Genuine DNA/polyethylenimine (PEI) Complexes Improve Transfection Properties and Cell Survival

Polyethylenimine (PEI) has been described as one of the most efficient cationic polymers for in vitro gene delivery. Systemic delivery of PEI/DNA polyplexes leads to a lung-expression tropism. Selective in vivo gene transfer would require targeting and stealth particles. Here, we describe two strategies for chemically coupling polyethylene glycol (PEG) to PEI, to form protected ligand-bearing particles. Pre-grafted PEG–PEI polymers lost their DNA condensing property, hence their poor performances. Coupling PEG to pre-formed PEI/DNA particles led to the expected physical properties. However, low transfection efficacies raised the question of the fate of excess free polymer in solution. We have developed a straightforward a purification assay, which uses centrifugation-based ultrafiltration. Crude polyplexes were purified, with up to 60% of the initial PEI dose being removed. The resulting purified and unshielded PEI/DNA polyplexes are more efficient for transfection and less toxic to cells in culture than the crude ones. Moreover, the in vivo toxicity of the polyplexes was greatly reduced, without affecting their efficacy

Blood myo-inositol concentrations in preterm and term infants

Objective: To describe relationship between cord blood (representing fetal) myo-inositol concentrations and gestational age (GA) and to determine trends of blood concentrations in enterally and parenterally fed infants from birth to 70 days of age. Design/methods: Samples were collected in 281 fed or unfed infants born in 2005 and 2006. Myo-inositol concentrations were displayed in scatter plots and analyzed with linear regression models of natural log-transformed values. Results: In 441 samples obtained from 281 infants, myo-inositol concentrations varied from nondetectable to 1494 μmol/L. Cord myo-inositol concentrations decreased an estimated 11.9% per week increase in GA. Postnatal myo-inositol concentrations decreased an estimated 14.3% per week increase in postmenstrual age (PMA) and were higher for enterally fed infants compared to unfed infants (51% increase for fed vs. unfed infants). Conclusions: Fetal myo-inositol concentrations decreased with increasing GA. Postnatal concentrations decreased with increasing PMA and were higher among enterally fed than unfed infants

Analysis of shared heritability in common disorders of the brain

ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders

Cuffed versus uncuffed endotracheal tubes for neonates

Background: Endotracheal intubation is a commonly performed procedure in neonates, the risks of which are well-described. Some endotracheal tubes (ETT) are equipped with a cuff that can be inflated after insertion of the ETT in the airway to limit leak or aspiration. Cuffed ETTs have been shown in larger children and adults to reduce gas leak around the ETT, ETT exchange, accidental extubation, and exposure of healthcare workers to anesthetic gas during surgery. With improved understanding of neonatal airway anatomy and the widespread use of cuffed ETTs by anesthesiologists, the use of cuffed tubes is increasing in neonates. Objectives: To assess the benefits and harms of cuffed ETTs (inflated or non-inflated) compared to uncuffed ETTs for respiratory support in neonates. Search methods: We searched CENTRAL, PubMed, and CINAHL on 20 August 2021; we also searched trial registers and checked reference lists to identify additional studies. Selection criteria: We included randomized controlled trials (RCTs), quasi-RCTs, and cluster-randomized trials comparing cuffed (inflated and non-inflated) versus uncuffed ETTs in newborns. We sought to compare 1. inflated, cuffed versus uncuffed ETT; 2. non-inflated, cuffed versus uncuffed ETT; and 3. inflated, cuffed versus non-inflated, cuffed ETT. Data collection and analysis: We used the standard methods of Cochrane Neonatal. Two review authors independently assessed studies identified by the search strategy for inclusion, extracted data, and assessed risk of bias. We used the GRADE approach to assess the certainty of evidence. Main results: We identified one eligible RCT for inclusion that compared the use of cuffed (inflated if ETT leak greater than 20% with cuff pressure 20 cm H2O or less) versus uncuffed ETT. The author provided a spreadsheet with individual data. Among 76 infants in the original manuscript, 69 met the inclusion and exclusion criteria for this Cochrane Review. We found possible bias due to lack of blinding and other bias. We are very uncertain about frequency of postextubation stridor, because the confidence intervals (CI) of the risk ratio (RR) were very wide (RR 1.36, 95% CI 0.35 to 5.25; risk difference (RD) 0.03, −0.11 to 0.18; 1 study, 69 participants; very low-certainty evidence). No neonate was diagnosed with postextubation subglottic stenosis; however, endoscopy was not available to confirm the clinical diagnosis. We are very uncertain about reintubation for stridor or subglottic stenosis because the CIs of the RR were very wide (RR 0.27, 95% CI 0.01 to 6.49; RD −0.03, 95% CI −0.11 to 0.05; 1 study, 69 participants; very low-certainty evidence). No neonate had surgical intervention (e.g. endoscopic balloon dilation, cricoid split, tracheostomy) for stridor or subglottic stenosis (1 study, 69 participants). Neonates randomized to cuffed ETT may be less likely to have a reintubation for any reason (RR 0.06, 95% CI 0.01 to 0.45; RD −0.39, 95% CI −0.57 to −0.21; number needed to treat for an additional beneficial outcome 3, 95% CI 2 to 5; 1 study, 69 participants; very low-certainty evidence). We are very uncertain about accidental extubation because the CIs of the RR were wide (RR 0.82, 95% CI 0.12 to 5.46; RD −0.01, 95% CI −0.12 to 0.10; 1 study, 69 participants; very low-certainty evidence). We are very uncertain about all-cause mortality during initial hospitalization because the CIs of the RR were extremely wide (RR 2.46, 95% CI 0.10 to 58.39; RD 0.03, 95% CI −0.05 to 0.10; 1 study, 69 participants; very low-certainty evidence). There is one ongoing trial. We classified two studies as awaiting classification because outcome data were not reported separately for newborns and older infants. Authors' conclusions: Evidence for comparing cuffed versus uncuffed ETTs in neonates is limited by a small number of babies in a single RCT with possible bias. There is very low certainty evidence for all outcomes of this review. CIs of the estimate for postextubation stridor were wide. No neonate had clinical evidence for subglottic stenosis; however, endoscopy results were not available to assess the anatomy. Additional RCTs are necessary to evaluate the benefits and harms of cuffed ETTs (inflated and non-inflated) in the neonatal population. These studies must include neonates and be conducted both for short-term use (in the setting of the operating room) and chronic use (in the setting of chronic lung disease) of cuffed ETTs

Cuffed versus uncuffed endotracheal tubes for neonates

Objectives: This is a protocol for a Cochrane Review (intervention). The objectives are as follows:. To assess the benefits and harms of cuffed endotracheal tubes (ETT) (inflated or non-inflated) compared to uncuffed endotracheal tubes for respiratory support in neonates. We will compare the following comparisons. Cuffed ETT (inflated or not) versus uncuffed ETT: cuffed not inflated versus uncuffed; cuffed inflated versus uncuffed. Cuffed inflated versus cuffed not inflated

Change in maternal BMI during pregnancy for cases and controls.

Change in maternal BMI during pregnancy for cases and controls.</p

A supporting information file containing de-identified raw data used for analysis has been provided and is available upon request.

A supporting information file containing de-identified raw data used for analysis has been provided and is available upon request.</p

Adjusted odds ratio (aOR) of NEC with logistic regression analysis of maternal BMI at delivery.

Adjusted odds ratio (aOR) of NEC with logistic regression analysis of maternal BMI at delivery.</p

Maternal (A) and Infant (B) characteristics of patients with NEC compared to matched controls.

Maternal (A) and Infant (B) characteristics of patients with NEC compared to matched controls.</p

Documented maternal BMI: Pre-pregnancy, at prenatal visits and at delivery.

Documented maternal BMI: Pre-pregnancy, at prenatal visits and at delivery.</p