Noninvasive Ventilation for Preoxygenation during Emergency Intubation.

BACKGROUND: Among critically ill adults undergoing tracheal intubation, hypoxemia increases the risk of cardiac arrest and death. The effect of preoxygenation with noninvasive ventilation, as compared with preoxygenation with an oxygen mask, on the incidence of hypoxemia during tracheal intubation is uncertain. METHODS: In a multicenter, randomized trial conducted at 24 emergency departments and intensive care units in the United States, we randomly assigned critically ill adults (age, ≥18 years) undergoing tracheal intubation to receive preoxygenation with either noninvasive ventilation or an oxygen mask. The primary outcome was hypoxemia during intubation, defined by an oxygen saturation of less than 85% during the interval between induction of anesthesia and 2 minutes after tracheal intubation. RESULTS: Among the 1301 patients enrolled, hypoxemia occurred in 57 of 624 patients (9.1%) in the noninvasive-ventilation group and in 118 of 637 patients (18.5%) in the oxygen-mask group (difference, -9.4 percentage points; 95% confidence interval [CI], -13.2 to -5.6; P<0.001). Cardiac arrest occurred in 1 patient (0.2%) in the noninvasive-ventilation group and in 7 patients (1.1%) in the oxygen-mask group (difference, -0.9 percentage points; 95% CI, -1.8 to -0.1). Aspiration occurred in 6 patients (0.9%) in the noninvasive-ventilation group and in 9 patients (1.4%) in the oxygen-mask group (difference, -0.4 percentage points; 95% CI, -1.6 to 0.7). CONCLUSIONS: Among critically ill adults undergoing tracheal intubation, preoxygenation with noninvasive ventilation resulted in a lower incidence of hypoxemia during intubation than preoxygenation with an oxygen mask. (Funded by the U.S. Department of Defense; PREOXI ClinicalTrials.gov number, NCT05267652.).

Sentinel lymph node biopsy in patients with T1a cutaneous malignant melanoma: A multicenter cohort study.

BACKGROUND: Sentinel lymph node biopsy is not routinely recommended for T1a cutaneous melanoma due to the overall low risk of positivity. Prognostic factors for positive sentinel lymph node (SLN+) in this population are poorly characterized. OBJECTIVE: To determine factors associated with SLN+ in patients with T1a melanoma. METHODS: Patients with pathologic T1a (<0.80 mm, nonulcerated) cutaneous melanoma from 5 high-volume melanoma centers from 2001 to 2020 who underwent wide local excision with sentinel lymph node biopsy were included in the study. Patient and tumor characteristics associated with SLN+ were analyzed by univariate and multivariable logistic regression analyses. Age was dichotomized into ≤42 (25% quartile cutoff) and >42 years. RESULTS: Of the 965 patients identified, the overall SLN+ was 4.4% (N = 43). Factors associated with SLN+ were age ≤42 years (7.5% vs 3.7%; odds ratio [OR], 2.14; P = .03), head/neck primary tumor location (9.2% vs 4%; OR, 2.75; P = .04), lymphovascular invasion (21.4% vs 4.2%; OR, 5.64; P = .01), and ≥2 mitoses/mm2 (8.2% vs 3.4%; OR, 2.31; P = .03). Patients <42 years with ≥2 mitoses/mm2 (N = 38) had a SLN+ rate of 18.4%. LIMITATIONS: Retrospective study. CONCLUSION: SLN+ is low in patients with T1a melanomas, but younger age, lymphovascular invasion, mitogenicity, and head/neck primary site appear to confer a higher risk of SLN+.

Early Developmental Trends in High-Risk Neonates Later Diagnosed With Autism Spectrum Disorder.

PURPOSE: We hypothesized that clinical data from a neonatal intensive care unit (NICU) infant developmental follow-up clinic would identify early manifestations of autism spectrum disorder (ASD). METHODS: One hundred forty-four infants were identified; 72 later diagnosed with ASD and 72 controls. Retrospective chart review provided data from the Test of Infant Motor Performance (TIMP) and the Bayley Scales of Infant and Toddler Development, third edition (Bayley-III), between 8 and 26 months of age. RESULTS: Between-group comparisons indicated no significant group difference in TIMP scores; however, Bayley-III scaled scores differed between the groups at 2 administration times. The within-group Bayley-III change scores declined significantly more for the ASD group in cognitive and communication subtests. CONCLUSION: High-risk neonates, due to prematurity or morbidity, later diagnosed with ASD demonstrated statistically significant differences, including a more precipitous drop in Bayley-III scores over time. Early, longitudinal developmental surveillance for neonates at risk of ASD is critical. What this adds to the evidence: Early identification of ASD is critical to optimize developmental outcomes in young children, including infants born prematurely or with neonatal morbidity, who are perceived to have an increased risk for ASD. Despite these findings, minimal research has been conducted to evaluate the utility of commonly administered norm-referenced developmental surveillance instruments to identify possible early signs of ASD in this high-risk population due to prematurity or neonatal morbidity and not familial association. The present study analyzed retrospectively collected clinical data from a NICU developmental follow-up clinic for 144 infants, 72 of which were later diagnosed with ASD and 72 sex- and gestational age-matched controls. Results demonstrated statistically significant poorer Bayley-III outcomes for the ASD group compared with controls at 2 different study time points, including a more precipitous drop in Bayley-III scaled scores over time. This study highlights the importance of early and longitudinal developmental surveillance for high-risk neonates at risk of ASD.

Prognostic Significance of Primary Tumor-Infiltrating Lymphocytes in a Contemporary Melanoma Cohort.

BACKGROUND: The prognostic impact of tumor-infiltrating lymphocytes (TILs) on outcomes and treatment efficacy for patients with melanoma in the contemporary era remains poorly characterized. METHODS: Consecutive patients who underwent wide excision and sentinel lymph node biopsy for cutaneous melanoma 1 mm thick or thicker at a single institution were identified (2006-2019). The patients were stratified based on primary tumor TIL status as brisk (bTILs), non-brisk (nbTILs), or absent (aTILs). Associations between patient factors and outcomes were analyzed using multivariable analysis. RESULTS: Of the 1017 patients evaluated, 846 (83.2 %) had primary TILs [nbTILs (n = 759, 89.7 %) and bTILs (n = 87, 10.3 %)]. In the multivariable analysis, the patients with any type of TILs had higher rates of regression [odds ratio (OR), 1.86; p = 0.016], lower rates of acral lentiginous histology (OR, 0.22; p < 0.001), and lower rates of SLN positivity (OR, 0.64; p = 0.042) than those without TILs. The multivariable analysis found no association between disease-specific survival and bTILs [hazard ratio (HR), 1.04; p = 0.927] or nbTILs (HR, 0.89; p = 0.683). An association was found between bTILs and recurrence-free survival (RFS) advantage [bTILs (HR 0.46; p = 0.047), nbTILs (HR 0.71; p = 0.088)], with 5-year RFS rates of 84 % for bTILs, 71.8 % for nbTILs, and 68.4 % for aTILs (p = 0.044). For the 114 immune checkpoint blockade (ICB)-naïve patients who experienced a recurrence treated with ICB therapy, no association was observed between progression-free survival and bTILs (HR, 0.64; p = 0.482) or nbTILs (HR, 0.58; p = 0.176). CONCLUSIONS: The prognostic significance of primary TILs in the contemporary melanoma era appears complex. Further studies characterizing the phenotype of TILs and their association with regional metastasis and responsiveness to ICB therapy are warranted.

Impact of the affordable care act's medicaid expansion on presentation stage and perioperative outcomes of colorectal cancer.

BACKGROUND AND OBJECTIVES: Medicaid expansion has improved healthcare coverage and preventive health service use. To what extent this has resulted in earlier stage colorectal cancer diagnoses and impacted perioperative outcomes is unclear. METHODS: This was a retrospective difference-in-difference study using the National Cancer Database on adults (40-64) with Medicaid or no insurance, diagnosed with colorectal adenocarcinomas before (2010-2013) and after (2015-2018) expansion. The primary outcome was early-stage (American Joint Committee on Cancer Stage 0-1) diagnosis. The secondary outcomes were rate of local excision, emergency surgery, postoperative length of stay, rates of minimally invasive surgery, postoperative mortality, and overall survival (OS). RESULTS: Medicaid expansion was associated with an increase in early-stage diagnoses for patients with colorectal cancers (odds ratio [OR]: 1.28, 95% confidence interval [CI]: 1.15-1.43), an increase in local excision (OR: 1.39, 95% CI: 1.13-1.69), and a decreased rate of emergent surgery (OR: 0.85, 95% CI: 0.75-0.97) and 90-day mortality (OR: 0.75, 95% CI: 0.59-0.97). Additionally, patients in expansion states postexpansion had an improved 5-year OS (hazard ratio: 0.88, 95% CI: 0.83-0.94). CONCLUSIONS: Insurance coverage expansion may be particularly important for optimizing stage of diagnosis, subsequent survival, and perioperative outcomes for socioeconomically vulnerable patients.

Predictors of Physical Activity in Patients With Fibromyalgia: A Path Analysis.

BACKGROUND/OBJECTIVE: The aim of this study was to identify psychological factors that influence moderate-vigorous physical activity (MVPA) participation in patients with fibromyalgia. METHODS: In this secondary data analysis, 170 patients received personalized exercise plans and completed baseline and follow-up assessments of self-reported physical activity at weeks 12, 24, and 36. Structural equation modeling was used to examine the predictive strengths of psychological factors (exercise self-efficacy, perceived barriers, and intention) on MVPA participation. RESULTS: Using a threshold increase in MVPA of 10 or greater metabolic equivalent hours per week (MET h/wk), 3 groups were defined based on subjects who achieved a minimum increase of 10 MET h/wk that was sustained for at least 12 weeks (SUS-PA), achieved an increase of 10 MET h/wk that was not sustained for at least 12 weeks (UNSUS-PA), and did not achieve an increase of 10 MET h/wk (LO-PA). Increases in exercise self-efficacy and intention and reductions in perceived barriers were associated with increased volume of PA, showing the greatest change in the SUS-PA, followed by UNSUS-PA. For the LO-PA group, there was no change in exercise self-efficacy, a decrease in intention, and an increase in barriers. Using path analysis, exercise self-efficacy and perceived barriers were associated with higher volumes of physical activity via greater intention to engage in MVPA. CONCLUSIONS: For patients with fibromyalgia, exercise self-efficacy, perceived barriers, and intention to exercise are important constructs for increasing physical activity. Our findings provide guidance for practitioners who seek to promote physical activity in fibromyalgia and suggestions for researchers aiming to improve prediction models.

The ClC-1 chloride channel inhibitor NMD670 improves skeletal muscle function in rat models and patients with myasthenia gravis.

Myasthenia gravis (MG) is a neuromuscular disease that results in compromised transmission of electrical signals at the neuromuscular junction (NMJ) from motor neurons to skeletal muscle fibers. As a result, patients with MG have reduced skeletal muscle function and present with symptoms of severe muscle weakness and fatigue. ClC-1 is a skeletal muscle specific chloride (Cl-) ion channel that plays important roles in regulating neuromuscular transmission and muscle fiber excitability during intense exercise. Here, we show that partial inhibition of ClC-1 with an orally bioavailable small molecule (NMD670) can restore muscle function in rat models of MG and in patients with MG. In severely affected MG rats, ClC-1 inhibition enhanced neuromuscular transmission, restored muscle function, and improved mobility after both single and prolonged administrations of NMD670. On this basis, NMD670 was progressed through nonclinical safety pharmacology and toxicology studies, leading to approval for testing in clinical studies. After successfully completing phase 1 single ascending dose in healthy volunteers, NMD670 was tested in patients with MG in a randomized, placebo-controlled, single-dose, three-way crossover clinical trial. The clinical trial evaluated safety, pharmacokinetics, and pharmacodynamics of NMD670 in 12 patients with mild MG. NMD670 had a favorable safety profile and led to clinically relevant improvements in the quantitative myasthenia gravis (QMG) total score. This translational study spanning from single muscle fiber recordings to patients provides proof of mechanism for ClC-1 inhibition as a potential therapeutic approach in MG and supports further development of NMD670.

Synthesis and biological evaluation of Esaprazole analogues showing σ1 binding and neuroprotective properties in vitro.

Esaprazole, a molecule previously acknowledged to protect against stomach and intestinal ulcers was surprisingly discovered to have neuroprotective activities and σ1 binding in vitro. A highly diverse set of Esaprazole analogues 2-5 was prepared in order to increase blood-brain barrier penetration. The analogues showed a structure-activity relationship at the σ1 receptor closely matching already published pharmacophores. Many of the analogues were shown to have neuroprotective properties in two assays using primary cultures of cortical neurons exposed to glutamate and hydrogen peroxide. However, no apparent SAR for these two assays could be developed. Metabolic stability of the analogues were also investigated and the structure of R(1) had a significant bearing on the ADME properties of the compound resulting in two series of compounds. Compounds in which R(1) was a H or acyl group had good metabolic stability in RLM but poor BBB penetration, whereas compounds where R(1) was a cyclo- or bicyclo-alkyl group had poor metabolic stability but good BBB penetration.

A prospective audit of the efficacy, safety, and acceptability of low-volume polyethylene glycol (2 L) versus standard volume polyethylene glycol (4 L) versus magnesium citrate plus stimulant laxative as bowel preparation for colonoscopy.

BACKGROUND: High-quality video colonoscopy requires adequate preparation of the bowel to ensure both adequate procedure completion rates and polyp detection rates. We sought to examine our practice to determine which bowel preparation cleansed most effectively in our patients. AIM: A prospective audit of the efficacy, safety, and acceptability of low-volume polyethylene glycol (2-L Moviprep; Norgine Pharmaceuticals) versus standard volume polyethylene glycol (4-L KleanPrep; Norgine Pharmaceuticals) versus magnesium citrate (Citramag; Sanochemia UK Ltd.) plus stimulant laxative as bowel preparation for colonoscopy. SETTING: District General Hospital. PATIENTS: Patients attending for day case colonoscopy. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Overall cleansing grades of preparations used: patient compliance, taste, and acceptability. METHODS: A prospective audit of patient experience of taking bowel preparation and blinded colonic scoring assessment of bowel cleansing of each of the tested regimes. RESULTS: A total of 258 (female,138; 53.5%) patients were recruited, 91 in the KleanPrep group (F:45, 49.5%), 86 patients in the Moviprep group (female, 45; 52.3%), and 81 in the Senna/Citramag group (female, 44; 54.3%). Significantly more patients were unable to take the prescribed dose of KleanPrep when compared with the other 2 regimes (19.6%; P<0.0001 vs. Moviprep; P<0.0001 vs. Senna/Citramag). A total of 45.65% of patients reported KleanPrep as tasting unpleasant. This was significantly more than both Moviprep (10.47%; P=0.008) and Senna/Citramag (9.88%; P<0.0001). The overall cleansing efficacy across the 3 groups (those with grades A or B) was 73.9%, 74.5%, and 86.5% for KleanPrep, Moviprep, and Senna/Citramag, respectively. In this series Senna/Citramag proved significantly better at bowel cleansing than KleanPrep (P<0.05) and it showed a trend toward better cleansing when compared with Moviprep (P=0.08). LIMITATIONS: Nonrandomized trial. Split-dosing regime for morning and afternoon lists may have confounded results. CONCLUSIONS: In summary, low-volume PEG (Moviprep) and Senna/Citramag combination were better tolerated than large volume PEG with Senna/Citramag providing superior mucosal cleansing.

Neuropeptide FF receptors have opposing modulatory effects on nociception.

The role of neuropeptide FF (NPFF) and its analogs in pain modulation is ambiguous. Although NPFF was first characterized as an antiopioid peptide, both antinociceptive and pronociceptive effects have been reported, depending on the route of administration. Currently, two NPFF receptors, termed FF1 and FF2, have been identified and cloned, but their roles in pain modulation remain elusive because of the lack of availability of selective compounds suitable for systemic administration in in vivo models. Ligand-binding studies confirm ubiquitous expression of both subtypes in brain, whereas only FF2 receptors are expressed spinally. This disparity in localization has served as the foundation of the hypothesis that FF1 receptors mediate the pronociceptive actions of NPFF. We have identified novel small molecule NPFF receptor agonists and antagonists with varying degrees of FF2/FF1 functional selectivity. Using these pharmacological tools in vivo has allowed us to define the roles of NPFF receptor subtypes as pertains to the modulation of nociception. We demonstrate that selective FF2 agonism does not modulate acute pain but instead ameliorates inflammatory and neuropathic pains. Treatment with a nonselective FF1/FF2 agonist potentiates allodynia in neuropathic rats and increases sensitivity to noxious thermal and to non-noxious mechanical stimuli in normal rats in an FF1 antagonist-reversible manner. Treatment with FF1 antagonists reversed established mechanical allodynia, indicating the possibility of increased NPFF tone through FF1 receptors. In conclusion, we provide evidence for the opposing roles of NPFF receptors and highlight selective FF2 agonism and/or selective FF1 antagonism as potential targets warranting further investigation.

In situ immobilization of palladium nanoparticles in microfluidic reactors and assessment of their catalytic activity.

We report on the synthesis and characterization of catalytic palladium nanoparticles (Pd NPs) and their immobilization in microfluidic reactors fabricated from polydimethylsiloxane (PDMS). The Pd NPs were stabilized with D-biotin or 3-aminopropyltrimethoxysilane (APTMS) to promote immobilization inside the microfluidic reactors. The NPs were homogeneous with narrow size distributions between 2 and 4 nm, and were characterized by transmission electron microscopy (TEM), selected-area electron diffraction (SAED), and x-ray diffraction (XRD). Biotinylated Pd NPs were immobilized on APTMS-modified PDMS and glass surfaces through the formation of covalent amide bonds between activated biotin and surface amino groups. By contrast, APTMS-stabilized Pd NPs were immobilized directly onto PDMS and glass surfaces rich in hydroxyl groups. Fourier transform infrared spectroscopy (FT-IR) and x-ray photoelectron spectroscopy (XPS) results showed successful attachment of both types of Pd NPs on glass and PDMS surfaces. Both types of Pd NPs were then immobilized in situ in sealed PDMS microfluidic reactors after similar surface modification. The effectiveness of immobilization in the microfluidic reactors was evaluated by hydrogenation of 6-bromo-1-hexene at room temperature and one atmosphere of hydrogen pressure. An average first-run conversion of 85% and selectivity of 100% were achieved in approximately 18 min of reaction time. Control experiments showed that no hydrogenation occurred in the absence of the nanocatalysts. This system has the potential to provide a reliable tool for efficient and high throughput evaluation of catalytic NPs, along with assessment of intrinsic kinetics.

Discovery of non-peptidergic MrgX1 and MrgX2 receptor agonists and exploration of an initial SAR using solid-phase synthesis.

A class of small molecules displaying comparable activities with peptide ligands BAM22 and corticostatin-14 at both the human and rhesus monkey MrgX1 and MrgX2 receptors, respectively, was discovered. A comparative study to compare solid-phase and solution-phase chemistries for the efficient synthesis of the active class, tetracyclic benzimidazoles, was undertaken. The solid-phase chemistry was found to be superior both for the synthesis of analogs and for the synthesis of gram quantities.

Acclimation capacity of the cardiac HSP70 and HSP90 response to thermal stress in lake trout (Salvelinus namaycush), a stenothermal ice-age relict.

The ability of cold-adapted species to persist in the face of climate change will depend on the capacity of individuals for thermal acclimation, adaptation, and the degree of physiological variation that exists among populations. We tested the acclimation capacity of cardiac HSP70 and HSP90 in four populations of lake trout (Salvelinus namaycush), a cold-adapted salmonid. We acclimated fish to four temperatures (8°C, 11°C, 15°C, and 19°C) and measured cardiac HSP70 and HSP90 levels by western blot prior to and following an acute (1h) heat shock at 23°C. Basal and induced cardiac HSP70 and HSP90 expression was similar among lake trout populations. Induced cardiac HSP70 was significantly lower in heat-shocked lake trout acclimated to 19°C compared to all other temperatures. Acclimation temperature had no significant effect on cardiac HSP90 prior to heat shock (control HSP90) and a significant effect on HSP90 in heat-shocked fish, although most significant treatment comparisons were marginal. However, for warm-acclimated fish (15°C and 19°C), cardiac HSP90 levels were lower in heat-shocked versus control fish. Together, this suggests that the induction temperature of cardiac HSP synthesis may increase with warm acclimation in lake trout. This plasticity in the cardiac HSR could assist lake trout populations in coping with longer periods of thermal stress as predicted by climate change models. The cardiac HSR supports previous research suggesting lake trout thermal physiology may be conserved across a wide geographic range.

Genomic insights into the mitochondria of 11 eastern North American species of Cladonia.

Cladonia is among the most species-rich genera of lichens globally. Species in this lineage, commonly referred to as reindeer lichens, are ecologically important in numerous regions worldwide. In some locations, species of Cladonia can comprise the dominant groundcover, and are a major food source for caribou and other mammals. Additionally, many species are known to produce substances with antimicrobial properties or other characteristics with potentially important medical applications. This exceptional morphological and ecological variation contrasts sharply with the limited molecular divergence often observed among species. As a new resource to facilitate ongoing and future studies of these important species, we analyse here the sequences of 11 Cladonia mitochondrial genomes, including new mitochondrial genome assemblies and annotations representing nine species: C. apodocarpa, C. caroliniana, C. furcata, C. leporina, C. petrophila, C. peziziformis, C. robbinsii, C. stipitata, and C. subtenuis. These 11 genomes varied in size, intron content, and complement of tRNAs. Genes annotated within these mitochondrial genomes include 15 protein-coding genes, the large and small ribosomal subunits (mtLSU and mtSSU), and 23-26 tRNAs. All Cladonia mitochondrial genomes contained atp9, an important energy transport gene that has been lost evolutionarily in some lichen mycobiont mitochondria. Using a concatenated alignment of five mitochondrial genes (nad2, nad4, cox1, cox2, and cox3), a Bayesian phylogeny of relationships among species was inferred and was consistent with previously published phylogenetic relationships, highlighting the utility of these regions in reconstructing phylogenetic history.

Dynamic behavior of venous collapsibility and central venous pressure during standardized crystalloid bolus: A prospective, observational, pilot study.

INTRODUCTION: Measurement of intravascular volume status is an ongoing challenge for physicians in the surgical intensive care unit (SICU). Most surrogates for volume status, including central venous pressure (CVP) and pulmonary artery wedge pressure, require invasive lines associated with a number of potential complications. Sonographic assessment of the collapsibility of the inferior vena cava (IVC) has been described as a noninvasive method for determining volume status. The purpose of this study was to analyze the dynamic response in IVC collapsibility index (IVC-CI) to changes in CVP in SICU patients receiving fluid boluses for volume resuscitation. MATERIALS AND METHODS: A prospective pilot study was conducted on a sample of SICU patients who met clinical indications for intravenous (IV) fluid bolus and who had preexisting central venous access. Boluses were standardized to crystalloid administration of either 500 mL over 30 min or 1,000 mL over 60 min, as clinically indicated. Concurrent measurements of venous CI (VCI) and CVP were conducted right before initiation of IV bolus (i.e. time 0) and then at 30 and 60 min (as applicable) after bolus initiation. Patient demographics, ventilatory parameters, and vital sign assessments were recorded, with descriptive outcomes reported due to the limited sample size. RESULTS: Twenty patients received a total of 24 IV fluid boluses. There were five recorded 500 mL boluses given over 30 min and 19 recorded 1,000 mL boluses given over 60 min. Mean (median) CVP measured at 0, 30, and 60 minutes post-bolus were 6.04 ± 3.32 (6.5), 9.00 ± 3.41 (8.0), and 11.1 ± 3.91 (12.0) mmHg, respectively. Mean (median) IVC-CI values at 0, 30, and 60 min were 44.4 ± 25.2 (36.5), 26.5 ± 22.8 (15.6), and 25.2 ± 21.2 (14.8), respectively. CONCLUSIONS: Observable changes in both VCI and CVP are apparent during an infusion of a standardized fluid bolus. Dynamic changes in VCI as a measurement of responsiveness to fluid bolus are inversely related to changes seen in CVP. Moreover, an IV bolus tends to produce an early response in VCI, while the CVP response is more gradual. Given the noninvasive nature of the measurement technique, VCI shows promise as a method of dynamically measuring patient response to fluid resuscitation. Further studies with larger sample sizes are warranted.