles for cells growing on the SWNT platform are similar to those grown on tissue culture substrates. This novel nano-sensor platform preserves cell health and cell functionality over time, offering opportunities to study extracellular analytes gradients in cellular communication.

External cardioversion of atrial fibrillation and flutter in patients with cardiac implantable electrical devices.

BACKGROUND: Atrial fibrillation and flutter are often treated with external electrical cardioversion (ECV) in patients with potentially electrically sensitive cardiovascular implantable electronic devices (CIED). Long-term follow-up data on contemporary CIED undergoing ECV is sparse. The aim is to investigate shock-related complications and impact on CIEDs. METHODS: All ECV procedures from 2010 to 2020 in patients with CIED performed at a tertiary university hospital were identified in the Danish National Patient Registry. Changes in device measurements after ECV were retrospectively studied and procedure-related complications were identified by review of medical records. RESULTS: We analyzed 763 ECV procedures in 372 patients, median device implant time 1.9 years. The mean age of patients was 69.9 ± 9.9 years of which 73.4% were men. We identified two cases of device programming changes and four cases of premature battery depletion (≤3 years after device implant). Minor changes in device measurements were found for impedances, sensing, and pacing thresholds. No patients died due to ECV-related device dysfunctions within the first 12 months after cardioversions. CONCLUSION: External cardioversion in patients with contemporary pacemakers and implantable cardioverter-defibrillators seems safe in the majority of patients. Clinically important changes in device function following cardioversion were rarely observed but may be critical for device function. In an observational study, causality between cardioversion and device dysfunction cannot be established. For patient safety, we suggest that routine device interrogation after cardioversion still should be part of standard care.

Gambierdiscus (Gonyaulacales, Dinophyceae) diversity in Vietnamese waters with description of G. vietnamensis sp. nov.

Viet Nam has a coastline of 3200 km with thousands of islands providing diverse habitats for benthic harmful algal species including species of Gambierdiscus. Some of these species produce ciguatera toxins, which may accumulate in large carnivore fish potentially posing major threats to public health. This study reports five species of Gambierdiscus from Vietnamese waters, notably G. australes, G. caribaeus, G. carpenteri, G. pacificus, and G. vietnamensis sp. nov. All species are identified morphologically by LM and SEM, and identifications are supported by molecular analyses of nuclear rDNA (D1-D3 and D8-D10 domains of LSU, SSU, and ITS1-5.8S-ITS2 region) based on cultured material collected during 2010-2021. Statistical analyses of morphometric measurements may be used to differentiate some species if a sufficiently large number of cells are examined. Gambierdiscus vietnamensis sp. nov. is morphologically similar to other strongly reticulated species, such as G. belizeanus and possibly G. pacificus; the latter species is morphologically indistinguishable from G. vietnamensis sp. nov., but they are genetically distinct, and molecular analysis is deemed necessary for proper identification of the new species. This study also revealed that strains denoted G. pacificus from Hainan Island (China) should be included in G. vietnamensis sp. nov.

Subclinical hypothyroidism in pregnancy - assessment of offspring thyroid status and mitochondrial robustness to stress.

Subclinical hypothyroidism's clinical implications on pregnancy are controversial. Consequently, thyrotropin (TSH) cutoff-values for pregnancy are continuously a subject for debate. In subclinical hypothyroidism, altered levels of thyroid hormones may affect mitochondrial function.Objectives were i) to analyze thyroid hormone levels in offspring of women with and without subclinical hypothyroidism ii) to analyze mitochondrial "robustness" in terms of MTG/TMRM ratio in pregnant women and their offspring in relation to thyroid function and iii) to perform differentiate analyses on different TSH thresholds to determine the importance of cutoff-values to results.Pregnant women were included by blood collections prior to a planned cesarean section, and cord samples were collected after delivery. Thyroid status (analyzed by Siemens Healthcare Diagnostics by an electrochemical luminescent immunoassay based on LOCI-technology) grouped the women and their offspring in euthyroid or subclinical hypothyroid, with groups established from previous recommended third-trimester cutoff-value (TSH > 3.0 mIU/L) and the recently recommended cutoff-value in Denmark (TSH > 3.7 mIU/L). Flow cytometric measurements of mitochondrial function in mononuclear blood cells with the fluorophores TetraMethylRhodamine Methyl Ester (TMRM) and Mitotracker Green (MTG) were used to evaluate mitochondrial robustness as the MTG/TMRM ratio.No significant differences in mitochondrial robustness between euthyroid and subclinical hypothyroid cohorts were observed, irrespective of TSH-cutoff applied. Maternal and cord MTG/TMRM ratios were positively correlated. Cord-TSH was elevated in subclinical hypothyroid offspring, independent of TSH cutoff applied. Cord-TSH was associated with maternal TSH-level, maternal smoking and cord arterial-pH.

Ribosomal DNA Sequence-Based Taxonomy and Antimicrobial Activity of Prorocentrum spp. (Dinophyceae) from Mauritius Coastal Waters, South-West Indian Ocean.

Microalgae are unicellular organisms and commonly present in the euphotic zone of marine ecosystems. From the western coast of Mauritius, three strains of Prorocentrum species were isolated from macrophytes and cultured under standard laboratory conditions. Morphologies were examined by light, fluorescence, and scanning electron microscopy, and phylogenetic analyses were based on partial large subunit LSU rDNA (D1-D2) and ITS1-5.8S-ITS2 (ITS) regions. Three Prorocentrum species, including the P. fukuyoi complex, P. rhathymum, and P. lima complex, were identified. The antimicrobial activities were assayed against potential human pathogenic bacterial strains. The highest zone of inhibition was recorded for intracellular and extracellular protein extracts of Prorocentrum rhathymum against Vibrio parahaemolyticus. The polysaccharide extracts of the Prorocentrum fukuyoi complex had a higher zone of inhibition (24 ± 0.4 mm) against MRSA at a minimum concentration of 0.625 µg/mL. The extracts from the three Prorocentrum species had different levels of activity against the pathogens used, and this can be of scientific interest in the search for antibiotics from natural marine sources.

Clinical features affecting efficacy of immune checkpoint inhibitors in pretreated patients with advanced NSCLC: a Danish nationwide real-world study.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are implemented as standard treatment for patients with advanced non-small cell lung cancer (NSCLC) in first-line and subsequent-line treatment. However, certain subgroups such as patients with older age, poor performance status (PS), and severe comorbidity are underrepresented in the randomized controlled trials (RCTs). This study aimed to assess overall survival (OS), treatment data, and clinical features affecting second- or subsequent-line ICI efficacy in an unselected, Danish, nationwide NSCLC population. METHODS: Patients with advanced NSCLC who started nivolumab or pembrolizumab as second-line or subsequent-line treatment between 1 September 2015, and 1 October 2018, were identified from institutional records of all Danish oncology departments. Clinical and treatment data were retrospectively collected. Descriptive statistics and survival analyses were performed. RESULTS: Data were available for 840 patients; 49% females. The median age was 68 years (19% were ≥75 years), 19% had PS ≥2, and 36% had moderate to severe comorbidity. The median OS (mOS) was 12.2 months; 15.1 months and 10.0 months in females and males, respectively. The median time-to-treatment discontinuation (mTTD) and median progression-free survival (mPFS) was 3.2 and 5.2 months, respectively. Patients with PS ≥2 had a mOS of 4.5 months, mTTD of 1.1 month, and mPFS of 2.0 months. In multivariable Cox regression analysis, male sex (HR = 1.35, 95% CI 1.11-1.62), PS >0 (PS 1, HR = 1.88, 95% CI 1.52-2.33; PS ≥2, HR = 4.15, 95% CI 3.13-5.5), liver metastases (HR = 1.72, 95% CI 1.34-2.22), and bone metastases (HR = 1.27, 95% CI 1.03-1.58) were significant poor prognostic OS factors. CONCLUSIONS: Danish real-world patients with advanced NSCLC treated with second- or subsequent-line ICI had an OS comparable to results from RCTs. Women, frail and older patients constituted a higher proportion than in previous RCTs. Clinical features associated with poor OS were male sex, PS ≥1 (in particular PS ≥2), bone-, and liver metastases.

Changes in systemic inflammation after pulmonary rehabilitation in patients with COPD and severe physical inactivity - an exploratory study.

BACKGROUND: Severe physical inactivity (SPI) in patients with COPD is associated with a poor prognosis. It is unknown whether there is a link between SPI and systemic inflammation, and if systemic inflammation in SPI changes following pulmonary rehabilitation (PR). METHODS: A prospective, observational study of patients referred for at least 7 weeks of PR comprising 2 h of exercise therapy and education twice weekly. At baseline and after PR, daily physical activity level (PAL) was measured with a validated activity monitor, SenseWear® as well as systemic inflammation: b-eosinophils, p-fibrinogen, p-CRP, s-IL-6 and s-CD 163. SPI was defined as PAL <1.4. RESULTS: At baseline, SPI was present in 31 of the 57 patients included, and 23% (7/31) improved to non-SPI after PR. We observed no differences between patients with SPI and non-SPI, except baseline plasma fibrinogen level was slightly yet significantly higher in patients with SPI (median 13.3 [6.2-23.6] vs 11.2 [6.5-16.7] µmol/l) but change in fibrinogen levels differed insignificantly between patients who improved to non-SPI at follow-up compared to patients with persistent SPI (-0.6 [-16.9-9.9] vs -0.4 [-11.2-1.2] µmol/l). CONCLUSION: SPI in COPD appears not to be associated with a distinct inflammatory profile compared to less sedentary COPD patients attending pulmonary rehabilitation. Currently biomarkers have no role in the detection of SPI in COPD.

Regression models for interval censored data using parametric pseudo-observations.

BACKGROUND: Time-to-event data that is subject to interval censoring is common in the practice of medical research and versatile statistical methods for estimating associations in such settings have been limited. For right censored data, non-parametric pseudo-observations have been proposed as a basis for regression modeling with the possibility to use different association measures. In this article, we propose a method for calculating pseudo-observations for interval censored data. METHODS: We develop an extension of a recently developed set of parametric pseudo-observations based on a spline-based flexible parametric estimator. The inherent competing risk issue with an interval censored event of interest necessitates the use of an illness-death model, and we formulate our method within this framework. To evaluate the empirical properties of the proposed method, we perform a simulation study and calculate pseudo-observations based on our method as well as alternative approaches. We also present an analysis of a real dataset on patients with implantable cardioverter-defibrillators who are monitored for the occurrence of a particular type of device failures by routine follow-up examinations. In this dataset, we have information on exact event times as well as the interval censored data, so we can compare analyses of pseudo-observations based on the interval censored data to those obtained using the non-parametric pseudo-observations for right censored data. RESULTS: Our simulations show that the proposed method for calculating pseudo-observations provides unbiased estimates of the cumulative incidence function as well as associations with exposure variables with appropriate coverage probabilities. The analysis of the real dataset also suggests that our method provides estimates which are in agreement with estimates obtained from the right censored data. CONCLUSIONS: The proposed method for calculating pseudo-observations based on the flexible parametric approach provides a versatile solution to the specific challenges that arise with interval censored data. This solution allows regression modeling using a range of different association measures.

The clinical utility of procainamide-induced late potentials on the signal averaged ECG.

BACKGROUND: Late potentials (LPs) identified on the signal averaged electrocardiogram (SAECG) are a marker for an increased risk of arrhythmias in Brugada syndrome (BrS). Procainamide is a sodium channel blocker used to diagnose BrS. The effects of Procainamide on the SAECG in those with BrS and the significance of Procainamide-induced LPs are unknown. METHODS: Procainamide provocation was performed for suspected BrS with 12-lead and SAECG pre- and post-infusion. Filtered QRS duration (fQRSd), duration of low amplitude signals <40 µV (LAS40) and root-mean-square voltage in the terminal 40 ms (RMS40) were determined. RESULTS: Data from 150 patients were included in the analysis (mean age 44.5 years, 109 males). Procainamide increased fQRSd (Pre 118.8 ± 10.5 ms, post 121.2 ± 10.2 ms, p < 0.001) and LAS40 (Pre 38.7 ± 9.8 ms, post 40.2 ± 10.5 ms, p = 0.005) and decreased RMS40 (Pre 24.6 ± 12 ms, post 22.8 ± 12 ms, p = 0.002). LPs were present in 68/150 (45%) at baseline. Fifteen patients with negative baseline SAECGs had LPs unmasked by Procainamide, but six patients had LPs at baseline that were no longer present following Procainamide. Comparing those with normal hearts (n = 48) to those with a final diagnosis of BrS (n = 38), Procainamide prolonged fQRSd to a greater extent in those with BrS. Comparing those with Procainamide-induced LPs to those with no LPs at any time did not highlight any aspect of phenotype and did not correlate with a history of ventricular arrhythmias. CONCLUSIONS: Procainamide influences the SAECG, provoking LPs in a small proportion of patients. However, there is no evidence that Procainamide-induced LPs provide additional diagnostic information or aid risk stratification.

Morphological and genetic analyses of Ostreopsis (Dinophyceae, Gonyaulacales, Ostreopsidaceae) species from Vietnamese waters with a re-description of the type species, O. siamensis.

Identification of species of the dinoflagellate genus Ostreopsis is difficult because several species have been poorly described, others misidentified in the literature, and the type species, O. siamensis, has not been described by contemporary taxonomic methods. In the present study, it is argued that Ostreopsis sp. 6 as described by previous authors is similar to the type species, and we offer an emended description of O. siamensis by LM, SEM, and molecular analyses of nuclear LSU and ITS rDNA based on material collected a few hundred kilometers from the type locality in the Gulf of Thailand and along the Vietnamese east coast. Ostreopsis siamensis is genetically different from the species reported as O. cf. siamensis in the literature and the latter should be described as a separate species. It is also concluded that with the poor knowledge of the morphological variability of many species of Ostreopsis, O. siamensis may not be distinguished from other similar-sized species by its morphological features, and hence molecular data are needed for reliable identification. The species Ostreopsis lenticularis and Ostreopsis cf. ovata were also found and described.

Effect of Vasopressin and Methylprednisolone vs Placebo on Return of Spontaneous Circulation in Patients With In-Hospital Cardiac Arrest: A Randomized Clinical Trial.

Importance: Previous trials have suggested that vasopressin and methylprednisolone administered during in-hospital cardiac arrest might improve outcomes. Objective: To determine whether the combination of vasopressin and methylprednisolone administered during in-hospital cardiac arrest improves return of spontaneous circulation. Design, Setting, and Participants: Multicenter, randomized, double-blind, placebo-controlled trial conducted at 10 hospitals in Denmark. A total of 512 adult patients with in-hospital cardiac arrest were included between October 15, 2018, and January 21, 2021. The last 90-day follow-up was on April 21, 2021. Intervention: Patients were randomized to receive a combination of vasopressin and methylprednisolone (n = 245) or placebo (n = 267). The first dose of vasopressin (20 IU) and methylprednisolone (40 mg), or corresponding placebo, was administered after the first dose of epinephrine. Additional doses of vasopressin or corresponding placebo were administered after each additional dose of epinephrine for a maximum of 4 doses. Main Outcomes and Measures: The primary outcome was return of spontaneous circulation. Secondary outcomes included survival and favorable neurologic outcome at 30 days (Cerebral Performance Category score of 1 or 2). Results: Among 512 patients who were randomized, 501 met all inclusion and no exclusion criteria and were included in the analysis (mean [SD] age, 71 [13] years; 322 men [64%]). One hundred of 237 patients (42%) in the vasopressin and methylprednisolone group and 86 of 264 patients (33%) in the placebo group achieved return of spontaneous circulation (risk ratio, 1.30 [95% CI, 1.03-1.63]; risk difference, 9.6% [95% CI, 1.1%-18.0%]; P = .03). At 30 days, 23 patients (9.7%) in the intervention group and 31 patients (12%) in the placebo group were alive (risk ratio, 0.83 [95% CI, 0.50-1.37]; risk difference: -2.0% [95% CI, -7.5% to 3.5%]; P = .48). A favorable neurologic outcome was observed in 18 patients (7.6%) in the intervention group and 20 patients (7.6%) in the placebo group at 30 days (risk ratio, 1.00 [95% CI, 0.55-1.83]; risk difference, 0.0% [95% CI, -4.7% to 4.9%]; P > .99). In patients with return of spontaneous circulation, hyperglycemia occurred in 77 (77%) in the intervention group and 63 (73%) in the placebo group. Hypernatremia occurred in 28 (28%) and 27 (31%), in the intervention and placebo groups, respectively. Conclusions and Relevance: Among patients with in-hospital cardiac arrest, administration of vasopressin and methylprednisolone, compared with placebo, significantly increased the likelihood of return of spontaneous circulation. However, there is uncertainty whether this treatment results in benefit or harm for long-term survival. Trial Registration: ClinicalTrials.gov Identifier: NCT03640949.

Impact of Left Common Pulmonary Veins in the Contact-Force vs. Cryoballoon Atrial Fibrillation Ablation (CIRCA-DOSE) Study.

BACKGROUND: Concerns remain regarding the effectiveness of PVI using the fixed diameter non-compliant cryoballoon in the presence of a left common pulmonary vein (LCPV). We sought to evaluate the effectiveness of PVI performed by contact-force guided radiofrequency (CF-RF) versus second-generation cryoballoon-based ablation in patients with LCPV. METHODS AND RESULTS: We enrolled 346 patients with paroxysmal AF and randomized them to CF-RF or cryoballoon ablation. PV anatomy was not assessed prior to enrolment, and there were no exclusions based on PV anatomy. All patients received an implantable cardiac monitor. LCPV was observed in 13.6% of patients (47/346). Left atrial time and fluoroscopy time did not differ between those with and without LCPV (P=0.58 and P=0.06, respectively). Freedom from any atrial tachyarrhythmia at one year was observed in 46.8% with LCPV and 54.5% without LCPV (P=0.06). In those with LCPV the freedom from any atrial tachyarrhythmia did not differ between those randomized to CF-RF or cryoballoon ablation (HR for recurrence 1.19, 95% CI 0.53-2.65, P=0.69). In those with LCPV the AF burden was reduced to a similar extent with CF-RF and cryoballoon ablation (99.7% vs. 99.5%, respectively; P=0.97). CONCLUSIONS: In this randomized clinical trial, the presence of a LCPV was associated with a trend towards higher rates of arrhythmia recurrence following PVI. No significant difference in arrhythmia recurrence was observed between patients with LCPV randomized to cryoballoon ablation or contact-force guided RF ablation, suggesting that either ablation modality is suitable in this population. (Cryoballoon vs. Irrigated Radiofrequency Catheter Ablation [CIRCA-DOSE], NCT01913522) This article is protected by copyright. All rights reserved.

Long-term follow-up of abandoned transvenous defibrillator leads: a nationwide cohort study.

AIMS: Commonly, a dysfunctional defibrillator lead is abandoned and a new lead is implanted. Long-term follow-up data on abandoned leads are sparse. We aimed to investigate the incidence and reasons for extraction of abandoned defibrillator leads in a nationwide cohort and to describe extraction procedure-related complications. METHODS AND RESULTS: All abandoned transvenous defibrillator leads were identified in the Danish Pacemaker and ICD Register from 1991 to 2019. The event-free survival of abandoned defibrillator leads was studied, and medical records of patients with interventions on abandoned defibrillator leads were audited for procedure-related data. We identified 740 abandoned defibrillator leads. Meantime from implantation to abandonment was 7.2 ± 3.8 years with mean patient age at abandonment of 66.5 ± 13.7 years. During a mean follow-up after abandonment of 4.4 ± 3.1 years, 65 (8.8%) abandoned defibrillator leads were extracted. Most frequent reason for extraction was infection (pocket and systemic) in 41 (63%) patients. Procedural outcome after lead extraction was clinical success in 63 (97%) patients. Minor complications occurred in 3 (5%) patients, and major complications in 1 (2%) patient. No patient died from complication to the procedure during 30-day follow-up after extraction. CONCLUSION: More than 90% of abandoned defibrillator leads do not need to be extracted during long-term follow-up. The most common indication for extraction is infection. Abandoned defibrillator leads can be extracted with high clinical success rate and low risk of major complications at high-volume centres.

Mitochondrial energetics and contents evaluated by flow cytometry in human maternal and umbilical cord blood.

Background: Mitochondrial dysfunction may relate to metabolic disorders. The relation between maternal and fetal mitochondrial function needs attention due to heritage.Objectives: To evaluate the use of the staining methods TetraMethylRhodamine Methyl Ester (TMRM) and Mitotracker Green (MTG) for flow cytometric measurements of umbilical cord blood mitochondrial function. Methods: 53 euthyroid at-term pregnant women and their offspring were included by blood collections. The offspring had blood drawn from the clamped umbilical cord. Flow cytometry with MTG, TMRM and Propidium Iodide were performed the following day. A cell count (antibody coating and flow cytometry) was performed for 9 maternal and cord samples. As a quality control, blood of 32 healthy donors was evaluated by flow cytometric analyzes same day as sampling and the following day to test stability of the measurements.Results: Cord mitochondrial measurements were lower than maternal. Maternal and cord mitochondrial function were positively correlated, especially reflected by MTG fluorescence-intensity (FI). Samples stored presented with very changed fluorescence patterns. However, the fluorescence intensity ratios MTG/TMRM of stained white blood cells were related within same day measurements, depicting an extensive and common bioenergetic cellular change.Conclusion: Cord blood flow cytometry by MTG- and TMRM- staining is possible with fluorescence intensity positively correlated to maternal fluorescence intensity. Storage of blood triggers mitochondrial dynamics. The methods are applicable with certain reservations, and they benefit from their non-invasive character compared to mitochondrial evaluation by muscle-biopsies.

WHO implementation workshop on guidelines on procedures and data requirements for changes to approved biotherapeutic products, Seoul, Republic of Korea, 25-26 June 2019.

The first global workshop on implementation of the WHO guidelines on procedures and data requirements for changes to approved biotherapeutic products adopted by the WHO Expert Committee in 2018 was held in June 2019. The workshop participants recognized that the principles based on sound science and the potential for risk, as described in the WHO Guidelines on post-approval changes, which constitute the global standard for product life-cycle management are providing clarity and helping national regulatory authorities in establishing guidance while improving time-lines for an efficient regulation of products. Consequently, the regulatory situation for post-approval changes and guideline implementation is changing but there is a disparity between different countries. While the guidelines are gradually being implemented in some countries and also being considered in other countries, the need for regional workshops and further training on post-approval changes was a common theme reiterated by many participants. Given the complexities relating to post-approval changes in different regions/countries, there was a clear understanding among all participants that an efficient approach for product life-cycle management at a national level is needed to ensure faster availability of high standard, safe and efficacious medicines to patients as per the World Health Assembly Resolution 67.21.

Reduced Gene Expression of Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1α in Whole Blood in Euthyroid Patients One Year After Hemithyroidectomy for Benign Euthyroid Goiter.

We have previously reported decreased thyroid function within the laboratory reference range and changes in mitochondrial function after hemithyroidectomy. Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and coactivator-1ß (PGC-1ß) are key regulators of mitochondrial biogenesis and function. The aim was to examine the influence of hemithyroidectomy on the longitudinal change in mRNA expression of these genes. In addition, we measured longitudinal changes in mRNA expressions of the mitochoncrial-related genes nuclear factor erythroid-derived 2-like 2 (NFE2L2), mitochondrial transcription factor A (TFAM), and sodium dismutase 2 (SOD2). Twenty-eight patients were examined before and 1, 3, 6, and 12 months after hemithyroidectomy for benign euthyroid goiter. Thyroid stimulating hormone (TSH) and thyroid hormones were measured, and whole blood gene expression of PGC-1α, PGC-1ß, NFE2L2, TFAM, and SOD2 was examined by reverse transcription quantitative Polymerase Chain Reaction. We used mixed effect regression models to investigate changes in gene expression with time. Averaged over all follow-up visits, TSH increased (p=0.001), tT3 declined (p=0.01), and fT4/tT3 ratio increased (p=0.03) over one-year follow-up, but fT4 remained unchanged. Averaged over all follow-up visits, whole blood PGC-1α levels (p<0.001) and SOD2 (p=0.009) levels declined, but PGC-1ß, TFAM, and NFE2L2 did not change over one-year follow-up. The study demonstrates significant downregulation of whole blood PGC-1α and SOD2 gene expressions in hemithyroidectomized patients with a concomitant increase in TSH concentration within the reference range. Thus, hemithyroidectomized patients may likely have impaired mitochondrial function.

The Association of a classical left bundle Branch Block Contraction Pattern by vendor-independent strain echocardiography and outcome after cardiac resynchronization therapy.

BACKGROUND: The association of a Classical left bundle branch block (LBBB) contraction pattern and better outcome after cardiac resynchronization therapy (CRT) has only been studied using vendor-specific software for echocardiographic speckle-tracked longitudinal strain analysis. The purpose of this study was to assess whether a Classical LBBB contraction pattern on longitudinal strain analysis using vendor-independent software is associated with clinical outcome in CRT recipients with LBBB. METHODS: This was a retrospective cohort study including CRT recipients with LBBB, heart failure, and left ventricular (LV) ejection fraction ≤35%. Speckle-tracked echocardiographic longitudinal strain analysis was performed retrospectively on echocardiograms using vendor-independent software. The presence of a Classical LBBB contraction pattern was determined by consensus of two readers. The primary end point was a composite of time to death, heart transplantation or LV assist device implantation. Secondary outcome was ≥15% reduction in LV end-systolic volume. Intra- and inter-reader agreement of the longitudinal strain contraction pattern was assessed by calculating Cohen's κ. RESULTS: Of 283 included patients, 113 (40%) were women, mean age was 66 ± 11 years, and 136 (48%) had ischemic heart disease. A Classical LBBB contraction pattern was present in 196 (69%). The unadjusted hazard ratio for reaching the primary end point was 1.93 (95% confidence interval, 1.36-2.76, p < 0.001) when comparing patients without to patients with a Classical LBBB contraction pattern. Adjusted for ischemic heart disease and QRS duration < 150 milliseconds the hazard ratio was 1.65 (95% confidence interval, 1.12-2.43, p = 0.01). Of the 123 (43%) patients with a follow-up echocardiogram, 64 of 85 (75%) of patients with a Classical LBBB contraction pattern compared to 13 of 38 (34%) without, had ≥15% reduction in LV end-systolic volume (p < 0.001). Cohen's κ were 0.86 (95% confidence interval, 0.71-1.00) and 0.42 (95% confidence interval, 0.30-0.54) for intra- and inter-reader agreement, respectively. CONCLUSION: Using vendor-independent strain software, a Classical LBBB contraction pattern is associated with better outcome in CRT recipients with LBBB, but inter-reader agreement for the classification of contraction pattern is only moderate.

Validation of defibrillator lead performance registry data: insight from the Danish Pacemaker and ICD Register.

AIMS: The validity of registry data on defibrillator lead performance is described only sparsely, despite its clinical importance. This study investigated the validity of defibrillator lead performance registry data in a nationwide and population-based registry. METHODS AND RESULTS: We identified all reported surgical interventions due to defibrillator lead events in the Danish Pacemaker and ICD Register (DPIR) from 2000 to 2013. Medical records of all patients (n = 753) were examined blinded for 5 predefined intervention types and 18 reasons for lead intervention. The overall level of agreement for the types of lead intervention had a positive predictive value (PPV) of 89.4% [95% confidence interval (CI): 87.0-91.5%] and an adjusted agreement (κ value) of 0.81 (95% CI: 0.77-0.85) representing an almost perfect match. Regarding the reasons for lead intervention, the overall PPV was 63.0% (95% CI: 54.8-61.7%) with a κ value of 0.60 (95% CI: 0.55-0.64) representing a moderate match with only few subcategories having low PPV. By redistribution of the specific reasons for lead interventions into three categories commonly used to report lead performance, the overall PPV improved to 87.9% (95% CI: 85.2-90.2%) with a κ value of 0.82 (95% CI:0.78-0.86) representing an almost perfect match. CONCLUSION: The validity of data on defibrillator lead performance recorded in the DPIR is excellent for the specific types of lead intervention and good for the specific reasons for defibrillator lead intervention. The validity of the less detailed overall reasons for lead interventions commonly used to report lead performance is also excellent. These findings indicate high registry data quality appropriate for scientific analysis and industry-independent post-marketing surveillance.