Probabilistic association of differentially expressed genes with cis-regulatory elements.

Differential gene expression in response to perturbations is mediated at least in part by changes in binding of transcription factors (TFs) and other proteins at specific genomic regions. Association of these cis-regulatory elements (CREs) with their target genes is a challenging task that is essential to address many biological and mechanistic questions. Many current approaches rely on chromatin conformation capture techniques or single-cell correlational methods to establish CRE-to-gene associations. These methods can be effective but have limitations, including resolution, gaps in detectable association distances, and cost. As an alternative, we have developed DegCre, a nonparametric method that evaluates correlations between measurements of perturbation-induced differential gene expression and differential regulatory signal at CREs to score possible CRE-to-gene associations. It has several unique features, including the ability to use any type of CRE activity measurement, yield probabilistic scores for CRE-to-gene pairs, and assess CRE-to-gene pairings across a wide range of sequence distances. We apply DegCre to six data sets, each using different perturbations and containing a variety of regulatory signal measurements, including chromatin openness, histone modifications, and TF occupancy. To test their efficacy, we compare DegCre associations to Hi-C loop calls and CRISPR-validated CRE-to-gene associations, establishing good performance by DegCre that is comparable or superior to competing methods. DegCre is a novel approach to the association of CREs to genes from a perturbation-differential perspective, with strengths that are complementary to existing approaches and allow for new insights into gene regulation.

Partial pressure of carbon dioxide/pH interaction and its association with mortality among patients mechanically ventilated in the emergency department.

OBJECTIVES: There is currently conflicting data as to the effects of hypercapnia on clinical outcomes among mechanically ventilated patients in the emergency department (ED). These conflicting results may be explained by the degree of acidosis. We sought to test the hypothesis that hypercapnia is associated with increased in-hospital mortality and decreased ventilator-free days at lower pH, but associated with decreased in-hospital mortality and increased ventilator-free days at higher pH, among patients requiring mechanical ventilation in the emergency department (ED). METHODS: Secondary analysis of patient level data from prior clinical trials and cohort studies that enrolled adult patients who required mechanical ventilation in the ED. Patients who had a documented blood gas while on mechanical ventilation in the ED were included in these analyses. The primary outcome was in-hospital mortality, and secondary outcome was ventilator-free days. Mixed-effects logistic, linear, and survival-time regression models were used to test if pH modified the association between partial pressure of carbon dioxide (pCO2) and outcome measures. RESULTS: Of the 2348 subjects included, the median [interquartile range (IQR)] pCO2 was 43 (35-54) and pH was 7.31 (7.22-7.39). Overall, in-hospital mortality was 27%. We found pH modified the association between pCO2 and outcomes, with higher pCO2 associated with increased probability of in-hospital mortality when pH is below 7.00, and decreased probability of in-hospital mortality when pH is above 7.10. These results remained consistent across multiple sensitivity and subgroup analyses. A similar relationship was found with ventilator-free days. CONCLUSIONS: Higher pCO2 is associated with decreased mortality and greater ventilator-free days when pH is >7.10; however, it is associated with increased mortality and fewer ventilator-free days when the pH is below 7.00. Targeting pCO2 based on pH in the ED may be a potential intervention target for future clinical trials to improve clinical outcomes.

A qualitative assessment of emergency physicians' experiences with robust emergency department buprenorphine bridge programs.

OBJECTIVES: Emergency departments (EDs) are a critical point of entry into treatment for patients struggling with opioid use disorder (OUD). When initiated in the ED, buprenorphine is associated with increased addiction treatment engagement at 30 days when initiated. Despite this association, it has had slow adoption. The barriers to ED buprenorphine utilization are well documented; however, the benefits of prescribing buprenorphine for emergency physicians (EPs) have not been explored. This study utilized semistructured interviews to explore and understand how EPs perceive their experiences working in EDs that have successfully implemented ED bridge programs (EDBPs) for patients with OUD. METHODS: Semistructured interviews were conducted with EPs from four geographically diverse academic hospitals with established EDBPs. Interviews were recorded and transcribed, and emergent themes were identified using codebook thematic analysis. Analysis credibility and transparency were confirmed with peer debriefing. RESULTS: Twenty-two interviews were conducted across the four sites. Three key themes were constructed during the analyses: (1) provided EPs agency; (2) transformed EPs' emotions, attitudes, and behaviors related to treating patients with OUD; and (3) improved EPs' professional quality of life. CONCLUSIONS: Participants in this study reported several common themes related to participation in their hospital's BP. Overall our results suggest that physicians who participate in EDBPs may feel a renewed sense of fulfillment and purpose in their personal and professional lives. These positive changes may lead to increased job satisfaction in hospitals that have successfully launched EDBP.

Neuronal MAPT expression is mediated by long-range interactions with cis-regulatory elements.

Tauopathies are a group of neurodegenerative diseases defined by abnormal aggregates of tau, a microtubule-associated protein encoded by MAPT. MAPT expression is near absent in neural progenitor cells (NPCs) and increases during differentiation. This temporally dynamic expression pattern suggests that MAPT expression could be controlled by transcription factors and cis-regulatory elements specific to differentiated cell types. Given the relevance of MAPT expression to neurodegeneration pathogenesis, identification of such elements is relevant to understanding disease risk and pathogenesis. Here, we performed chromatin conformation assays (HiC & Capture-C), single-nucleus multiomics (RNA-seq+ATAC-seq), bulk ATAC-seq, and ChIP-seq for H3K27ac and CTCF in NPCs and differentiated neurons to nominate candidate cis-regulatory elements (cCREs). We assayed these cCREs using luciferase assays and CRISPR interference (CRISPRi) experiments to measure their effects on MAPT expression. Finally, we integrated cCRE annotations into an analysis of genetic variation in neurodegeneration-affected individuals and control subjects. We identified both proximal and distal regulatory elements for MAPT and confirmed the regulatory function for several regions, including three regions centromeric to MAPT beyond the H1/H2 haplotype inversion breakpoint. We also found that rare and predicted damaging genetic variation in nominated CREs was nominally depleted in dementia-affected individuals relative to control subjects, consistent with the hypothesis that variants that disrupt MAPT enhancer activity, and thereby reduced MAPT expression, may be protective against neurodegenerative disease. Overall, this study provides compelling evidence for pursuing detailed knowledge of CREs for genes of interest to permit better understanding of disease risk.

Pilot implementation of a telemedicine care bundle: Antimicrobial stewardship, patient satisfaction, clinician satisfaction, and usability in patients with sinusitis.

BACKGROUND: Telemedicine-specific clinical pathways (CPWs), coupled with electronic health record (EHR) order panels, provide an opportunity to ensure evidence and guideline concordant care for conditions at risk for inconsistent diagnoses and management strategies. Standardized provider and patient-facing illness scripts may fill gaps in clinicians' communication skills secondary to a training deficit in virtual care delivery. We aimed to implement and assess the impact of a novel care bundle for sinusitis on antimicrobial use, patient satisfaction, clinician satisfaction, and usability in patients with sinusitis. METHODS: A sinusitis care bundle (SCB) for virtual urgent care patients included a sinusitis CPW with communication scripts, sinusitis order panels (SOP), and a patient education smart-phrase (SPESP) within visit instructions. Antimicrobial use was assessed during a 15-month period prior to the start of SCB element implementations and 14-months following, using statistical process control charts. Patient satisfaction was measured using Likert-style surveys. Clinician satisfaction was assessed using a novel survey addressing the SCB-targeted domains (decision support, communication, efficiency, usability, and overall satisfaction). RESULTS: There were 69,785 and 64,019 evaluable patients in the pre-care and post-care bundle periods, respectively. Despite a significant increase in patients receiving a sinusitis diagnosis in the post-care bundle period (3.2% pre- vs. 6.2% post-, p < 0.001), antimicrobial prescribing decreased by 3.9% (p < 0.001), with statistical process control evidence of special cause change. There was a 5.1% decrease (p < 0.001) in negative patient survey responses after implementation. Clinician survey revealed substantial agreement in the domains relating to improving communication with patients and/or families, with the highest satisfaction for the SPESP over the SOP. CONCLUSIONS: Implementation of a telemedicine care bundle for patients diagnosed with sinusitis can balance multiple elements of quality care. The combination of a clinical care pathway, standardized language, and order panels within the EHR has the potential to improve patient satisfaction and decrease antimicrobial prescribing.

Awareness with paralysis and symptoms of post-traumatic stress disorder among mechanically ventilated emergency department survivors (ED-AWARENESS-2 Trial): study protocol for a pragmatic, multicenter, stepped wedge cluster randomized trial.

BACKGROUND: Awareness with paralysis (AWP) is memory recall during neuromuscular blockade (NMB) and can cause significant psychological harm. Decades of effort and rigorous trials have been conducted to prevent AWP in the operating room, where prevalence is 0.1-0.2%. By contrast, AWP in mechanically ventilated emergency department (ED) patients is common, with estimated prevalence of 3.3-7.4% among survivors given NMB. Longer-acting NMB use is a critical risk for AWP, and we have shown an association between ED rocuronium use and increased AWP prevalence. As NMB are given to more than 90% of ED patients during tracheal intubation, this trial provides a platform to test an intervention aimed at reducing AWP. The overall objective is to test the hypothesis that limiting ED rocuronium exposure will significantly reduce the proportion of patients experiencing AWP. METHODS: This is a pragmatic, stepped wedge cluster randomized trial conducted in five academic EDs, and will enroll 3090 patients. Per the design, all sites begin in a control phase, under observational conditions. At 6-month intervals, sites sequentially enter a 2-month transition phase, during which we will implement the multifaceted intervention, which will rely on use of nudges and defaults to change clinician decisions regarding ED NMB use. During the intervention phase, succinylcholine will be the default NMB over rocuronium. The primary outcome is AWP, assessed with the modified Brice questionnaire, adjudicated by three independent, blinded experts. The secondary outcome is the proportion of patients developing clinically significant symptoms of post-traumatic stress disorder at 30 and 180 days after hospital discharge. We will also assess for symptoms of depression and anxiety, and health-related quality of life. A generalized linear model, adjusted for time and cluster interactions, will be used to compare AWP in control versus intervention phases, analyzed by intention-to-treat. DISCUSSION: The ED-AWARENESS-2 Trial will be the first ED-based trial aimed at preventing AWP, a critical threat to patient safety. Results could shape clinical use of NMB in the ED and prevent more than 10,000 annual cases of AWP related to ED care. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT05534243 . Registered 06, September 2022.

Arterial to end-tidal carbon dioxide gap and its characterization in mechanically ventilated adults in the emergency department.

PURPOSE: To evaluate early measurement of the arterial to end-tidal carbon dioxide (PaCO2-PetCO2) gap, a surrogate for physiologic dead space, and its association with clinical outcomes in intubated adults in the emergency department (ED). MATERIALS AND METHODS: Observational cohort study of invasively mechanically ventilated adults in an academic medical center (years 2009 to 2016). The association of the PaCO2-PetCO2 gap was evaluated with respect to clinical outcomes; the primary outcome was in-hospital mortality. RESULTS: 519 patients were included. 325 (63%) patients had an elevated (>5 mmHg) PaCO2-PetCO2. Patients with an elevated PaCO2-PetCO2 were significantly older, had higher APACHE II scores, more frequently had chronic obstructive pulmonary disease (COPD), had lower arterial oxygen to fraction of inspired oxygen (P:F) ratios, and were more likely to be intubated for exacerbation of COPD or sepsis. There was no difference in mortality for patients with an elevated PaCO2-PetCO2 (25% vs 26%) in unadjusted analysis (p = 0.829) or adjusted analysis (aOR = 0.81 [95% CI: 0.53-1.26]), as compared to a non-elevated PaCO2-PetCO2. CONCLUSIONS: An elevated PaCO2-PetCO2 gap is common in the post-intubation period in the ED, but not significantly associated with clinical outcomes.

Immunoinformatic Risk Assessment of Host Cell Proteins During Process Development for Biologic Therapeutics.

The identification and removal of host cell proteins (HCPs) from biologic products is a critical step in drug development. Despite recent improvements to purification processes, biologics such as monoclonal antibodies, enzyme replacement therapies, and vaccines that are manufactured in a range of cell lines and purified using diverse processes may contain HCP impurities, making it necessary for developers to identify and quantify impurities during process development for each drug product. HCPs that contain sequences that are less conserved with human homologs may be more immunogenic than those that are more conserved. We have developed a computational tool, ISPRI-HCP, that estimates the immunogenic potential of HCP sequences by evaluating and quantifying T cell epitope density and relative conservation with similar T cell epitopes in the human proteome. Here we describe several case studies that support the use of this method for classifying candidate HCP impurities according to their immunogenicity risk.

Asymmetric effects of sudden changes in timbre on auditory stream segregation.

Two experiments explored the effects of abrupt transitions in timbral properties [amplitude modulation (AM), pure tones vs narrow-band noises, and attack/decay envelope] on streaming. Listeners reported continuously the number of streams heard during 18-s-long alternating low- and high-frequency (LHL-) sequences (frequency separation: 2-6 semitones) that underwent a coherent transition at 6 s or remained unchanged. In experiment 1, triplets comprised unmodulated pure tones or 100%-depth AM was created using narrowly spaced tone pairs (dyads: 30- or 50-Hz modulation). In experiment 2, triplets comprised narrow-band noises, dyads, or pure tones with quasi-trapezoidal envelopes (10/80/10 ms), fast attacks and slow decays (10/90 ms), or vice versa (90/10 ms). Abrupt transitions led to direction-dependent changes in stream segregation. Transitions from modulated to unmodulated (or slower-modulated) tones, from noise bands to pure tones, or from slow- to fast-attack tones typically caused substantial loss of segregation (resetting), whereas transitions in the opposite direction mostly caused less or no resetting. Furthermore, for the smallest frequency separation, transitions in the latter direction usually led to increased segregation (overshoot). Overall, the results are reminiscent of the perceptual asymmetries found in auditory search for targets with or without a salient additional feature (or greater activation of that feature).

Immunogenicity risk assessment of synthetic peptide drugs and their impurities.

Peptide drugs play an important part in medicine owing to their many therapeutic applications. Of the 80 peptide drugs approved for use in humans, at least five are now off-patent and are consequently being developed as generic alternatives to the originator products. To accelerate access to generic products, the FDA has proposed new regulatory pathways that do not require direct comparisons of generics to originators in clinical trials. The 'Abbreviated New Drug Application' (ANDA) pathway recommends that sponsors provide information on any new impurities in the generic drug, compared with the originator product, because the impurities can have potential to elicit unwanted immune responses owing to the introduction of T-cell epitopes. This review describes how peptide drug impurities can elicit unexpected immunogenicity and describes a framework for performing immunogenicity risk assessment of all types of bioactive peptide products. Although this report primarily focuses on generic peptides and their impurities, the approach might also be of interest for developers of novel peptide drugs who are preparing their products for an initial regulatory review.

Survey Outcome on Immunogenicity Risk Assessment Tools for Biotherapeutics: an Insight into Consensus on Methods, Application, and Utility in Drug Development.

A survey conducted by the Therapeutic Product Immunogenicity (TPI) community within the American Association of Pharmaceutical Scientists (AAPS) posed questions to the participants on their immunogenicity risk assessment strategies prior to clinical development. The survey was conducted in 2 phases spanning 5 years, and queried information about in silico algorithms and in vitro assay formats for immunogenicity risk assessments and how the data were used to inform early developability effort in discovery, chemistry, manufacturing and control (CMC), and non-clinical stages of development. The key findings representing the trends from a majority of the participants included the use of high throughput in silico algorithms, human immune cell-based assays, and proteomics based outputs, as well as specialized assays when therapeutic mechanism of action could impact risk assessment. Additional insights into the CMC-related risks could also be gathered with the same tools to inform future process development and de-risk critical quality attributes with uncertain and unknown risks. The use of the outputs beyond supporting early development activities was also noted with participants utilizing the risk assessments to drive their clinical strategy and streamline bioanalysis.

MAPT expression is mediated by long-range interactions with cis-regulatory elements.

Background: Tauopathies are a group of neurodegenerative diseases driven by abnormal aggregates of tau, a microtubule associated protein encoded by the MAPT gene. MAPT expression is absent in neural progenitor cells (NPCs) and increases during differentiation. This temporally dynamic expression pattern suggests that MAPT expression is controlled by transcription factors and cis-regulatory elements specific to differentiated cell types. Given the relevance of MAPT expression to neurodegeneration pathogenesis, identification of such elements is relevant to understanding genetic risk factors. Methods: We performed HiC, chromatin conformation capture (Capture-C), single-nucleus multiomics (RNA-seq+ATAC-seq), bulk ATAC-seq, and ChIP-seq for H3K27Ac and CTCF in NPCs and neurons differentiated from human iPSC cultures. We nominated candidate cis-regulatory elements (cCREs) for MAPT in human NPCs, differentiated neurons, and pure cultures of inhibitory and excitatory neurons. We then assayed these cCREs using luciferase assays and CRISPR interference (CRISPRi) experiments to measure their effects on MAPT expression. Finally, we integrated cCRE annotations into an analysis of genetic variation in AD cases and controls. Results: Using orthogonal genomics approaches, we nominated 94 cCREs for MAPT, including the identification of cCREs specifically active in differentiated neurons. Eleven regions enhanced reporter gene transcription in luciferase assays. Using CRISPRi, 5 of the 94 regions tested were identified as necessary for MAPT expression as measured by RT-qPCR and RNA-seq. Rare and predicted damaging genetic variation in both nominated and confirmed CREs was depleted in AD cases relative to controls (OR = 0.40, p = 0.004), consistent with the hypothesis that variants that disrupt MAPT enhancer activity, and thereby reduce MAPT expression, may be protective against neurodegenerative disease. Conclusions: We identified both proximal and distal regulatory elements for MAPT and confirmed the regulatory function for several regions, including three regions centromeric to MAPT beyond the well-described H1/H2 haplotype inversion breakpoint. This study provides compelling evidence for pursuing detailed knowledge of CREs for genes of interest to permit better understanding of disease risk.

The Practice Change and Clinical Impact of Lung-Protective Ventilation Initiated in the Emergency Department: A Secondary Analysis of Individual Patient-Level Data From Prior Clinical Trials and Cohort Studies.

OBJECTIVES: Mechanically ventilated emergency department (ED) patients experience high morbidity and mortality. In a prior trial at our center, ED-based lung-protective ventilation was associated with improved care delivery and outcomes. Whether this strategy has persisted in the years after the trial remains unclear. The objective was to assess practice change and clinical outcomes associated with ED lung-protective ventilation. DESIGN: Secondary analysis of individual patient-level data from prior clinical trials and cohort studies. SETTING: ED and ICUs of a single academic center. PATIENTS: Mechanically ventilated adults. INTERVENTIONS: A lung-protective ventilator protocol used as the default approach in the ED. MEASUREMENTS AND MAIN RESULTS: The primary ventilator-related outcome was tidal volume, and the primary clinical outcome was hospital mortality. Secondary outcomes included ventilator-, hospital-, and ICU-free days. Multivariable logistic regression, propensity score (PS)-adjustment, and multiple a priori subgroup analyses were used to evaluate outcome as a function of the intervention. A total of 1,796 patients in the preintervention period and 1,403 patients in the intervention period were included. In the intervention period, tidal volume was reduced from 8.2 mL/kg predicted body weight (PBW) (7.3-9.1) to 6.5 mL/kg PBW (6.1-7.1), and low tidal volume ventilation increased from 46.8% to 96.2% ( p < 0.01). The intervention period was associated with lower mortality (35.9% vs 19.1%), remaining significant after multivariable logistic regression analysis (adjusted odds ratio [aOR], 0.43; 95% CI, 0.35-0.53; p < 0.01). Similar results were seen after PS adjustment and in subgroups. The intervention group had more ventilator- (18.8 [10.1] vs 14.1 [11.9]; p < 0.01), hospital- (12.2 [9.6] vs 9.4 [9.5]; p < 0.01), and ICU-free days (16.6 [10.1] vs 13.1 [11.1]; p < 0.01). CONCLUSIONS: ED lung-protective ventilation has persisted in the years since implementation and was associated with improved outcomes. These data suggest the use of ED-based lung-protective ventilation as a means to improve outcome.

Awareness With Paralysis Among Critically Ill Emergency Department Patients: A Prospective Cohort Study.

OBJECTIVES: In mechanically ventilated patients, awareness with paralysis (AWP) can have devastating consequences, including post-traumatic stress disorder (PTSD), depression, and thoughts of suicide. Single-center data from the emergency department (ED) demonstrate an event rate for AWP factors higher than that reported from the operating room. However, there remains a lack of data on AWP among critically ill, mechanically ventilated patients. The objective was to assess the proportion of ED patients experiencing AWP and investigate modifiable variables associated with its occurrence. DESIGN: An a priori planned secondary analysis of a multicenter, prospective, before-and-after clinical trial. SETTING: The ED of three academic medical centers. PATIENTS: Mechanically ventilated adult patients that received neuromuscular blockers. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: All data related to sedation and analgesia were collected. AWP was the primary outcome, assessed with the modified Brice questionnaire, and was independently adjudicated by three expert reviewers. Perceived threat, in the causal pathway for PTSD, was the secondary outcome. A total of 388 patients were studied. The proportion of patients experiencing AWP was 3.4% ( n = 13), the majority of whom received rocuronium ( n = 12/13; 92.3%). Among patients who received rocuronium, 5.5% ( n = 12/230) experienced AWP, compared with 0.6% ( n = 1/158) among patients who did not receive rocuronium in the ED (odds ratio, 8.64; 95% CI, 1.11-67.15). Patients experiencing AWP had a higher mean ( sd ) threat perception scale score, compared with patients without AWP (15.6 [5.8] vs 7.7 [6.0]; p < 0.01). CONCLUSIONS: AWP was present in a concerning proportion of mechanically ventilated ED patients, was associated with rocuronium exposure in the ED, and led to increased levels of perceived threat, placing patients at greater risk for PTSD. Studies that aim to further quantify AWP in this vulnerable population and eliminate its occurrence are urgently needed.

Comparison of knee arthrocentesis first-attempt success between Ultrasound-Guided, Ultrasound-Localised and Landmark-Guided techniques in the novice: A crossover study with random order of events.

Introduction/Purpose: To compare knee arthrocentesis first-attempt success using landmark-guided, ultrasound-localised and ultrasound-guided techniques when performed by third-year medical students. Methods: In this prospective, crossover study with randomised order of events, medical students performed three different arthrocentesis techniques on knee models: landmark-guided, ultrasound-localised and ultrasound-guided. Each subject attempted the techniques in a randomly assigned permutation at both high- and low-volume simulated knee effusions. The data were analysed with general estimating equations, which produced odds ratios comparing first-attempt success between different techniques at all effusion volumes. Results: Ninety four of 111 third-year medical students were enrolled. Proportions of first-attempt success for the landmark-guided, US-localised and US-guided were 72%, 86% and 75%, respectively. For all effusion volumes, US-localised demonstrated a statistically significant increase in first-attempt success over the landmark-guided technique, OR = 2.38 (95% CI: 1.52-3.70). There was a greater increase in first-attempt success at low-volume effusions, OR = 2.86 (95% CI: 1.47-5.56), but no significant increase at high-volume effusions: OR = 1.85 (95% CI: 1.00-3.45). For all effusion volumes, US-guided demonstrated no difference to first-attempt success compared with landmark, OR = 1.15 (95% CI: 0.71-1.85). At low-volume effusions, US-guided demonstrated a statistically significant increase in first-attempt success over landmark-guided, OR = 2.17 (95% CI: 1.10-4.35), with no significant difference at high volumes, OR: 0.55 (95% CI: 0.28-1.06). Discussion: The data presented here suggest that in this simulated knee model of arthrocentesis, ultrasound-guided approaches tend to have best efficacy at lower volume effusions, while ultrasound localized tends to do best at higher volume effusions, and both tended to perform better than the landmark technique. This study specifically looked at novices to both arthrocentesis and ultrasound, so extrapolating these results to other groups would require more study, but suggests that ultrasound incorporation into arthrocentesis benefits may offer some benefits for success rates and first attempt success. Conclusion: In simulated knee arthrocentesis, ultrasound-guided techniques increased first-attempt success over landmark-guided techniques among medical students. This increase was most evident for arthrocentesis of smaller volume effusions.

Effects of stimulus naturalness and contralateral interferers on lexical bias in consonant identification.

Lexical bias is the tendency to perceive an ambiguous speech sound as a phoneme completing a word; more ambiguity typically causes greater reliance on lexical knowledge. A speech sound ambiguous between /g/ and /k/ is more likely to be perceived as /g/ before /ɪft/ and as /k/ before /ɪs/. The magnitude of this difference-the Ganong shift-increases when high cognitive load limits available processing resources. The effects of stimulus naturalness and informational masking on Ganong shifts and reaction times were explored. Tokens between /gɪ/ and /kɪ/ were generated using morphing software, from which two continua were created ("giss"-"kiss" and "gift"-"kift"). In experiment 1, Ganong shifts were considerably larger for sine- than noise-vocoded versions of these continua, presumably because the spectral sparsity and unnatural timbre of the former increased cognitive load. In experiment 2, noise-vocoded stimuli were presented alone or accompanied by contralateral interferers with constant within-band amplitude envelope, or within-band envelope variation that was the same or different across bands. The latter, with its implied spectro-temporal variation, was predicted to cause the greatest cognitive load. Reaction-time measures matched this prediction; Ganong shifts showed some evidence of greater lexical bias for frequency-varying interferers, but were influenced by context effects and diminished over time.

A dual-center cohort study on the association between early deep sedation and clinical outcomes in mechanically ventilated patients during the COVID-19 pandemic: The COVID-SED study.

BACKGROUND: Mechanically ventilated patients have experienced greater periods of prolonged deep sedation during the coronavirus disease (COVID-19) pandemic. Multiple studies from the pre-COVID era demonstrate that early deep sedation is associated with worse outcome. Despite this, there is a lack of data on sedation depth and its impact on outcome for mechanically ventilated patients during the COVID-19 pandemic. We sought to characterize the emergency department (ED) and intensive care unit (ICU) sedation practices during the COVID-19 pandemic, and to determine if early deep sedation was associated with worse clinical outcomes. STUDY DESIGN AND METHODS: Dual-center, retrospective cohort study conducted over 6 months (March-August, 2020), involving consecutive, mechanically ventilated adults. All sedation-related data during the first 48 h were collected. Deep sedation was defined as Richmond Agitation-Sedation Scale of - 3 to - 5 or Riker Sedation-Agitation Scale of 1-3. To examine impact of early sedation depth on hospital mortality (primary outcome), we used a multivariable logistic regression model. Secondary outcomes included ventilator-, ICU-, and hospital-free days. RESULTS: 391 patients were studied, and 283 (72.4%) experienced early deep sedation. Deeply sedated patients received higher cumulative doses of fentanyl, propofol, midazolam, and ketamine when compared to light sedation. Deep sedation patients experienced fewer ventilator-, ICU-, and hospital-free days, and greater mortality (30.4% versus 11.1%) when compared to light sedation (p < 0.01 for all). After adjusting for confounders, early deep sedation remained significantly associated with higher mortality (adjusted OR 3.44; 95% CI 1.65-7.17; p < 0.01). These results were stable in the subgroup of patients with COVID-19. CONCLUSIONS: The management of sedation for mechanically ventilated patients in the ICU has changed during the COVID pandemic. Early deep sedation is common and independently associated with worse clinical outcomes. A protocol-driven approach to sedation, targeting light sedation as early as possible, should continue to remain the default approach.

Mechanical Ventilation Practices and Low Tidal Volume Ventilation in Air Medical Transport Patients: The AIR-VENT Study.

BACKGROUND: The management of mechanical ventilation critically impacts outcome for patients with acute respiratory failure. Ventilator settings in the early post-intubation period may be especially influential on outcome. Low tidal volume ventilation in the prehospital setting has been shown to impact the provision of low tidal volume after admission and influence outcome. However, there is an overall paucity of data on mechanical ventilation for air medical transport patients. The objectives of this study were to characterize air medical transport ventilation practices and assess variables associated with nonprotective ventilation. METHODS: This was a multi-center, nationwide (approximately 130 bases) retrospective cohort study conducted on consecutive, adult mechanically ventilated air medical transport patients treated in the prehospital environment. Descriptive statistics were used to assess the cohort; the chi-square test compared categorical variables, and continuous variables were compared using independent samples t test or Mann-Whitney U test. To assess for predictors of nonprotective ventilation, a multivariable logistic regression model was constructed to adjust for potentially confounding variables. Low tidal volume ventilation was defined as a tidal volume of ≤ 8 mL/kg predicted body weight (PBW). RESULTS: A total of 68,365 subjects were studied. Height was documented in only 4,186 (6.1%) subjects. Significantly higher tidal volume/PBW (8.6 [8.3-9.2] mL vs 6.5 [6.1-7.0] mL) and plateau pressure (20.0 [16.5-25.0] cm H2O vs 18.0 [15.0-22.0] cm H2O) were seen in the nonpro-tective ventilation group (P < .001 for both). According to sex, females received higher tidal volume/PBW compared to males (7.4 [6.6-8.0] mL vs 6.4 [6.0-6.8] mL, P < .001) and composed 75% of those subjects with nonprotective ventilation compared to 25% male, P < .001. After multivariable logistic regression, female sex was an independent predictor of nonprotective ventilation (adjusted odds ratio 6.79 [95% CI 5.47-8.43], P < .001). CONCLUSIONS: The overwhelming majority of air medical transport subjects had tidal volume set empirically, which may be exposing patients to nonprotective ventilator settings. Given a lack of PBW assessments, the frequency of low tidal volume use remains unknown. Performance improvement initiatives aimed at indexing tidal volume to PBW are easy targets to improve the delivery of mechanical ventilation in the prehospital arena, especially for females.

The Feasibility of Implementing Targeted SEDation in Mechanically Ventilated Emergency Department Patients: The ED-SED Pilot Trial.

OBJECTIVES: Deep sedation in the emergency department (ED) is common, increases deep sedation in the ICU, and is negatively associated with outcome. Limiting ED deep sedation may, therefore, be a high-yield intervention to improve outcome. However, the feasibility of conducting an adequately powered ED-based clinical sedation trial is unknown. Our objectives were to assess trial feasibility in terms of: 1) recruitment, 2) protocol implementation and practice change, and 3) safety. Patient-centered clinical outcomes were assessed to better plan for a future large-scale clinical trial. DESIGN: Pragmatic, multicenter ( n = 3), prospective before-after pilot and feasibility trial. SETTING: The ED and ICUs at three medical centers. PATIENTS: Consecutive, adult mechanically ventilation ED patients. INTERVENTIONS: An educational initiative aimed at reliable ED sedation depth documentation and reducing the proportion of deeply sedated patients (primary outcome). MEASUREMENTS AND MAIN RESULTS: Sedation-related data in the ED and the first 48 ICU hours were recorded. Deep sedation was defined as a Richmond Agitation-Sedation Scale of -3 to -5 or a Sedation-Agitation Scale of 1-3. One thousand three hundred fifty-six patients were screened; 415 comprised the final population. Lighter ED sedation was achieved in the intervention group, and the proportion of deeply sedated patients was reduced from 60.2% to 38.8% ( p < 0.01). There were no concerning trends in adverse events (i.e., inadvertent extubation, device removal, and awareness with paralysis). Mortality was 10.0% in the intervention group and 20.4% in the preintervention group ( p < 0.01). Compared with preintervention, the intervention group experienced more ventilator-free days [22.0 (9.0) vs 19.9 (10.6)] and ICU-free days [20.8 (8.7) vs 18.1 (10.4)], p < 0.05 for both. CONCLUSIONS: This pilot trial confirmed the feasibility of targeting the ED in order to improve sedation practices and reduce deep sedation. These findings justify an appropriately powered clinical trial regarding ED-based sedation to improve clinical outcomes.