Translational design for limited resource settings as demonstrated by Vent-Lock, a 3D-printed ventilator multiplexer

BACKGROUND: Mechanical ventilators are essential to patients who become critically ill with acute respiratory distress syndrome (ARDS), and shortages have been reported due to the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: We utilized 3D printing (3DP) technology to rapidly prototype and test critical components for a novel ventilator multiplexer system, Vent-Lock, to split one ventilator or anesthesia gas machine between two patients. FloRest, a novel 3DP flow restrictor, provides clinicians control of tidal volumes and positive end expiratory pressure (PEEP), using the 3DP manometer adaptor to monitor pressures. We tested the ventilator splitter circuit in simulation centers between artificial lungs and used an anesthesia gas machine to successfully ventilate two swine. RESULTS: As one of the first studies to demonstrate splitting one anesthesia gas machine between two swine, we present proof-of-concept of a de novo, closed, multiplexing system, with flow restriction for potential individualized patient therapy. CONCLUSIONS: While possible, due to the complexity, need for experienced operators, and associated risks, ventilator multiplexing should only be reserved for urgent situations with no other alternatives. Our report underscores the initial design and engineering considerations required for rapid medical device prototyping via 3D printing in limited resource environments, including considerations for design, material selection, production, and distribution. We note that optimization of engineering may minimize 3D printing production risks but may not address the inherent risks of the device or change its indications. Thus, our case report provides insights to inform future rapid prototyping of medical devices

The PROVENT-C19 registry: A study protocol for international multicenter SIAARTI registry on the use of prone positioning in mechanically ventilated patients with COVID-19 ARDS

Background The worldwide use of prone position (PP) for invasively ventilated patients with COVID-19 is progressively increasing from the first pandemic wave in everyday clinical practice. Among the suggested treatments for the management of ARDS patients, PP was recommended in the Surviving Sepsis Campaign COVID-19 guidelines as an adjuvant therapy for improving ventilation. In patients with severe classical ARDS, some authors reported that early application of prolonged PP sessions significantly decreases 28-day and 90-day mortality. Methods and analysis Since January 2021, the COVID19 Veneto ICU Network research group has developed and implemented nationally and internationally the "PROVENT-C19 Registry", endorsed by the Italian Society of Anesthesia Analgesia Resuscitation and Intensive Care. . .'(SIAARTI). The PROVENT-C19 Registry wishes to describe 1. The real clinical practice on the use of PP in COVID-19 patients during the pandemic at a National and International level; and 2. Potential baseline and clinical characteristics that identify subpopulations of invasively ventilated patients with COVID-19 that may improve daily from PP therapy. This web-based registry will provide relevant information on how the database research tools may improve our daily clinical practice. Conclusions This multicenter, prospective registry is the first to identify and characterize the role of PP on clinical outcome in COVID-19 patients. In recent years, data emerging from large registries have been increasingly used to provide real-world evidence on the effectiveness, quality, and safety of a clinical intervention. Indeed observation-based registries could be effective tools aimed at identifying specific clusters of patients within a large study population with widely heterogeneous clinical characteristics. Copyright

Next generation sequencing‐based copy number analysis reveals low prevalence of deletions and duplications in 46 genes associated with genetic cardiomyopathies

Abstract Background: Diagnostic testing for genetic cardiomyopathies has undergone dramatic changes in the last decade with next generation sequencing (NGS) expanding the number of genes that can be interrogated simultaneously. Exon resolution copy number analysis is increasingly incorporated into routine diagnostic testing via cytogenomic arrays and more recently via NGS. While NGS is an attractive option for laboratories that have no access to array platforms, its higher false positive rate requires weighing the added cost incurred by orthogonal confirmation against the magnitude of the increase in diagnostic yield. Although copy number variants (CNVs) have been reported in various cardiomyopathy genes, their contribution has not been systematically studied. Methods: We performed single exon resolution NGS‐based deletion/duplication analysis for up to 46 cardiomyopathy genes in >1400 individuals with cardiomyopathies including HCM, DCM, ARVC, RCM, and LVNC. Results and Conclusion Clinically significant deletions and duplications were identified in only 9 of 1425 (0.63%) individuals. The majority of those (6/9) represented intragenic events. We conclude that the added benefit of exon level deletion/duplication analysis is low for currently known cardiomyopathy genes and may not outweigh the increased cost and complexity of incorporating it into routine diagnostic testing for these disorders

Explorative studies of an innovative superconducting gantry

The Heavy Ion Therapy Research Integration plus (HITRIplus) is an European project that aims to integrate and propel research and technologies related to cancer treatment with heavy ion beams. Among the ambitious goals of the project, a specific work package includes the design of a gantry for carbon ions, based on superconducting magnets. The first milestone to achieve is the choice of the fundamental gantry parameters, namely the beam optics layout, the superconducting magnet technology, and the main user requirements. Starting from a reference 3 T design, the collaboration widely explored dozens of possible gantry configurations at 4 T, aiming to find the best compromise in terms of footprint, capital cost, and required R&D. We present here a summary of these configurations, underlying the initial correlation between the beam optics, the mechanics and the main superconducting dipoles design: the bending field (up to 4 T), combined function features (integrated quadrupoles), magnet aperture (up to 90 mm), and angular length (30° – 45°). The resulting main parameters are then listed, compared, and used to drive the choice of the best gantry layout to be developed in HITRIplus. © 2023 Institute of Physics Publishing

Explorative Studies of an Innovative Superconducting Gantry

The Heavy Ion Therapy Research Integration plus (HITRIplus) is a European project that aims to integrate and propel research and technologies related to cancer treatment with heavy ions beams. Among the ambitious goals of the project, a specific work package includes the design of a gantry for carbon ions, based on superconducting magnets. The first milestone to achieve is the choice of the fundamental gantry parameters, namely the beam optics layout, the superconducting magnet technology, and the main user requirements. Starting from a reference 3T design, the collaboration widely explored dozens of possible gantry configurations at 4T, aiming to find the best compromise in terms of footprint, capital cost, and required R&D.; We present here a summary of these configurations, underlying the initial correlation between the beam optics, the mechanics, and the main superconducting dipoles design: the bending field (up to 4 T), combined function features (integrated quadrupole), magnet aperture (up to 90 mm), and angular length (30°-45°). The resulting main parameters are then listed, compared, and used to drive the choice of the best gantry layout to be developed in HITRIplus

Gene transfer of human acid sphingomyelinase corrects neuropathology and motor deficits in a mouse model of Niemann-Pick type A disease

Niemann-Pick type A disease is a lysosomal storage disorder caused by a deficiency in acid sphingomyelinase (ASM) activity. Previously we showed that storage pathology in the ASM knockout (ASMKO) mouse brain can be corrected by adeno-associated virus serotype 2 (AAV2)-mediated gene transfer. The present experiment compared the relative therapeutic efficacy of different recombinant AAV serotype vectors (1, 2, 5, 7, and 8) using histological, biochemical, and behavioral endpoints. In addition, we evaluated the use of the deep cerebellar nuclei (DCN) as a site for injection to facilitate global distribution of the viral vector and enzyme. Seven-week-old ASM knockout mice were injected within the DCN with different AAV serotype vectors encoding human ASM (hASM) and then killed at either 14 or 20 weeks of age. Results showed that AAV1 was superior to serotypes 2, 5, 7, and 8 in its relative ability to express hASM, alleviate storage accumulation, and correct behavioral deficits. Expression of hASM was found not only within the DCN, but also throughout the cerebellum, brainstem, midbrain, and spinal cord. This finding demonstrates that targeting the DCN is an effective approach for achieving widespread enzyme distribution throughout the CNS. Our results support the continued development of AAV based vectors for gene therapy of the CNS manifestations in Niemann-Pick type A disease