Comparing Outcomes Between Standard Mepilex and Mepilex Silver for Tracheotomy Dressings.

OBJECTIVE: The purpose of the study is to compare the incidence of early postoperative tracheotomy stoma wound complications in pediatric patients using a silver-impregnated barrier dressing (Mepilex Ag) versus a standard absorbent foam dressing (standard Mepilex). METHODS: This is a prospective, non-blinded, randomized trial of pediatric patients undergoing tracheotomy at a tertiary care children's hospital. Patients were randomized to receive Mepilex Ag versus standard Mepilex tracheostoma dressings following tracheotomy. All patients received standard postoperative wound care and daily stomal examination. Wound related complications, breakdown, granulation, and infection were recorded for the first 7 days after surgery. A non-inferiority study design was used to test the hypothesis that the Mepilex group had a non-inferior wound complication rate (within 10% margin) compared to the Mepilex Ag group. RESULTS: Eighty-two patients were enrolled; 52 received Mepilex Ag, and 30 received standard Mepilex. There was no difference between the groups with respect to age, sex, race, surgical indication, or postoperative length of stay. Non-inferiority testing demonstrated that the Mepilex standard cohort had no more than 10% greater stomal wound complication rate than that of Mepilex Ag dressing group (p = 0.0108). CONCLUSION: Standard Mepilex was found to be non-inferior to Mepilex Ag in the prevention of tracheotomy stomal wound complications. Standard Mepilex may be used effectively in the postoperative period, potentially reducing costs to caregivers and the institution. Further work is needed to analyze additional factors that could contribute to poor postoperative stoma healing such as bacterial colonization. LEVEL OF EVIDENCE: Randomized Controlled Trial, Level 2 Laryngoscope, 2024.

De novo GRIN variants in M3 helix associated with neurological disorders control channel gating of NMDA receptor.

N-methyl-D-aspartate receptors (NMDARs) are members of the glutamate receptor family and participate in excitatory postsynaptic transmission throughout the central nervous system. Genetic variants in GRIN genes encoding NMDAR subunits are associated with a spectrum of neurological disorders. The M3 transmembrane helices of the NMDAR couple directly to the agonist-binding domains and form a helical bundle crossing in the closed receptors that occludes the pore. The M3 functions as a transduction element whose conformational change couples ligand binding to opening of an ion conducting pore. In this study, we report the functional consequences of 48 de novo missense variants in GRIN1, GRIN2A, and GRIN2B that alter residues in the M3 transmembrane helix. These de novo variants were identified in children with neurological and neuropsychiatric disorders including epilepsy, developmental delay, intellectual disability, hypotonia and attention deficit hyperactivity disorder. All 48 variants in M3 for which comprehensive testing was completed produce a gain-of-function (28/48) compared to loss-of-function (9/48); 11 variants had an indeterminant phenotype. This supports the idea that a key structural feature of the M3 gate exists to stabilize the closed state so that agonist binding can drive channel opening. Given that most M3 variants enhance channel gating, we assessed the potency of FDA-approved NMDAR channel blockers on these variant receptors. These data provide new insight into the structure-function relationship of the NMDAR gate, and suggest that variants within the M3 transmembrane helix produce a gain-of-function.

A Case of Severe, Difficult-to-Diagnose Legionnaires' Disease in a Young Welder.

Legionellosis among welders and other metalworkers is a rare but potentially underappreciated occupational hazard. The same mechanisms that predispose welders to severe pneumonia from Streptococcus pneumoniae and Bacillus cereus may similarly predispose them to Legionella pneumophila infection. We present a case of a previously healthy, immunocompetent 31-year-old male welder presenting with three days of shortness of breath, hypoxia, high-grade fever, and blood-tinged sputum. Chest computed tomography (CT) revealed a lobar consolidation of the right middle and lower lobes. Laboratory evaluation showed borderline hyponatremia, hypophosphatemia, and elevated liver enzymes. The patient was ultimately intubated and started on broad-spectrum antibiotics. Multiple respiratory cultures were negative and Legionella urine antigen testing was also negative. Eventually, bronchial Legionella culture was positive for Legionella pneumophila, and a blood next-generation sequencing test also confirmed the diagnosis. He was extubated six days following admission and subsequently discharged.

Negative allosteric modulation of GluN1/GluN3 NMDA receptors.

NMDA receptors are ligand-gated ion channels that mediate excitatory neurotransmission. Most native NMDA receptors are tetrameric assemblies of two glycine-binding GluN1 and two glutamate-binding GluN2 subunits. Co-assembly of the glycine-binding GluN1 with glycine-binding GluN3 subunits (GluN3A-B) creates glycine activated receptors that possess strikingly different functional and pharmacological properties compared to GluN1/GluN2 NMDA receptors. The role of GluN1/GluN3 receptors in neuronal function remains unknown, in part due to lack of pharmacological tools with which to explore their physiological roles. We have identified the negative allosteric modulator EU1180-438, which is selective for GluN1/GluN3 receptors over GluN1/GluN2 NMDA receptors, AMPA, and kainate receptors. EU1180-438 is also inactive at GABA, glycine, and P2X receptors, but displays inhibition of some nicotinic acetylcholine receptors. Furthermore, we demonstrate that EU1180-438 produces robust inhibition of glycine-activated current responses mediated by native GluN1/GluN3A receptors in hippocampal CA1 pyramidal neurons. EU1180-438 is a non-competitive antagonist with activity that is independent of membrane potential (i.e. voltage-independent), glycine concentration, and extracellular pH. Non-stationary fluctuation analysis of neuronal current responses provided an estimated weighted mean unitary conductance of 6.1 pS for GluN1/GluN3A channels, and showed that EU1180-438 has no effect on conductance. Site-directed mutagenesis suggests that structural determinants of EU1180-438 activity reside near a short pre-M1 helix that lies parallel to the plane of the membrane below the agonist binding domain. These findings demonstrate that structural differences between GluN3 and other glutamate receptor subunits can be exploited to generate subunit-selective ligands with utility in exploring the roles GluN3 in neuronal function.

De novo GRIN variants in NMDA receptor M2 channel pore-forming loop are associated with neurological diseases.

N-methyl-D-aspartate receptors (NMDARs) mediate slow excitatory postsynaptic transmission in the central nervous system, thereby exerting a critical role in neuronal development and brain function. Rare genetic variants in the GRIN genes encoding NMDAR subunits segregated with neurological disorders. Here, we summarize the clinical presentations for 18 patients harboring 12 de novo missense variants in GRIN1, GRIN2A, and GRIN2B that alter residues in the M2 re-entrant loop, a region that lines the pore and is intolerant to missense variation. These de novo variants were identified in children with a set of neurological and neuropsychiatric conditions. Evaluation of the receptor cell surface expression, pharmacological properties, and biophysical characteristics show that these variants can have modest changes in agonist potency, proton inhibition, and surface expression. However, voltage-dependent magnesium inhibition is significantly reduced in all variants. The NMDARs hosting a single copy of a mutant subunit showed a dominant reduction in magnesium inhibition for some variants. These variant NMDARs also show reduced calcium permeability and single-channel conductance, as well as altered open probability. The data suggest that M2 missense variants increase NMDAR charge transfer in addition to varied and complex influences on NMDAR functional properties, which may underlie the patients' phenotypes.