Outcomes of Unplanned Extubations in a Large Children's Hospital.

BACKGROUND: Unplanned extubation (UE) is defined as unintentional dislodgement of an endotracheal tube (ETT) from the trachea. UEs can lead to instability, cardiac arrest, and may require emergent tracheal re-intubation. As part of our hospital-wide quality improvement (QI) work, a multidisciplinary committee reviewed all UEs to determine contributing factors and evaluation of clinical outcomes to develop QI interventions aimed to minimize UEs. The objective was to investigate occurrence, contributing factors, and clinical outcomes of UEs in the pediatric ICU (PICU), cardiac ICU (CICU), and neonatal ICU (NICU) in a large academic children's hospital. We hypothesized that these would be substantially different across 3 ICUs. METHODS: A single-center retrospective review of UEs in the PICU, CICU, and NICU was recorded in a prospective database for the last 5 y. Consensus-based standardized operational definitions were developed to capture contributing factors and adverse events associated with UEs. Data were extracted through electronic medical records by 3 respiratory therapists and local Virtual Pediatric Systems (VPS) database. Consistency of data extraction and classification were evaluated. RESULTS: From January 2016-December 2021, 408 UEs in 339 subjects were reported: PICU 52 (13%), CICU 31 (7%), and NICU 325 (80%). The median (interquartile range) of age and weight was 2.0 (0-4.0) months and 5.3 (3.0-8.0) kg. Many UE events were not witnessed (54%). Common contributing factors were routine nursing care (no. = 70, 18%), ETT retaping (no. = 62, 16%), and being held (no. = 15, 3.9%). The most common adverse events with UE were desaturation < 80% (33%) and bradycardia (22.8%). Cardiac arrest occurred in 12%. Sixty-seven percent of UEs resulted in re-intubation within 72 h. The proportion of re-intubation across 3 units was significantly different: PICU 62%, CICU 35%, NICU 71%, P < .001. CONCLUSIONS: UEs occurred commonly in a large academic children's hospital. Whereas UE was associated with adverse events, re-intubation rates within 72 h were < 70% and variable across the units.

The Effect of Rating Method on Reliability of Judgments of Strain Across Populations.

PURPOSE: Variability in auditory-perceptual ratings of voice limits their utility, with the poorest reliability often noted for vocal strain. The purpose of this study was to determine whether an experimental method, called visual sort and rate (VSR), promoted stronger rater reliability than visual analog scale (VAS), for ratings of strain in two clinical populations: adductor laryngeal dystonia (ADLD) and vocal hyperfunction (VH). METHOD: Connected speech samples from speakers with ADLD and VH as well as age- and sex-matched controls were selected from a database. Fifteen inexperienced listeners rated strain for two speaker sets (25 ADLD speakers and five controls; 25 VH speakers and five controls) across four rating blocks: VAS-ADLD, VSR-ADLD, VAS-VH, and VSR-VH. For the VAS task, listeners rated each speaker for strain using a vertically oriented 100-mm VAS. For the VSR task, stimuli were distributed into sets of samples with a range of severities in each set. Listeners sorted and ranked samples for strain within each set, and final ratings were captured on a vertically oriented 100-mm VAS. Intrarater reliability (Pearson's r) and interrater variability (mean of the squared differences between a listener's ratings and group mean ratings) were compared across rating methods and populations using two repeated-measures analyses of variance. RESULTS: Intrarater reliability of strain was significantly stronger when listeners used VSR compared to VAS; listeners also showed significantly better intrarater reliability in ADLD than VH. Listeners demonstrated significantly less interrater variability (better reliability) when using VSR compared to VAS. No significant effect of population or interactions was found between listeners for measures of interrater variability. CONCLUSIONS: VSR increases intrarater reliability for ratings of vocal strain in speakers with VH and ADLD. VSR decreases variability of auditory-perceptual judgments of strain between inexperienced listeners in these clinical populations. Future research should determine whether benefits of VSR extend to voice clinicians and/or clinical settings.

A Multigenerational Turing Model Reproduces Transgressive Petal Spot Phenotypes in Hybrid Mimulus.

The origin of phenotypic novelty is a perennial question of genetics and evolution. To date, few studies of biological pattern formation specifically address multi-generational aspects of inheritance and phenotypic novelty. For quantitative traits influenced by many segregating alleles, offspring phenotypes are often intermediate to parental values. In other cases, offspring phenotypes can be transgressive to parental values. For example, in the model organism Mimulus (monkeyflower), the offspring of parents with solid-colored petals exhibit novel spotted petal phenotypes. These patterns are controlled by an activator-inhibitor gene regulatory network with a small number of loci. Here we develop and analyze a model of hybridization and pattern formation that accounts for the inheritance of a diploid gene regulatory network composed of either homozygous or heterozygous alleles. We find that the resulting model of multi-generational Turing-type pattern formation can reproduce transgressive petal phenotypes similar to those observed in Mimulus. The model gives insight into how non-patterned parent phenotypes can yield phenotypically transgressive, patterned offspring, aiding in the development of empirically testable hypotheses.

Digital Technology Characteristics and Literacy Among Families With Children With Asthma: Cross-Sectional Study.

Background: The use of digital technology in pediatric asthma management has emerged as a potential tool for improving asthma management. However, the use of digital tools has the potential to contribute to the inequitable delivery of asthma care because of existing social factors associated with asthma disparities. Our study focused on parents' chosen language and sociodemographic factors that might shape the use of digital technology in asthma self-management. Objective: This study aims to estimate and compare patient, family, and technology-related characteristics by parents' chosen language (English or Spanish) and compare a digital literacy measure by sociodemographic factors. Methods: Survey data were collected from July to December 2021 from parents of children with asthma who were seen by a Chicago pediatric health system pulmonary provider. Questions assessed patient and family characteristics, digital technology use, and digital literacy, measured using the validated eHealth Literacy Scale (eHEALS). Chi-square tests and multivariable logistic regression were used for comparisons, and Kruskal-Wallis tests were used for comparing median eHEALS scores by social characteristics. Results: Of the 197 parents surveyed, 24.4% (n=49) of parents identified as a race categorized as other, 37.1% (n=67) as White, and 38.6% (n=75) as Black; 47.2% (n=93) identified as Hispanic/Latino/Latina. Additionally, 79.7% (n=157) of parents preferred English, and 20.3% (n=40) preferred Spanish. English-speaking parents were more likely to report having a data plan for their smartphone (117/157, 74.5%) or high-speed internet (138/157, 87.9%) compared to Spanish-speaking parents (smartphone: 23/40, 58%; P=.03; internet: 27/40, 68%; P=.002). Compared with Spanish-speaking parents, English-speaking parents were less likely to report having a lot or some concern about paying for internet (28/40, 70% vs 83/157, 52.9%; P=.046) or about data privacy (35/40, 88% vs 105/157, 67.5%; P=.01). Digital literacy scores differed significantly by race, income, education level, and language. In a multivariable model, language was not a significant factor for having high-speed internet service (P=.12) or concern about paying for internet at home (P=.60), but it was a significant factor for concerns about data privacy (P=.04). Conclusions: The significant differences in technology-related characteristics suggest that digital connectivity, affordability, and data privacy may also be important factors in considering digital technology use in asthma care.

Archaeal Hel308 suppresses recombination through a catalytic switch that controls DNA annealing.

Hel308 helicases promote genome stability in archaea and are conserved in metazoans, where they are known as HELQ. Their helicase mechanism is well characterised, but it is unclear how they specifically contribute to genome stability in archaea. We show here that a highly conserved motif of Hel308/HELQ helicases (motif IVa, F/YHHAGL) modulates both DNA unwinding and a newly identified strand annealing function of archaeal Hel308. A single amino acid substitution in motif IVa results in hyper-active DNA helicase and annealase activities of purified Hel308 in vitro. All-atom molecular dynamics simulations using Hel308 crystal structures provided a molecular basis for these differences between mutant and wild type Hel308. In archaeal cells, the same mutation results in 160000-fold increased recombination, exclusively as gene conversion (non-crossover) events. However, crossover recombination is unaffected by the motif IVa mutation, as is cell viability or DNA damage sensitivity. By contrast, cells lacking Hel308 show impaired growth, increased sensitivity to DNA cross-linking agents, and only moderately increased recombination. Our data reveal that archaeal Hel308 suppresses recombination and promotes DNA repair, and that motif IVa in the RecA2 domain acts as a catalytic switch to modulate the separable recombination and repair activities of Hel308.

The regulatory network for petal anthocyanin pigmentation is shaped by the MYB5a/NEGAN transcription factor in Mimulus.

Much of the visual diversity of angiosperms is due to the frequent evolution of novel pigmentation patterns in flowers. The gene network responsible for anthocyanin pigmentation, in particular, has become a model for investigating how genetic changes give rise to phenotypic innovation. In the monkeyflower genus Mimulus, an evolutionarily recent gain of petal lobe anthocyanin pigmentation in M. luteus var. variegatus was previously mapped to genomic region pla2. Here, we use sequence and expression analysis, followed by transgenic manipulation of gene expression, to identify MYB5a-orthologous to the NEGAN transcriptional activator from M. lewisii-as the gene responsible for the transition to anthocyanin-pigmented petals in M. l. variegatus. In other monkeyflower taxa, MYB5a/NEGAN is part of a reaction-diffusion network that produces semi-repeating spotting patterns, such as the array of spots in the nectar guides of both M. lewisii and M. guttatus. Its co-option for the evolution of an apparently non-patterned trait-the solid petal lobe pigmentation of M. l. variegatus-illustrates how reaction-diffusion can contribute to evolutionary novelty in non-obvious ways. Transcriptome sequencing of a MYB5a RNAi line of M. l. variegatus reveals that this genetically simple change, which we hypothesize to be a regulatory mutation in cis to MYB5a, has cascading effects on gene expression, not only on the enzyme-encoding genes traditionally thought of as the targets of MYB5a but also on all of its known partners in the anthocyanin regulatory network.

Improving Geriatric Care Processes on Two Medical-Surgical Acute Care Units: A Pilot Study.

The Acute Care for Elders (ACE) Unit model improves cognitive and functional outcomes for hospitalized elders but reaches a small proportion of patients. To disseminate ACE Unit principles, we piloted the "Virtual ACE Intervention" that standardizes care processes for cognition and function without daily geriatrician oversight on two non-ACE units. The Virtual ACE Intervention includes staff training on geriatric assessments for cognition and function and on nurse-driven care algorithms. Completion of the geriatric assessments by nursing staff in patients aged 65 years and older and measures of patient mobility and prevalence of an abnormal delirium screening score were compared preintervention and postintervention. Postintervention, the completion of the assessments for current functional status and delirium improved (62.5% vs. 88.5%, p < .001) and (4.2% vs. 96.5%, p < .001). In a subsample analysis, in the postintervention period, more patients were up to the chair in the past day (36.4% vs. 63.5%, p = .04) and the prevalence of an abnormal delirium screening score was lower (13.6% vs. 4.8%, p = .16). The Virtual ACE Intervention is a feasible model for disseminating ACE Unit principles to non-ACE Units and may lead to increased adherence to care processes and improved clinical outcomes.

Acute Care for Elders (ACE) Team Model of Care: A Clinical Overview.

The Institute of Medicine (IOM) Reports of To Err is Human and Crossing the Quality Chasm have called for more interprofessional and coordinated hospital care. For over 20 years, Acute Care for Elders (ACE) Units and models of care that disseminate ACE principles have demonstrated outcomes in-line with the IOM goals. The objective of this overview is to provide a concise summary of studies that describe outcomes of ACE models of care published in 1995 or later. Twenty-two studies met the inclusion. Of these, 19 studies were from ACE Units and three were evaluations of ACE Services, or teams that cared for patients on more than one hospital unit. Outcomes from these studies included increased adherence to evidence-based geriatric care processes, improved patient functional status at time of hospital discharge, and reductions in length of stay and costs in patients admitted to ACE models compared to usual care. These outcomes represent value-based care. As interprofessional team models are adopted, training in successful team functioning will also be needed.

Chronic treatment with varenicline changes expression of four nAChR binding sites in mice.

INTRODUCTION: Chronic treatment with nicotine is known to increase the α4ß2-nAChR sites in brain, to decrease α6ß2-nAChR sites and to have minimal effect on α3ß4-and α7-nAChR populations. Varenicline is now used as a smoking cessation treatment, with and without continued smoking or nicotine replacement therapy. Varenicline, like nicotine, upregulates the α4ß2-nAChR sites; however, it is not known whether varenicline treatment changes expression of the other nAChR subtypes. METHODS: Using a mouse model, chronic treatments (10 days) with varenicline (0.12  mg/kg/h) and/or nicotine (1 mg/kg/hr), alone or in combination, were compared for plasma and brain levels of drugs, tolerance to subsequent acute nicotine and expression of four subtypes of nAChR using autoradiography. RESULTS: The upregulation of α4ß2-nAChR sites elicited by chronic varenicline was very similar to that elicited by chronic nicotine. Treatment with both drugs somewhat increased up-regulation, indicating that these doses were not quite at maximum effect. Similar down-regulation was seen for α6ß2-nAChR sites. Varenicline significantly increased both α3ß4-and α7-nAChR sites while nicotine had less effect on these sites. The drug combination was similar to varenicline alone for α3ß4-nAChR sites, while for α7 sites the drug combination was less effective than varenicline alone. Varenicline had small but significant effects on tolerance to acute nicotine. CONCLUSIONS: Effects of varenicline in vivo may not be limited to the α4ß2*-nAChR subtype. In addition, smoking cessation treatment with varenicline may not allow receptor numbers to be restored to baseline and may, in addition, change expression of other receptor subtypes.

Jet lag modification.

Athletes often are required to travel for sports participation, both for practice and competition. A number of those crossing multiple time zones will develop jet lag disorder with possible negative consequences on their performance. This review will discuss the etiology of jet lag disorder and the techniques that are available to shorten or minimize its effects. This includes both pharmacological and nonpharmacological approaches.

Patients' perceptions of research biopsies in phase I oncology trials.

OBJECTIVE: Research biopsies are increasingly incorporated into phase I oncology trials resulting in ethical and logistical challenges for patients and clinicians. Patients' understanding and willingness to undergo these biopsies are crucial. METHODS: Over 12 months, we administered a questionnaire comprising three sections: demographics and previous cancer therapy, understanding of phase I trials and personalized medicine, and understanding of biopsies and associated risks. RESULTS: Out of 56 patients approached, 47 patients completed the questionnaire. Overall, the patients were well informed about the concepts of personalized medicine and 89% (n = 42) were aware that early phase clinical trials aim to define a dose and explore side effects of new drugs. Interestingly, 76% (n = 36) expected early phase trials to improve symptoms, quality of life and survival. Offering hope and feeling in control of their treatment were important components for 80% (n = 38) and 57% (n = 27), respectively. The majority of this highly selective patient cohort understood the concept of research biopsies, with 59% (n = 28) willing to have a fresh research biopsy for trial participation. Although 72% (n = 34) felt that research biopsies should be optional, only 19% (n = 9) would not participate in a clinical trial with mandatory biopsies. Compared to diagnostic biopsies, the patients were less likely to accept associated risks with research biopsies. CONCLUSION: As research biopsies are crucial to many components of the drug development process, our study provides evidence for patients' overall willingness to undergo research biopsies for trial purposes. A consent process tailored to the biopsy site may help patients weigh up the associated risks versus benefits.

Research biopsies in the context of early phase oncology studies: clinical and ethical considerations.

The Personalized Medicine approach in oncology is a direct result of an improved understanding of complex tumor biology and advances in diagnostic technologies. In recent years, there has been an increased demand for archival and fresh tumor analysis in early clinical trials to foster proof-of-concept biomarker development, to understand resistance mechanisms, and ultimately to assess biological response. Although phase I studies are aimed at defining drug safety, pharmacokinetics, and to recommend a phase II dose for further testing, there is now increasing evidence of mandatory tumor biopsies even at the earliest dose-finding stages of drug development. The increasing demand for fresh tumor biopsies adds to the complexity of novel phase I studies and results in different challenges, ranging from logistical support to ethical concerns. This paper investigates key issues, including patients' perceptions of research biopsies, the need for accurate informed consent, and alternative strategies that may guide the drug development process.

A blinded, randomized, palatability study comparing variations of 2 popular field water disinfection tablets.

OBJECTIVE: Halogen-based water disinfection tablets may render an unpleasant taste to treated water. Proposed safe additives such as ascorbic acid may reduce this objectionable taste. We compared the palatability of 2 field water disinfectants: iodine-based tetraglycine hydroperiodide (TGHP) and chlorine-based chlorine dioxide (CD) both with and without the concomitant use of an ascorbic acid taste neutralizer. METHODS: Blinded participants randomly sampled 5 different distilled water samples containing combinations of disinfectant tablets and ascorbic acid: 1) water; 2) water with TGHP; 3) water with CD; 4) water with TGHP plus ascorbic acid; and 5) water with CD plus ascorbic acid. Participants rated beverage taste via a 100 mm visual analogue scale (VAS) and ranked the samples from "most pleasant" to "least pleasant." RESULTS: Sixty participants evaluated the samples. On the VAS, water with TGHP tasted worst and water with CD tasted second worst. Water with TGHP plus ascorbic acid, water alone, and water with CD plus ascorbic acid measured similarly as significantly best tasting. Water with TGHP was ranked by 58% as "least pleasant" tasting, while water with TGHP and ascorbic acid was ranked by 40% as "most pleasant" tasting. CONCLUSIONS: Participants found halogen-based disinfected water significantly less palatable prior to the addition of ascorbic acid. Addition of ascorbic acid to treated water created a beverage of similar preference to distilled water. These results may increase compliance with the use of disinfecting tablets by increasing the palatability of drinking water made potable via addition of ascorbic acid to halogen-based chemical disinfection.

Toll-like receptor 3 and geographic atrophy in age-related macular degeneration.

BACKGROUND: Age-related macular degeneration is the most common cause of irreversible visual impairment in the developed world. Advanced age-related macular degeneration consists of geographic atrophy and choroidal neovascularization. The specific genetic variants that predispose patients to geographic atrophy are largely unknown. METHODS: We tested for an association between the functional toll-like receptor 3 gene (TLR3) variant rs3775291 (involving the substitution of phenylalanine for leucine at amino acid 412) and age-related macular degeneration in Americans of European descent. We also tested for the effect of TLR3 Leu and Phe variants on the viability of human retinal pigment epithelial cells in vitro and on apoptosis of retinal pigment epithelial cells from wild-type mice and Tlr3-knockout (Tlr3(-/-)) mice. RESULTS: The Phe variant (encoded by the T allele at rs3775291) was associated with protection against geographic atrophy (P=0.005). This association was replicated in two independent case-control series of geographic atrophy (P=5.43x10(-4) and P=0.002). No association was found between TLR3 variants and choroidal neovascularization. A prototypic TLR3 ligand induced apoptosis in a greater fraction of human retinal pigment epithelial cells with the Leu-Leu genotype than those with the Leu-Phe genotype and in a greater fraction of wild-type mice than Tlr3(-/-) mice. CONCLUSIONS: The TLR3 412Phe variant confers protection against geographic atrophy, probably by suppressing the death of retinal pigment epithelial cells. Since double-stranded RNA (dsRNA) can activate TLR3-mediated apoptosis, our results suggest a role of viral dsRNA in the development of geographic atrophy and point to the potential toxic effects of short-interfering-RNA therapies in the eye.

Rhesus monkeys and humans share common susceptibility genes for age-related macular disease.

Age-related macular degeneration (AMD), a complex multigenic disorder and the most common cause of vision loss in the elderly, is associated with polymorphisms in the LOC387715/ARMS2 and HTRA1 genes on 10q26. Like humans, macaque monkeys possess a macula and develop age-related macular pathologies including drusen, the phenotypic hallmark of AMD. We genotyped a cohort of 137 unrelated rhesus macaques with and without macular drusen. As in humans, one variant within LOC387715/ARMS2 and one in HTRA1 were significantly associated with affected status. HTRA1 and the predicted LOC387715/ARMS2 gene were both transcribed in rhesus and human retina and retinal pigment epithelium. Among several primate species, orthologous exons for the human LOC387715/ARMS2 gene were present only in Old World monkeys and apes. In functional analyses, the disease-associated HTRA1 polymorphism resulted in a 2-fold increase in gene expression, supporting a role in pathogenesis. These results demonstrate that two genes associated with AMD in humans are also associated with macular disease in rhesus macaques and that one of these genes is specific to higher primates. This is the first evidence that humans and macaques share the same genetic susceptibility factors for a common complex disease.