Frequency, Penetrance, and Variable Expressivity of Dilated Cardiomyopathy-Associated Putative Pathogenic Gene Variants in UK Biobank Participants.

BACKGROUND: There is a paucity of data regarding the phenotype of dilated cardiomyopathy (DCM) gene variants in the general population. We aimed to determine the frequency and penetrance of DCM-associated putative pathogenic gene variants in a general adult population, with a focus on the expression of clinical and subclinical phenotype, including structural, functional, and arrhythmic disease features. METHODS: UK Biobank participants who had undergone whole exome sequencing, ECG, and cardiovascular magnetic resonance imaging were selected for study. Three variant-calling strategies (1 primary and 2 secondary) were used to identify participants with putative pathogenic variants in 44 DCM genes. The observed phenotype was graded DCM (clinical or cardiovascular magnetic resonance diagnosis); early DCM features, including arrhythmia or conduction disease, isolated ventricular dilation, and hypokinetic nondilated cardiomyopathy; or phenotype-negative. RESULTS: Among 18 665 individuals included in the study, 1463 (7.8%) possessed ≥1 putative pathogenic variant in 44 DCM genes by the main variant calling strategy. A clinical diagnosis of DCM was present in 0.34% and early DCM features in 5.7% of individuals with putative pathogenic variants. ECG and cardiovascular magnetic resonance analysis revealed evidence of subclinical DCM in an additional 1.6% and early DCM features in an additional 15.9% of individuals with putative pathogenic variants. Arrhythmias or conduction disease (15.2%) were the most common early DCM features, followed by hypokinetic nondilated cardiomyopathy (4%). The combined clinical/subclinical penetrance was ≤30% with all 3 variant filtering strategies. Clinical DCM was slightly more prevalent among participants with putative pathogenic variants in definitive/strong evidence genes as compared with those with variants in moderate/limited evidence genes. CONCLUSIONS: In the UK Biobank, ≈1 of 6 of adults with putative pathogenic variants in DCM genes exhibited early DCM features potentially associated with DCM genotype, most commonly manifesting with arrhythmias in the absence of substantial ventricular dilation or dysfunction.

Integrating 3Rs approaches in WHO guidelines for the batch release testing of biologicals: Responses from a survey of National Control Laboratories and National Regulatory Authorities.

The UK National Centre for the Replacement, Refinement, and Reduction of Animals in Research (NC3Rs) is reviewing World Health Organization (WHO) manuals, guidelines and recommendations for vaccines and biotherapeutics to identify the extent to which animal-based testing methods are described. The aim is to recommend where updates to these documents can lead to an increased and more harmonised adoption of 3Rs principles (i.e. Replacement, Reduction and Refinement of animal tests) in the quality control and batch release testing requirements for vaccines and biotherapeutics. Improved adoption of 3Rs principles and non-animal testing strategies will help to reduce the delays and costs associated with product release testing. Developing recommendations that are widely applicable by both the manufacturers and national regulatory authorities for vaccines and biological therapeutics globally requires a detailed understanding of how different organisations view the opportunities and barriers to better integration of the 3Rs. To facilitate this, we developed and distributed a survey aimed at individuals who work for national regulatory authorities (NRAs) and/or national control laboratories (NCLs). In this paper, we present the key findings from this survey and how these will help inform the recommendations for wider integration of 3Rs approaches by WHO in their guidance documents applicable to the quality control and batch release testing of vaccines and biotherapeutics.

Integrating 3Rs approaches in WHO guidelines for the batch release testing of biologicals: Responses from a survey of vaccines and biological therapeutics manufacturers.

The UK National Centre for the Replacement, Refinement, and Reduction of Animals in Research (NC3Rs) has been tasked by the World Health Organization (WHO) to review the extent to which animal-based testing methods are described in their manuals, guidelines and recommendations for vaccines and biotherapeutics. The aim is to identify and recommend where updates to these documents can lead to an increased and more harmonised adoption of 3Rs principles (i.e. Replacement, Reduction and Refinement of animal tests) in the quality control and batch release testing requirements for vaccines and biotherapeutics. Developing recommendations that are widely applicable by both the manufacturers and national regulatory authorities for vaccines and biologicals globally requires a detailed understanding of how different organisations view the opportunities and barriers to better integration of the 3Rs. To facilitate this, we developed and distributed a survey aimed at vaccine and biotherapeutics manufacturers in July 2021. In this paper, we present the key findings from this survey and how these will help inform the recommendations for wider integration of 3Rs approaches by WHO in their guidance documents applicable to the quality control and batch testing of vaccines and biotherapeutics.

Integrating 3Rs approaches in WHO guidelines for the batch release testing of biologicals.

Animal testing has long been integral to the development of biologicals, including vaccines. The use of animals can provide important information on potential toxicity, insights into their mechanism of action, pharmacokinetics and dynamics, physiologic distribution, and potency. However, the use of these same methods is often adopted into the post-licensure phase of the product life cycle for the monitoring of product qualities, such as potency or safety, as part of their routine batch release. The UK National Centre for the Replacement, Refinement, and Reduction of Animals in Research (NC3Rs) and the World Health Organization (WHO) are collaborating on a project to review animal-based testing methods described in WHO manuals, guidelines and recommendations for biologicals to identify where updates can lead to a more harmonised adoption of 3Rs principles (i.e. Replacement, Reduction, and Refinement of animal tests) in batch release testing requirements. An international working group consisting of more than 30 representatives from pharmaceutical and biotechnology companies, national control laboratories and regulatory bodies is performing this review. This project aims to address concerns about inconsistencies in the guidance for the scientifically justified use of animal methods required for the post-licensure quality control and batch release testing of biologicals, and the near absence of recommendations for the application of 3Rs principles within the relevant guidelines. Improved adoption of 3Rs principles and non-animal testing strategies will help to reduce the delays and costs associated with product release testing and help support faster access to products by the global communities who need them most urgently.

Is myocardial repolarization duration associated with repolarization heterogeneity?

BACKGROUND: Dispersion of repolarization is theorized as one mechanism by which myocardial repolarization prolongation causes lethal torsades de pointes, (TdP). Our primary purpose was to determine whether prolongation of myocardial repolarization as measured by the heart rate-corrected J-to-T peak interval (JTpkc), is associated with repolarization heterogeneity as measured by transmural dispersion, defined as the median duration from the peak to the end of the T wave (TpTe). METHODS: A retrospective cohort study was performed at a single urban tertiary ED from July 2011-September 2012. Inclusion criteria included all consecutive ED patients with ECG based on QTc and QRS intervals. Automated measurements of all intervals were performed. The association of JTpkc with the dependent variable TpTe was assessed after adjustment for QRS and RR interval durations with a multiple linear regression model. A secondary analysis included a similar adjusted assessment of the association of JTpkc with QT dispersion, QTd. Finally, we constructed two multiple regression models to assess the association of clinical causative factors of TdP with TpTe and JTpkc. RESULTS: Eight hundred seventy-four cases were included: 186 with QTc <500 ms, 118 with QTc ≥500 and QRS ≥120 ms, and 570 with QTc ≥500 and QRS <120 ms. The coefficient for association of JTpkc with TpTe was -0.10 (95%CI -0.15 to -0.05), and for JTpkc with QTd was 0.03 (95% CI -0.01 to 0.06). Clinical causative TdP factors were associated more with JTpkc than TpTe. CONCLUSION: Repolarization duration as measured by JTpkc is not positively associated with dispersion of repolarization as measured by TpTe or QTd. Dispersion of repolarization may not be a critical mechanistic link between QTc prolongation and TdP.

Percutaneous versus surgical cut-down access in transfemoral transcatheter aortic valve replacement: A meta-analysis.

BACKGROUND: The transfemoral (TF) approach has become the preferred approach for transcatheter aortic valve replacement (TAVR) because of its low risk profile. However, the relative safety of the percutaneous approach (PC) compared to surgical cut-down (SC) remains unclear. Our aim was to compare the outcomes between PC versus SC access in patients undergoing TF-TAVR using a meta-analysis. METHODS: We conducted a systematic electronic database search for studies reporting major and minor vascular complications (VC), major and minor bleeding, and perioperative all-cause mortality, in PC versus SC TF-TAVR cases. Complications were reported based on the Valve Academic Research Consortium criteria. A random-effects model was used to calculate odds ratios and 95% confidence intervals. RESULTS: Eight observational cohort studies and one randomized control trial (2513 patients in PC and 1767 patients in SC) were included in the analysis. Major and minor VC, as well as bleeding complications, were comparable between the two approaches. The need for surgical intervention for VC was comparable between PC and SC. There was no difference in perioperative all-cause mortality. CONCLUSIONS: PC and SC have similar safety profiles and outcomes when used appropriately in selected patients.

Impact of transcatheter aortic valve implantation on left atrial appendage flow velocities.

PURPOSE: Left atrial appendage (LAA) flow velocity has not been extensively studied in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI). The aim of this study was to assess the impact of TAVI on LAA flow velocity. METHODS: Medical records of consecutive TAVI recipients were reviewed retrospectively. Patients with persistent atrial fibrillation were excluded. LAA velocities were measured before and after TAVI by transesophageal echocardiography. RESULTS: Sixty-one patients were included. Mean LAA emptying (EV) and filling (FV) flow velocity before TAVI were 33 ± 16 cm/s and 31 ± 14 cm/s, respectively. They increased to 37 ± 20 (p = 0.0036) and 33 ± 13 cm/s (p = 0.047) after TAVI in the whole population sample, but not in patients with normal flow AS. In low-flow, low-gradient (LFLG) AS patients, EV and FV increased from 36 ± 22 to 47 ± 30 cm/s (p < 0.01), and from 29 ± 12 to 40 ± 15 cm/s (p < 0.01), respectively, after TAVI. There was no difference between normal flow and LFLG AS patients in the number of patients who achieved EV ≥ 40 cm/s post-TAVI (35% versus 47%, p = 0.54, respectively). CONCLUSIONS: LAA EV and FV were low prior to TAVI and increased significantly after TAVI only in patients with LFLG AS. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound 44:375-382, 2016.

Iatrogenic Ventricular Septal Defect Following Transcatheter Aortic Valve Replacement: A Systematic Review.

BACKGROUND: Ventricular septal defects (VSD) are rarely reported as a complication following transcatheter aortic valve replacement (TAVR). We sought to characterise the patients, clinical management, and outcomes regarding this rare phenomenon. METHODS: Relevant articles were identified by a systematic search of MEDLINE and EMBASE databases from January, 2002 to September, 2015. RESULTS: A total of 18 case reports, including 20 patients, were identified. The median age was 83 years and six were male. Twelve were performed by trans-femoral approach. Pre-dilation was performed in 12 patients and post-dilation in four. Balloon expandable valves were used in the majority (85%) of cases. The clinical presentation varied from asymptomatic to progressive heart failure. The timing of the diagnosis also varied significantly from immediately post valve implantation to one year afterwards. There were two cases of Gerbode-type defect while the rest were inter-ventricular defects. The location was mostly membranous or perimembranous (79%) and adjacent to the valve landing zone. A total of seven interventions (one open surgery and six percutaneous closure) were performed. Four patients died during the same hospital admission. Sixteen survived past discharge (range 12 days to two years). CONCLUSIONS: Ventricular septal defects post-TAVR were seen more with balloon expandable valves and with pre-dilation or post-dilation. Percutaneous treatment of the VSD was preferred over open cardiac surgery given the high surgical risk in this patient population. Some, but not all, patients survived TAVR and VSD and had a good prognosis for both patient groups with or without VSD closure.

Human tissue models for a human disease: what are the barriers?

Asthma represents an area of significant unmet medical need, with few new drugs making it to the clinic in the past 50 years. Much asthma research is currently carried out in non-human models. However, as asthma is a uniquely human condition, it is difficult to translate findings from these models to efficacious therapies. Based on the results of a survey of the UK asthma research community carried out jointly between the NC3Rs, Asthma UK, the UK Respiratory Research Collaborative and the Human Tissue Authority, we propose that more emphasis be placed on the use of human tissue studies to provide more relevant models that better translate to the clinic and which reduce the reliance of the asthma community on less predictive animal models.

Midline Cleft Lip and Bifid Nose Deformity: Description, Classification, and Treatment.

BACKGROUND: Midline facial clefts are rare and challenging deformities caused by failure of fusion of the medial nasal prominences. These anomalies vary in severity, and may include microform lines or midline lip notching, incomplete or complete labial clefting, nasal bifidity, or severe craniofacial bony and soft tissue anomalies with orbital hypertelorism and frontoethmoidal encephaloceles. In this study, the authors present 4 cases, classify the spectrum of midline cleft anomalies, and review our technical approaches to the surgical correction of midline cleft lip and bifid nasal deformities. Embryology and associated anomalies are discussed. METHODS: The authors retrospectively reviewed our experience with 4 cases of midline cleft lip with and without nasal deformities of varied complexity. In addition, a comprehensive literature search was performed, identifying studies published relating to midline cleft lip and/or bifid nose deformities. Our assessment of the anomalies in our series, in conjunction with published reports, was used to establish a 5-tiered classification system. Technical approaches and clinical reports are described. RESULTS: Functional and aesthetic anatomic correction was successfully achieved in each case without complication. A classification and treatment strategy for the treatment of midline cleft lip and bifid nose deformity is presented. CONCLUSIONS: The successful treatment of midline cleft lip and bifid nose deformities first requires the identification and classification of the wide variety of anomalies. With exposure of abnormal nasolabial anatomy, the excision of redundant skin and soft tissue, anatomic approximation of cartilaginous elements, orbicularis oris muscle repair, and craniofacial osteotomy and reduction as indicated, a single-stage correction of midline cleft lip and bifid nasal deformity can be safely and effectively achieved.