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KCNQ1 suppression-replacement gene therapy in transgenic rabbits with type 1 long QT syndrome.
Get PDFBACKGROUND AND AIMS
Type 1 long QT syndrome (LQT1) is caused by pathogenic variants in the KCNQ1-encoded Kv7.1 potassium channels, which pathologically prolong ventricular action potential duration (APD). Herein, the pathologic phenotype in transgenic LQT1 rabbits is rescued using a novel KCNQ1 suppression-replacement (SupRep) gene therapy.
METHODS
KCNQ1-SupRep gene therapy was developed by combining into a single construct a KCNQ1 shRNA (suppression) and an shRNA-immune KCNQ1 cDNA (replacement), packaged into adeno-associated virus serotype 9, and delivered in vivo via an intra-aortic root injection (1E10 vg/kg). To ascertain the efficacy of SupRep, 12-lead electrocardiograms were assessed in adult LQT1 and wild-type (WT) rabbits and patch-clamp experiments were performed on isolated ventricular cardiomyocytes.
RESULTS
KCNQ1-SupRep treatment of LQT1 rabbits resulted in significant shortening of the pathologically prolonged QT index (QTi) towards WT levels. Ventricular cardiomyocytes isolated from treated LQT1 rabbits demonstrated pronounced shortening of APD compared to LQT1 controls, leading to levels similar to WT (LQT1-UT vs. LQT1-SupRep, P < .0001, LQT1-SupRep vs. WT, P = ns). Under β-adrenergic stimulation with isoproterenol, SupRep-treated rabbits demonstrated a WT-like physiological QTi and APD90 behaviour.
CONCLUSIONS
This study provides the first animal-model, proof-of-concept gene therapy for correction of LQT1. In LQT1 rabbits, treatment with KCNQ1-SupRep gene therapy normalized the clinical QTi and cellular APD90 to near WT levels both at baseline and after isoproterenol. If similar QT/APD correction can be achieved with intravenous administration of KCNQ1-SupRep gene therapy in LQT1 rabbits, these encouraging data should compel continued development of this gene therapy for patients with LQT1
Correction to: Patterns of airway obstruction of non-acquired origin in children with and without major congenital anomalies.
Get PDFEngineering the future of 3D pathology.
No full textIn recent years, technological advances in tissue preparation, high-throughput volumetric microscopy, and computational infrastructure have enabled rapid developments in nondestructive 3D pathology, in which high-resolution histologic datasets are obtained from thick tissue specimens, such as whole biopsies, without the need for physical sectioning onto glass slides. While 3D pathology generates massive datasets that are attractive for automated computational analysis, there is also a desire to use 3D pathology to improve the visual assessment of tissue histology. In this perspective, we discuss and provide examples of potential advantages of 3D pathology for the visual assessment of clinical specimens and the challenges of dealing with large 3D datasets (of individual or multiple specimens) that pathologists have not been trained to interpret. We discuss the need for artificial intelligence triaging algorithms and explainable analysis methods to assist pathologists or other domain experts in the interpretation of these novel, often complex, large datasets
Management of swallowing disorders in ICU patients - A multinational expert opinion.
Get PDFBACKGROUND
Dysphagia is common in intensive care unit (ICU) patients, yet it remains underrecognized and often unmanaged despite being associated with life-threatening complications, prolonged ICU stays and hospitalization.
PURPOSE
To propose an expert opinion for the diagnosis and management of dysphagia developed from evidence-based clinical recommendations and practitioner insights.
METHODS
A multinational group of dysphagia and critical care experts conducted a literature review using a modified ACCORD methodology. Based on a fusion of the available evidence and the panel's clinical experience, an expert opinion on best practice management was developed.
RESULTS
The panel recommends adopting clinical algorithms intended to promote standardized, high-quality care that triggers timely systematic dysphagia screening, assessment, and treatment of extubated and tracheostomized patients in the ICU.
CONCLUSIONS
Given the lack of robust scientific evidence, two clinical management algorithms are proposed for use by multidisciplinary teams to improve early systematic detection and effective management of dysphagia in ICU patients. Additionally, emerging therapeutic options such as neurostimulation have the potential to improve the quality of ICU dysphagia care
Can lung airway geometry be used to predict autism? A preliminary machine learning-based study.
No full textThe goal of this study is to assess the feasibility of airway geometry as a biomarker for autism spectrum disorder (ASD). Chest computed tomography images of children with a documented diagnosis of ASD as well as healthy controls were identified retrospectively. Fifty-four scans were obtained for analysis, including 31 ASD cases and 23 controls. A feature selection and classification procedure using principal component analysis and support vector machine achieved a peak cross validation accuracy of nearly 89% using a feature set of eight airway branching angles. Sensitivity was 94%, but specificity was only 78%. The results suggest a measurable difference in airway branching angles between children with ASD and the control population
Relationship between multimorbidity, functional limitation, and quality of life among middle-aged and older adults: findings from the longitudinal analysis of the 2013-2020 Survey of Health, Ageing, and Retirement in Europe (SHARE).
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The increased burden of multimorbidity is restricting individuals' ability to live autonomously, leading to a poorer quality of life. This study estimated trajectories of functional limitation and quality of life among middle-aged (ages 50 to 64 years) and older (aged 65 years and older) individuals with and without multimorbidity. We also assessed differences in the relationship between these two trajectories by multimorbidity status and separately for each age cohort.
METHODS
Data originated from the Survey of Health, Ageing, and Retirement in Europe (SHARE). In Luxembourg, data were obtained between 2013 and 2020, involving 1,585 respondents ≥ 50 years of age. Multimorbidity was defined as a self-reported diagnosis of two or more out of 16 chronic conditions; functional limitation was assessed by a combined (Instrumental) Activities of Daily Living (ADL/IADLI) scale; and to measure quality of life, we used the Control, Autonomy, Self-Realization, and Pleasure (CASP-12) scale. Latent growth curve modelling techniques were used to conduct the analysis where repeated measures of quality of life and functional limitation were treated as continuous and zero-inflated count variables, respectively. The model was assessed separately in each age cohort, controlling for the baseline covariates, and the estimates from the two cohorts were presented as components of a synthetic cohort covering the life course from the age of 50.
RESULTS
Middle-aged and older adults living with multimorbidity experienced poorer quality of life throughout the life course and were at a higher risk of functional limitation than those without multimorbidity. At baseline, functional limitation had a negative impact on quality of life. Furthermore, among middle-aged adults without multimorbidity and older adults with multimorbidity, an increase in the number of functional limitations led to a decline in quality of life. These results imply that the impact of multimorbidity on functional limitation and quality of life may vary across the life course.
CONCLUSION
Using novel methodological techniques, this study contributes to a better understanding of the longitudinal relationship between functional limitation and quality of life among individuals with and without multimorbidity and how this relationship changes across the life course. Our findings suggest that lowering the risk of having multimorbidity can decrease functional limitation and increase quality of life
Pre-emptive TIPS in high-risk acute variceal bleeding. An updated and revised individual patient data meta-analysis.
No full textBACKGROUND AIMS
A previous individual patient data meta-analysis (IPD-MA) showed that compared with drugs+endoscopy, placement of transjugular portosystemic shunt within 72 hrs of admission (preemptive TIPS: p-TIPS) increases the survival of high-risk patients (Child-Pugh B+active bleeding and Child-Pugh C<14points) with cirrhosis and acute variceal bleeding (AVB). However, previous IPD-MA was not a two-stage MA, did not take into consideration the potential risk of selection bias of observational studies, and did not include the most recent RCT. We performed an updated and revised IPD-MA to reassess the efficacy of p-TIPS addressing all previous issues.
APPROACH RESULTS
We included all studies from the previous IPD-MA and searched for other possible eligible publications until September 2022. We performed a two-stage IPD-MA of data from 8 studies (4 RCTs and 4 observational). In addition, we performed a sensitivity analysis excluding those patients dying up to the first 72 hours after admission, in the Drugs+Endoscopy arms of the 4 observational studies. The primary endpoint was the effects of p-TIPS versus Drugs+Endoscopy on 1-year survival.We identified 1389 patients (342 p-TIPS and 1047 Drugs+Endoscopy). The two-stage IPD-MA, showed that p-TIPS significantly reduced the mortality in overall population, HR=0·43, 95% CI 0·32-0·60, p<0·001. This effect was observed in both subgroups of Child-Pugh patients. The sensitivity analysis, confirmed the survival benefit of p-TIPS.
CONCLUSIONS
The updated two-stage IPD-MA confirms the significant survival advantage of p-TIPS in high-risk patients with cirrhosis and AVB. As a result, we recommend p-TIPS as the preferred first-choice treatment for these patients
Re: Jakob Klemm, Michael Rink, Markus von Deimling, et al. Time-to-complication Patterns After Radical Cystectomy: A Secondary Analysis of a 30-day Morbidity Assessment Using the European Association of Urology Quality Criteria for Standardized Reporting. Eur Urol Focus. In press. https://doi.org/10.1016/j.euf.2023.06.005.
No full textLong-term quantitative hepatitis B surface antigen (HBsAg) trajectories in persons with and without HBsAg loss on tenofovir-containing antiretroviral therapy.
No full textOBJECTIVES
Improving the understanding of the patterns of quantitative hepatitis B surface antigen (qHBsAg) trajectories associated with HBsAg loss is important in light of novel anti-hepatitis B virus agents being developed. We evaluated long-term qHBsAg trajectories in persons with HIV and HBV during tenofovir-containing antiretroviral therapy in the Swiss HIV Cohort Study.
METHODS
We included 29 participants with and 29 without HBsAg loss, defined as qHBsAg <0.05 IU/mL. We assessed qHBsAg decline during therapy in both groups and used agglomerative hierarchical clustering to identify different qHBsAg trajectory profiles in persons with HBsAg loss.
RESULTS
The median follow-up time was 11.9 years (IQR 8.4-14.1), and the median time to HBsAg loss was 48 months (IQR 12-96). Among participants with HBsAg loss, 79% had a qHBsAg decline ≥1 log10 IU/mL 2 years after starting tenofovir. The trajectories in qHBsAg levels during tenofovir therapy were heterogeneous, characterized by five distinct profiles. Among participants without HBsAg loss, only 7% had a qHBsAg decline ≥1 log10 IU/ml after 2 years.
CONCLUSIONS
Most persons with HIV who experienced HBsAg loss had an early decline in qHBsAg levels, with diverse trajectories during long-term tenofovir therapy. In persons without HBsAg loss, qHBsAg levels remained remarkably stable over time
Evaluation of the Rotational Stability of Directional Deep Brain Stimulation Leads: A Case Series and Systematic Review.
No full textBACKGROUND
The rotational stability of directional deep brain stimulation leads is a major prerequisite for sustained clinical effects. Data on directional lead stability are limited and controversial.
METHODS
We aimed to evaluate the long-term rotational stability of directional leads and define confounding factors in our own population and the current literature. We retrospectively evaluated the orientation of directional leads in patients with available postoperative computed tomography (CT; T1; day of surgery) and an additional postoperative image (T2; CT or rotational fluoroscopy) performed more than 7 days after the initial scan. The potential impact of intracranial air was assessed. We also reviewed the literature to define factors impacting stability.
RESULTS
Thirty-six leads were evaluated. The mean follow-up between T1 and T2 was 413.3 (7-1,171) days. The difference in rotation between T1 and T2 was 2.444 ± 2.554 degrees (range: 0-9.0 degrees). The volume of intracranial air did not impact the rotation. The literature search identified one factor impacting the stability of directional leads, which is the amount of twist applied at implantation.
CONCLUSION
Directional leads for deep brain stimulation show stable long-term orientation after implantation. Based on our literature review, large amounts of twist during implantation can lead to delayed rotation and should thus be avoided
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