Current understanding of and emerging treatment options for spinal muscular atrophy with respiratory distress type 1 (SMARD1).

Spinal muscular atrophy (SMA) with respiratory distress type 1 (SMARD1) is an autosomal recessive motor neuron disease that is characterized by distal and proximal muscle weakness and diaphragmatic palsy that leads to respiratory distress. Without intervention, infants with the severe form of the disease die before 2 years of age. SMARD1 is caused by mutations in the IGHMBP2 gene that determine a deficiency in the encoded IGHMBP2 protein, which plays a critical role in motor neuron survival because of its functions in mRNA processing and maturation. Although it is rare, SMARD1 is the second most common motor neuron disease of infancy, and currently, treatment is primarily supportive. No effective therapy is available for this devastating disease, although multidisciplinary care has been an essential element of the improved quality of life and life span extension in these patients in recent years. The objectives of this review are to discuss the current understanding of SMARD1 through a summary of the presently known information regarding its clinical presentation and pathogenesis and to discuss emerging therapeutic approaches. Advances in clinical care management have significantly extended the lives of individuals affected by SMARD1 and research into the molecular mechanisms that lead to the disease has identified potential strategies for intervention that target the underlying causes of SMARD1. Gene therapy via gene replacement or gene correction provides the potential for transformative therapies to halt or possibly prevent neurodegenerative disease in SMARD1 patients. The recent approval of the first gene therapy approach for SMA associated with mutations in the SMN1 gene may be a turning point for the application of this strategy for SMARD1 and other genetic neurological diseases.

Effect of frequency on pressure cost of ventilation and gas exchange in newborns receiving high-frequency oscillatory ventilation.

BackgroundWe hypothesized that ventilating at the resonant frequency of the respiratory system optimizes gas exchange while limiting the mechanical stress to the lung in newborns receiving high-frequency oscillatory ventilation (HFOV). We characterized the frequency dependence of oscillatory mechanics, gas exchange, and pressure transmission during HFOV.MethodsWe studied 13 newborn infants with a median (interquartile range) gestational age of 29.3 (26.4-30.4) weeks and body weight of 1.00 (0.84-1.43) kg. Different frequencies (5, 8, 10, 12, and 15 Hz) were tested, keeping carbon dioxide diffusion coefficient (DCO2) constant. Oscillatory mechanics and transcutaneous blood gas were measured at each frequency. The attenuation of pressure swings (ΔP) from the airways opening to the distal end of the tracheal tube (TT) and to the alveolar compartment was mathematically estimated.ResultsBlood gases were unaffected by frequency. The mean (SD) resonant frequency was 16.6 (3.5) Hz. Damping of ΔP increased with frequency and with lung compliance. ΔP at the distal end of the TT was insensitive to frequency, whereas ΔP at the peripheral level decreased with frequency.ConclusionThere is no optimal frequency for gas exchange when DCO2 is held constant. Greater attenuation of oscillatory pressure at higher frequencies offers more protection from barotrauma, especially in patients with poor compliance.

Brachial Tunneled Peripherally Inserted Central Catheters and the Risk of Catheter Complications: A Systematic Review and Meta-Analysis.

INTRODUCTION: Situations involving increased workloads and stress (i.e., the COVID-19 pandemic) underline the need for healthcare professionals to minimize patient complications. In the field of vascular access, tunneling techniques are a possible solution. This systematic review and meta-analysis aimed to compare the effectiveness of tunneled Peripherally Inserted Central Catheters (tPICCs) to conventional Peripherally Inserted Central Catheters (cPICCs) in terms of bleeding, overall success, procedural time, and late complications. METHODS: Randomized controlled trials without language restrictions were searched using PUBMED®, EMBASE®, EBSCO®, CINAHL®, and the Cochrane Controlled Clinical Trials Register from August 2022 to August 2023. Five relevant papers (1238 patients) were included. RESULTS: There were no significant differences in overall success and nerve or artery injuries between the two groups (p = 0.62 and p = 0.62, respectively), although cPICCs caused slightly less bleeding (0.23 mL) and had shorter procedural times (2.95 min). On the other hand, tPICCs had a significantly reduced risk of overall complications (p < 0.001; RR0.41 [0.31-0.54] CI 95%), catheter-related thrombosis (p < 0.001; RR0.35 [0.20-0.59] IC 95%), infection-triggering catheter removal (p < 0.001; RR0.33 [0.18-0.61] IC 95%), wound oozing (p < 0.001; RR0.49 [0.37-0.64] IC 95%), and dislodgement (p < 0.001; RR0.4 [0.31-0.54] CI 95%). CONCLUSIONS: The tunneling technique for brachial access appears to be safe concerning intra-procedural bleeding, overall success, and procedural time, and it is effective in reducing the risk of late complications associated with catheterization.

Clinical risk scores for the early prediction of severe outcomes in patients hospitalized for COVID-19.

Coronavirus disease of 2019 (COVID-19) is associated with severe acute respiratory failure. Early identification of high-risk COVID-19 patients is crucial. We aimed to derive and validate a simple score for the prediction of severe outcomes. A retrospective cohort study of patients hospitalized for COVID-19 was carried out by the Italian Society of Internal Medicine. Epidemiological, clinical, laboratory, and treatment variables were collected at hospital admission at five hospitals. Three algorithm selection models were used to construct a predictive risk score: backward Selection, Least Absolute Shrinkage and Selection Operator (LASSO), and Random Forest. Severe outcome was defined as the composite of need for non-invasive ventilation, need for orotracheal intubation, or death. A total of 610 patients were included in the analysis, 313 had a severe outcome. The subset for the derivation analysis included 335 patients, the subset for the validation analysis 275 patients. The LASSO selection identified 6 variables (age, history of coronary heart disease, CRP, AST, D-dimer, and neutrophil/lymphocyte ratio) and resulted in the best performing score with an area under the curve of 0.79 in the derivation cohort and 0.80 in the validation cohort. Using a cut-off of 7 out of 13 points, sensitivity was 0.93, specificity 0.34, positive predictive value 0.59, and negative predictive value 0.82. The proposed score can identify patients at low risk for severe outcome who can be safely managed in a low-intensity setting after hospital admission for COVID-19.

R-Loops in Motor Neuron Diseases.

R loops are transient three-stranded nucleic acid structures that form physiologically during transcription when a nascent RNA transcript hybridizes with the DNA template strand, leaving a single strand of displaced nontemplate DNA. However, aberrant persistence of R-loops can cause DNA damage by inducing genomic instability. Indeed, evidence has emerged that R-loops might represent a key element in the pathogenesis of human diseases, including cancer, neurodegeneration, and motor neuron disorders. Mutations in genes directly involved in R-loop biology, such as SETX (senataxin), or unstable DNA expansion eliciting R-loop generation, such as C9ORF72 HRE, can cause DNA damage and ultimately result in motor neuron cell death. In this review, we discuss current advancements in this field with a specific focus on motor neuron diseases associated with deregulation of R-loop structures. These mechanisms can represent novel therapeutic targets for these devastating, incurable diseases.