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Bradley E Chipps,1 Robert S Zeiger,2 David A Beuther,3 Robert A Wise,4 William McCann,5 Joan Reibman,6 Maureen George,7 Ileen Gilbert,8 James M Eudicone,8 Karin S Coyne,9 Gale Harding,9 Kevin R Murphy10 1Capital Allergy & Respiratory Disease Center, Sacramento, CA, USA; 2Department of Clinical Science, Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, CA, USA; 3Department of Medicine, National Jewish Health, Denver, CO, USA; 4Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 5Allergy Partners, Asheville, NC, USA; 6Department of Medicine, New York University School of Medicine, New York, NY, USA; 7Columbia University School of Nursing, New York, NY, USA; 8BioPharmaceuticals Medical, AstraZeneca, Wilmington, DE, USA; 9Evidera, Bethesda, MD, USA; 10Boys Town National Research Hospital, Boys Town, NE, USACorrespondence: Bradley E Chipps, Capital Allergy & Respiratory Disease Center, 5609 J Street, Suite C, Sacramento, CA, 95819, USA, Tel +1 916-453-1454, Email bchipps@capitalallergy.com

Theresa W Guilbert,1 Kevin R Murphy,2 Eckard Hamelmann,3 Kristie R Ross,4 Atul Gupta,5 Alessandro Fiocchi,6 Changming Xia,7 Rebecca Gall,7 Olivier Ledanois,8 Amr Radwan,7 Juby A Jacob-Nara,9 Paul J Rowe,9 Yamo Deniz7 1Cincinnati Children’s Hospital and University of Cincinnati, Cincinnati, OH, USA; 2Boys Town National Research Hospital, Omaha, NE, USA; 3Department of Pediatrics, Children’s Center Bethel, University of Bielefeld, Bielefeld, Germany; 4UH Rainbow Babies and Children’s Hospital, Cleveland, OH, USA; 5King’s College Hospital, London, UK; 6Bambino Gesù Children’s Hospital IRCCS, Rome, Italy; 7Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA; 8Sanofi, Paris, France; 9Sanofi, Bridgewater, NJ, USACorrespondence: Theresa W Guilbert, Cincinnati Children’s Hospital and University of Cincinnati, Cincinnati, OH, USA, Tel +1 513-636-6771, Email theresa.guilbert@cchmc.orgBackground: Severe, uncontrolled asthma and asthma exacerbations in children are associated with abnormal lung function and airway development, and increased risk of chronic obstructive lung disease in adulthood. The rationale for this post hoc analysis was to explore the relationship between changes in asthma exacerbation rates and lung function in children treated with dupilumab.Methods: This post hoc analysis included children aged 6 to 11 years with uncontrolled, moderate-to-severe type 2 asthma (blood eosinophils ≥ 150 cells/μL or fractional exhaled nitric oxide ≥ 20 ppb) who received dupilumab or placebo in the phase 3 LIBERTY ASTHMA VOYAGE study (NCT02948959). Endpoints were the proportion of patients achieving clinically meaningful improvements (≥ 5% or ≥ 10%) in pre-bronchodilator percent-predicted forced expiratory volume in 1 second (ppFEV1) by Week 12, annualized severe asthma exacerbation rates from Week 12– 52, and mean change from baseline in ppFEV1 to Week 12.Results: At Week 12 of VOYAGE, 141/236 (60%) of children treated with dupilumab and 57/114 (50%) of children receiving placebo showed improvements of ≥ 5% in ppFEV1; 106/236 (45%) children receiving dupilumab and 36/114 (32%) receiving placebo achieved improvements in ppFEV1 ≥ 10%. During the Week 12– 52 treatment period, dupilumab vs placebo significantly reduced severe exacerbation rates in all subgroups by 52– 60% (all P< 0.05). Dupilumab treatment resulted in rapid and sustained improvements in ppFEV1 (Week 12 least squares mean difference [95% CI] vs placebo: 3.54 [0.30, 6.78] percentage points; P=0.03) in children who achieved improvements of ≥ 5%.Conclusion: Dupilumab vs placebo significantly improved pre-bronchodilator ppFEV1, with a higher proportion of patients achieving a clinically meaningful response at Week 12. Dupilumab also significantly reduced severe exacerbation rates, independent of pre-bronchodilator ppFEV1 response at Week 12.Trial Registration: NCT02948959.Keywords: asthma, children, dupilumab, exacerbations, lung function, moderate-to-severe asthma, percent-predicted FEV1, uncontrolled asthma

Joan Reibman,1 Bradley E Chipps,2 Robert S Zeiger,3 David A Beuther,4 Robert A Wise,5 William McCann,6 Ileen Gilbert,7 James M Eudicone,7 Hitesh N Gandhi,7 Gale Harding,8 Katelyn Cutts,8 Karin S Coyne,8 Kevin R Murphy,9 Maureen George10 1New York University School of Medicine, New York, NY, USA; 2Capital Allergy & Respiratory Disease Center, Sacramento, CA, USA; 3Department of Clinical Science Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, CA, USA; 4National Jewish Health, Denver, CO, USA; 5Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 6Allergy Partners, Asheville, NC, USA; 7BioPharmaceuticals Medical, AstraZeneca, Wilmington, DE, USA; 8Evidera, Bethesda, MD, USA; 9Boys Town National Research Hospital, Boys Town, NE, USA; 10Office of Research & Scholarship, Columbia University School of Nursing, New York, NY, USACorrespondence: Joan Reibman, New York University School of Medicine, 550 1st Avenue, Room NB7N24, New York, NY, 10016, USA, Tel +1 212-263-6479, Fax +1 212-263-8442, Email joan.reibman@nyumc.orgPurpose: Critical asthma outcomes highlighted in clinical guidelines include asthma-related quality of life, asthma exacerbations, and asthma control. An easy-to-implement measure of asthma control that assesses both symptom impairment and exacerbation risk and reflects the impact of asthma on patients’ lives is lacking. Hence, the objective of this study was to assess the Asthma Impairment and Risk Questionnaire (AIRQ®) construct validity relative to patient self-perception of asthma status and validated disease-specific patient-reported outcome (PRO) measures.Patients and methods: Baseline data were analyzed from patients (aged ≥ 12 years) with asthma participating in a 12-month observational study assessing the ability of AIRQ to predict exacerbations. At entry, patients completed a sociodemographic questionnaire, AIRQ, 3 questions addressing self-perceived asthma status, Saint George’s Respiratory Questionnaire (SGRQ), mini-Asthma Quality of Life Questionnaire (AQLQ), and Adult Asthma Adherence Questionnaire (AAAQ). Descriptive statistics were calculated for demographic and clinical characteristics. AIRQ construct validity was evaluated by assessing correlations between total AIRQ score and patient self-assessments, SGRQ, mini-AQLQ, and AAAQ scores. Comparisons of SGRQ, mini-AQLQ, and AAAQ total and component/domain scores by AIRQ control category were performed using general linear models and Scheffe’s post hoc adjustments for pairwise comparisons.Results: A total of 1112 patients were enrolled: 70% female, 78% White, mean (standard deviation) age 43.9 (19.5) years. There were highly significant correlations between AIRQ score and patient self-perception of overall control (r = 0.69; p < 0.001), total SGRQ (r = 0.74, p < 0.001), and mini-AQLQ (r = − 0.78, p < 0.001) scores. As AIRQ control category worsened, so did total and domain SGRQ, mini-AQLQ, and AAAQ impediment-to-inhaled-corticosteroid-adherence scores (all pairwise comparisons p < 0.001).Conclusion: Findings demonstrate the construct validity of AIRQ relative to patient self-perception of asthma status, disease-specific PRO measures, and treatment adherence barriers. AIRQ can be a useful instrument to raise awareness of the unrecognized impacts of asthma on patients’ lives.Keywords: exacerbation, patient-reported outcomes, construct validity, impact of asthma

Kelly R Murphy, John E McManigle, Benjamin M Wildman-Tobriner, Amy Little Jones, Travis J Dekker, Barrett A Little, Joseph P Doty, Dean C Taylor Duke Healthcare Leadership Program, Duke University School of Medicine, Durham, NC, USA Abstract: The medical community has recognized the importance of leadership skills among its members. While numerous leadership assessment tools exist at present, few are specifically tailored to the unique health care environment. The study team designed a 24-item survey (Healthcare Evaluation & Assessment of Leadership [HEAL]) to measure leadership competency based on the core competencies and core principles of the Duke Healthcare Leadership Model. A novel digital platform was created for use on handheld devices to facilitate its distribution and completion. This pilot phase involved 126 health care professionals self-assessing their leadership abilities. The study aimed to determine both the content validity of the survey and the feasibility of its implementation and use. The digital platform for survey implementation was easy to complete, and there were no technical problems with survey use or data collection. With regard to reliability, initial survey results revealed that each core leadership tenet met or exceeded the reliability cutoff of 0.7. In self-assessment of leadership, women scored themselves higher than men in questions related to patient centeredness (P=0.016). When stratified by age, younger providers rated themselves lower with regard to emotional intelligence and integrity. There were no differences in self-assessment when stratified by medical specialty. While only a pilot study, initial data suggest that HEAL is a reliable and easy-to-administer survey for health care leadership assessment. Differences in responses by sex and age with respect to patient centeredness, integrity, and emotional intelligence raise questions about how providers view themselves amid complex medical teams. As the survey is refined and further administered, HEAL will be used not only as a self-assessment tool but also in “360” evaluation formats. Keywords: emotional intelligence, patient centeredness, sex, specialty, age, leadership assessment

Poloidal ultra-low frequency (ULF) waves between 5-10 mHz were observed by multiple satellites and three high-latitude Super Dual Auroral Radar Network (SuperDARN) radars during the recovery phase of a moderate geomagnetic storm on Jan 24-27, 2016. The long-lasting ULF waves were observed in the magnetic field and energetic particle flux perturbations during three successive passes by two Geostationary Operational Environmental Satellites (GOES) through the dayside magnetosphere, during which plasmasphere expansion and refilling were observed by two Time History of Events and Macroscale Interactions during Substorms (THEMIS) probes. The radial magnetic field oscillation was in phase (~ 180° out of phase) with the northward (southward) moving proton flux oscillation at 95 keV, consistent with high-energy drift-bounce resonance signatures of protons with second harmonic poloidal standing Alfvén waves. The longitudinal extent of the waves approached 10 hours in local time on the dayside and gradually decreased with time. High-time resolution (~ 6 s) data from three high-latitude SuperDARN radars show that the wave intensification region was localized in latitude with a radial extent of ~ 135-225 km in the subauroral ionosphere. No signature of these waves were observed by ground-based magnetometers colocated with the GOES satellites suggesting that the poloidal waves were high-m mode and thus screened by the ionosphere. During this interval one of the THEMIS probes observed a bump-on-tail ion distribution at 1-3 keV which we suggest is the source of the long-lasting second harmonic poloidal ULF waves.

Budesonide inhalation suspension (Pulmicort Respules®), administered through jet nebulization, and budesonide dry powder inhaler (Pulmicort Turbuhaler®) are used for the treatment of asthma; however, the age indication for these products varies by country. In the United States, the indication for budesonide inhalation suspension is limited to children aged 12 months to 8 years. In many countries, budesonide Turbuhaler is indicated for use in children as young as 5 years. This clinical study assessed asthma control in children aged 4-6 years when transitioning from budesonide inhalation suspension to budesonide Turbuhaler. Ten children maintained on once-daily budesonide inhalation suspension (0.25 or 0.5 mg) were transitioned to once-daily budesonide Turbuhaler (200 µg) for 6 weeks after a 2-week run-in period, during which the original dose of budesonide inhalation suspension was continued. The primary outcome assessment was the change from baseline to the average during the last 2 weeks of treatment in morning and evening peak expiratory flow (PEF) measurements. Secondary outcomes were short-acting ß2-adrenergic agonist (SABA) use, asthma symptom scores, and adverse events; peak inspiratory flow (PIF) also was assessed. Patients were able to maintain asthma control when transitioned from budesonide inhalation suspension to budesonide Turbuhaler. Mean improvements from baseline in morning and evening PEF were 19.1 and 16.8 L/min, respectively. At study end, no differences were observed in SABA use or daytime and nighttime asthma symptom scores compared with baseline. All but one patient demonstrated PIF values >/= 30 L/min at all visits throughout the study. No unexpected adverse events were observed, and no patients discontinued from the study. These results suggest that children with asthma aged 4-6 years can successfully be transitioned from once-daily budesonide inhalation suspension to budesonide Turbuhaler while maintaining asthma control. [ABSTRACT FROM AUTHOR]

The objectives of this study was to examine asthma prescription patterns in young children and the association between outcomes and controller therapy adherence. A retrospective cohort study was conducted using a U.S. multi-managed care plan database (1998-2004; PharMetrics). Inclusion criteria were: age /=1 emergency department visit or hospitalization) were assessed and compared with respect to controller therapy adherence using multivariate logistic regression. The majority of the 11,407 asthma patients were male (58.7%); mean age was 2.2 years. Most common initial treatments (alone or in combination) were short-acting beta2-adrenergic agonists (80.2%) and oral corticosteroids (34.2%); nebulized inhaled corticosteroid (ICS) was the most commonly prescribed initial controller therapy (4.9%). Fewer patients prescribed nebulized ICS as initial therapy (n = 553) had exacerbations (25.1%) versus those prescribed it as second- (n = 955; 29.3%) or third-line therapy (n = 514; 40.9%). Patients more adherent with controller medications had a decrease in exacerbations (23.2% vs. 16.8%, p = 0.001); those less adherent had a smaller decrease (23.1% vs. 19.1%, p = 0.049). Patients more adherent with nebulized ICS had a decrease in exacerbations (25.3% vs. 18.6%, p = 0.020); those less adherent did not (20.1% vs. 20.8%, p = 0.814). Greater nebulized ICS adherence significantly protected against exacerbations (OR = 0.6; 95% CI 0.37-0.99), while greater overall controller adherence showed a similar trend (OR = 0.8; 95% CI 0.59-.10). In young children, earlier initiation of nebulized ICS and adherence with controller therapies were associated with significantly lower emergency department/hospitalization rates. [ABSTRACT FROM AUTHOR]

The objective of this survey was to evaluate variability of symptoms in adult and pediatric patients with persistent asthma. Prospective participants from a US database of patients with asthma were invited to complete an Internet-based survey designed to assess the occurrence of asthma symptoms during the past year. A total of 1311 adult patients and 491 caregivers of pediatric patients were surveyed. Adult patients (18%-30%) and pediatric patients (8%-20%) experienced a variety of symptoms on a daily basis. At least 50% of patients receiving treatment experienced variability in 1 or more symptoms during the previous year. The most common treatment recommendation when asthma symptoms were experienced included changing the number of medication (reliever or controller) inhalations (48% and 55% of adult and pediatric patients, respectively) or adding another medication (31% and 39%). This survey indicates that adult patients and caregivers of pediatric patients report variability in asthma symptoms over time, even when asthma medications are taken. [ABSTRACT FROM AUTHOR]

Asthma incurs considerable economic costs, and the physical and emotional burden of asthma can be significant, even for patients with mild disease. Adherence to a guidelines-based treatment approach can greatly reduce the significant morbidity and associated health resources used due to asthma. [ABSTRACT FROM AUTHOR]

Background: Deficits in executive functioning (EF) are implicated in neurobiological and cognitive-processing theories of depression. EF deficits are also associated with Attention-deficit/hyperactivity disorder (ADHD) in adults, who are also at increased risk for depressive disorders. Given debate about the ecological validity of laboratory measures of EF, we investigated the relationship between depression diagnoses and symptoms and EF as measured by both rating scales and tests in a sample of adults referred for evaluation of adult ADHD.Method: Data from two groups of adults recruited from an ADHD specialty clinic were analyzed together: Adults diagnosed with ADHD (N=146) and a clinical control group of adults referred for adult ADHD assessment but not diagnosed with the disorder ADHD (N=97). EF was assessed using a rating scale of EF deficits in daily life and a battery of tests tapping various EF constructs. Depression was assessed using current and lifetime SCID diagnoses (major depression, dysthymia) and self-report symptom ratings.Results: EF as assessed via rating scale predicted depression across measures even when controlling for current anxiety and impairment. Self-Management to Time and Self-Organization and Problem-Solving showed the most robust relationships. EF tests were weakly and inconsistently related to depression measures.Limitations: Prospective studies are needed to rigorously evaluate EF problems as true risk factors for depressive onset.Conclusions: EF problems in everyday life were important predictors of depression. Researchers and clinicians should consistently assess for the ADHD-depression comorbidity. Clinicians should consider incorporating strategies to address EF deficits when treating people with depression. [ABSTRACT FROM AUTHOR]

Background: Asthma control assessment is based on impairment (current symptoms) and risk (exacerbation history)., Objective: To understand the extent of uncontrolled asthma, we assessed relationships between prescription fills for systemic corticosteroids (SCS) and short-acting β 2 -agonists (SABA) as risk and impairment markers, respectively., Methods: Annual SCS and SABA fills among US patients with asthma were evaluated by a retrospective analysis of the IQVIA Longitudinal Access and Adjudication Data. Patients' disease severity was assigned based on the Global Initiative for Asthma step-therapy level. Exacerbations were evaluated by SCS fills within 12 months of a first asthma prescription fill. Uncontrolled asthma was defined as 2 or more SCS and/or 3 or more SABA fills annually. Individual patient relationships between SCS and SABA fills were assessed using Pearson's correlation coefficients., Results: A total of 4,506,527 patients were included; 15.1% had 2 or more SCS fills, 29.1% had 3 or more SABA fills, and 37.4% fulfilled either or both criteria. If only SCS use was assessed, 21.4% of cases that were treated as mild to moderate and 27.6% that were treated as severe asthma would have been misclassified as controlled. If only SABA use was evaluated, 7.8% of cases treated as mild to moderate and 11.2% treated as severe asthma would have been misclassified. Overall, 80.9% of uncontrolled asthma occurred in patients treated for mild to moderate disease. Among patients with 2 or more SCS fills, the mean SABA fills were 2.9; the correlation between SCS and SABA fills per patient was significant but weak (r = 0.18; P < .001)., Conclusion: High symptom burden and SCS exposures are not limited to severe asthma but are also characteristic of patients treated for mild to moderate disease. Both impairment and risk assessments are required to understand the full extent of uncontrolled asthma across disease severities., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The Asthma Impairment and Risk Questionnaire (AIRQ) is a 10-item, yes/no, equally weighted control tool. Lower scores indicate better control. Moreover, 7 impairment items reflect previous 2-week symptoms, and 3 risk items assess previous 12-month exacerbations. The Follow-up AIRQ for use between annual assessments has a 3-month recall period for exacerbation items., Objective: To evaluate the responsiveness of the AIRQ over time and identify a minimal important difference (MID)., Methods: The AIRQ longitudinal study data were analyzed from patients with asthma aged 12 years and older. Anchor-based methods assessed differences in AIRQ scores relative to Patient Global Impression of Change, the accepted MIDs for St. George's Respiratory Questionnaire and Asthma Control Test, and exacerbation occurrence over 12 months. Baseline and 12-month data reflected 12-month recall AIRQ scores; Follow-up AIRQ scores were used for 3-, 6-, and 9-month analyses., Results: A total of 1070 patients were included. The Patient Global Impression of Change rating of "much improved" was associated with AIRQ mean score changes from baseline to months 3, 6, 9, and 12 of -2.0, -1.9, -1.9, and -1.8, respectively. The mean AIRQ score change among patients who met the St. George's Respiratory Questionnaire MID (≥4-point decrease) was -1.8 at 6 and 12 months. The AIRQ mean scores decreased from baseline by -2.2 to -2.5 points at months 3, 6, 9, and 12 for patients who met the Asthma Control Test MID (≥ 3-point increase). A 2-point higher baseline AIRQ score was associated with a 1.7 odds ratio of 12-month exacerbation occurrence (95% CI, 1.53-1.89)., Conclusion: A change score of 2 is recommended as the AIRQ MID., Competing Interests: Disclosures Dr McCann has served as a consultant and speaker for AstraZeneca, a speaker for Regeneron, and a consultant for Aimmune and Genentech. Dr Murphy has served as a consultant and is a speaker for AstraZeneca, Boehringer Ingelheim, Genentech, Greer, Merck, Mylan, Novartis, Regeneron, Sanofi, Optinose, and Teva. Dr Zeiger has received grants from Aerocrine, Genentech, MedImmune/AstraZeneca, Merck, GlaxoSmithKline, Teva, Quest, Sanofi, and the National Heart, Lung, and Blood Institute; has completed consultant activity for AstraZeneca, Regeneron, Merck, Genentech/Novartis, and Bayer; and holds warrant shares in DBV Technologies. Dr Beuther has participated in advisory boards for AstraZeneca. Dr Wise received consultant fees and honoraria from AstraZeneca, GlaxoSmithKline, Novartis, Boehringer Ingelheim, ContraFect, Pulmonx, Roche, Regeneron, AbbVie, Spiration, Sunovion, Merck, Circassia, Pneuma, Verona, Bonti, Denali, Aradigm, Mylan, Theravance, Propeller Health, Kiniksa, and Syneos. Dr Reibman has served as an advisory committee member for AstraZeneca, received grant/research support from Novartis, served on an advisory board for Novartis and Genentech, and participated in clinical trials funded by AstraZeneca, Novartis, and Teva. Dr George has served as a consultant and speaker to AstraZeneca, Regeneron, and Sanofi. Dr Gilbert and Mr Eudicone are employees of AstraZeneca. Dr Gandhi was an employee of AstraZeneca at the time this work was completed and is a current employee of Alexion, AstraZeneca Rare Disease. Ms Cutts and Dr Coyne are employees of Evidera, which was contracted by AstraZeneca for study design and to collect and analyze data for this study. Dr Chipps has served as an advisor, consultant, and speaker for AstraZeneca, Boehringer Ingelheim, Circassia, Genentech, Novartis, Regeneron, and Sanofi., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Complex models combining impairment-based control assessments with clinical characteristics and biomarkers have been developed to predict asthma exacerbations. The composite Asthma Impairment and Risk Questionnaire (AIRQ) with adjustments for demographics (age, sex, race, and body mass index) predicts 12-month exacerbation occurrence similarly to these more complex models., Objective: To examine whether AIRQ exacerbation prediction is enhanced when models are adjusted for a wider range of clinical characteristics and biomarkers., Methods: Patients aged 12 years and older completed monthly online surveys regarding exacerbation-related oral corticosteroid use, emergency department or urgent care visits, and hospitalizations. Univariate logistic regressions to predict exacerbations were performed with sociodemographics, comorbidities, exacerbation history, lung function, blood eosinophils, IgE, and FeNO. Significant (P ≤ .05) variables were included in multivariable logistic regressions with and without AIRQ control categories to predict 12-month exacerbations (log odds ratio [95% Wald confidence interval]). Model performances were compared., Results: Over 12 months, 1,070 patients (70% female; mean [SD] age, 43.9 [19.4] years; 22% non-White; body mass index [SD], 30.6 [8.7]) completed one or more survey (mean [SD], 10.5 [2.8] surveys). In the multivariable analysis, AIRQ control category adjusted for significant clinical characteristics and biomarkers was predictive of one or more exacerbations: odds ratio (95% CI) not well-controlled versus well-controlled: 1.93 (1.41-2.62), very poorly controlled versus well-controlled: 3.81 (2.65-5.47). Receiver operating characteristic area under the curve (AUC) for this more complex model of exacerbation prediction (AUC = 0.72) did not differ from AIRQ (AUC = 0.70). Models with AIRQ performed better than those without AIRQ (AUC = 0.67; P < .05)., Conclusion: Costly and time-consuming complex modeling with clinical characteristics and biomarkers does not enhance the strong exacerbation prediction ability of AIRQ., (Copyright © 2024. Published by Elsevier Inc.)

Focused ultrasound can non-invasively modulate neural activity, but whether effective stimulation parameters generalize across brain regions and cell types remains unknown. We used focused ultrasound coupled with fiber photometry to identify optimal neuromodulation parameters for four different arousal centers of the brain in an effort to yield overt changes in behavior. Applying coordinate descent, we found that optimal parameters for excitation or inhibition are highly distinct, the effects of which are generally conserved across brain regions and cell types. Optimized stimulations induced clear, target-specific behavioral effects, whereas non-optimized protocols of equivalent energy resulted in substantially less or no change in behavior. These outcomes were independent of auditory confounds and, contrary to expectation, accompanied by a cyclooxygenase-dependent and prolonged reduction in local blood flow and temperature with brain-region-specific scaling. These findings demonstrate that carefully tuned and targeted ultrasound can exhibit powerful effects on complex behavior and physiology., Competing Interests: Declaration of interests K.R.M. and L.d.L. are co-inventors on a patent application assigned to Stanford University containing disclosures related to technology used in this article., (Copyright © 2024. Published by Elsevier Inc.)

Background: National and international asthma guidelines and reports do not include control tools that combine impairment assessment with exacerbation history in one instrument., Objective: To analyze the performance of the composite Asthma Impairment and Risk Questionnaire (AIRQ) in assessing both domains of control and predicting exacerbation risk compared with the Global Initiative for Asthma (GINA) 4-question symptom control tool (GINA SCT), Asthma Control Test (ACT), and physician expert opinion (EO) informed by GINA SCT responses and appraisal of GINA-identified risk factors for poor asthma outcomes., Methods: Multivariable logistic regressions evaluated AIRQ and GINA SCT as predictors of ACT. McNemar's test compared the proportion of patients categorized at baseline as completely or well-controlled by each assessment but with current impairment or previous-year and subsequent-year exacerbations., Results: The analysis included 1064 patients aged 12 years or older; mean (SD) age 43.8 years (19.3); 70% female; 79% White; and 6% Hispanic or Latino. AIRQ and GINA SCT were highly predictive of ACT well-controlled vs not well-controlled and very poorly controlled (receiver operator characteristic area under curve AIRQ = 0.90, GINA SCT = 0.86, P = .03 AIRQ vs GINA SCT) and ACT very poorly controlled vs well-controlled and not well-controlled asthma (receiver operator characteristic area under curve AIRQ = 0.91, GINA SCT = 0.87, P = .01 AIRQ vs GINA SCT). AIRQ rated fewer patients as having completely or well-controlled asthma who had current impairment (P < .01) or with previous-year and subsequent-year exacerbations (P < .001) than did GINA SCT, ACT, and EO., Conclusion: AIRQ performs better in assessing both domains of current control and predicting exacerbation risk than do control tools and EO informed by GINA SCT and risk factors for poor asthma outcomes., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Sleep and feeding are vital homeostatic behaviors, and disruptions in either can result in substantial metabolic consequences. Distinct neuronal manipulations in Drosophila can dissociate sleep loss from subsequent homeostatic rebound, offering an optimal platform to examine the precise interplay between these fundamental behaviors. Here, we investigate concomitant changes in sleep and food intake in individual animals, as well as respiratory metabolic expenditure, that accompany behavioral and genetic manipulations that induce sleep loss in Drosophila melanogaster . We find that sleep disruptions resulting in energy deficit through increased metabolic expenditure and manifested as increased food intake were consistently followed by rebound sleep. In contrast, "soft" sleep loss, which does not induce rebound sleep, is not accompanied by increased metabolism and food intake. Our results demonstrate that homeostatic sleep rebound is linked to energy deficit accrued during sleep loss. Collectively, these findings support the notion that sleep functions to conserve energy and highlight the need to examine the effects of metabolic therapeutics on sleep., Competing Interests: Declaration of Interests The authors declare no competing interests.

Rapid conversion of force into a biological signal enables living cells to respond to mechanical forces in their environment. The force is believed to initially affect the plasma membrane and then alter the behavior of membrane proteins. Phospholipase D2 (PLD2) is a mechanosensitive enzyme that is regulated by a structured membrane-lipid site comprised of cholesterol and saturated ganglioside (GM1). Here we show stretch activation of TWIK-related K + channel (TREK-1) is mechanically evoked by PLD2 and spatial patterning involving ordered GM1 and 4,5-bisphosphate (PIP 2 ) clusters in mammalian cells. First, mechanical force deforms the ordered lipids, which disrupts the interaction of PLD2 with the GM1 lipids and allows a complex of TREK-1 and PLD2 to associate with PIP 2 clusters. The association with PIP 2 activates the enzyme, which produces the second messenger phosphatidic acid (PA) that gates the channel. Co-expression of catalytically inactive PLD2 inhibits TREK-1 stretch currents in a biological membrane. Cellular uptake of cholesterol inhibits TREK-1 currents in culture and depletion of cholesterol from astrocytes releases TREK-1 from GM1 lipids in mouse brain. Depletion of the PLD2 ortholog in flies results in hypersensitivity to mechanical force. We conclude PLD2 mechanosensitivity combines with TREK-1 ion permeability to elicit a mechanically evoked response., Competing Interests: EP, MP, SH, MG, HW, ZY, KM, WJ, HF, EJ, SH No competing interests declared, (© 2023, Petersen et al.)

Endotherms can survive low temperatures and food shortage by actively entering a hypometabolic state known as torpor. Although the decrease in metabolic rate and body temperature (Tb) during torpor is controlled by the brain, the specific neural circuits underlying these processes have not been comprehensively elucidated. In this study, we identify the neural circuits involved in torpor regulation by combining whole-brain mapping of torpor-activated neurons, cell-type-specific manipulation of neural activity, and viral tracing-based circuit mapping. We find that Trpm2-positive neurons in the preoptic area and Vgat-positive neurons in the dorsal medial hypothalamus are activated during torpor. Genetic silencing shows that the activity of either cell type is necessary to enter the torpor state. Finally, we show that these cells receive projections from the arcuate and suprachiasmatic nucleus and send projections to brain regions involved in thermoregulation. Our results demonstrate an essential role of hypothalamic neurons in the regulation of Tb and metabolic rate during torpor and identify critical nodes of the torpor regulatory network., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Neuropeptide S (NPS) is a highly conserved peptide found in all tetrapods that functions in the brain to promote heightened arousal; however, the subpopulations mediating these phenomena remain unknown. We generated mice expressing Cre recombinase from the Nps gene locus (Nps Cre ) and examined populations of NPS+ neurons in the lateral parabrachial area (LPBA), the peri-locus coeruleus (peri-LC) region of the pons, and the dorsomedial thalamus (DMT). We performed brain-wide mapping of input and output regions of NPS+ clusters and characterized expression patterns of the NPS receptor 1 (NPSR1). While the activity of all three NPS+ subpopulations tracked with vigilance state, only NPS+ neurons of the LPBA exhibited both increased activity prior to wakefulness and decreased activity during REM sleep, similar to the behavioral phenotype observed upon NPSR1 activation. Accordingly, we found that activation of the LPBA but not the peri-LC NPS+ neurons increased wake and reduced REM sleep. Furthermore, given the extended role of the LPBA in respiration and the link between behavioral arousal and breathing rate, we demonstrated that the LPBA but not the peri-LC NPS+ neuronal activation increased respiratory rate. Together, our data suggest that NPS+ neurons of the LPBA represent an unexplored subpopulation regulating breathing, and they are sufficient to recapitulate the sleep/wake phenotypes observed with broad NPS system activation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Transcranial ultrasound neuromodulation is a promising potential therapeutic tool for the noninvasive treatment of neuropsychiatric disorders. However, the expansive parameter space and difficulties in controlling for peripheral auditory effects make it challenging to identify ultrasound sequences and brain targets that may provide therapeutic efficacy. Careful preclinical investigations in clinically relevant behavioral models are critically needed to identify suitable brain targets and acoustic parameters. However, there is a lack of ultrasound devices allowing for multi-target experimental investigations in awake and unrestrained rodents. We developed a miniaturized 64-element ultrasound array that enables neurointerventional investigations with within-trial active control targets in freely behaving rats. We first characterized the acoustic field with measurements in free water and with transcranial propagation. We then confirmed in vivo that the array can target multiple brain regions via electronic steering, and verified that wearing the device does not cause significant impairments to animal motility. Finally, we demonstrated the performance of our system in a high-throughput neuromodulation experiment, where we found that ultrasound stimulation of the rat central medial thalamus, but not an active control target, promotes arousal and increases locomotor activity., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: RDA has equity and has received consulting fees from Cordance Medical and Lumos Labs and grant funding from AbbVie Inc. LdL and KRM have equity/stock options from Attune Neurosciences, Inc and are co-inventors on a patent application assigned to Stanford University. KPM is an employee of Sonic Concepts, Inc. TDI has equity/stock options and has received consulting fees from Attune Neurosciences, Inc. All other authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Asthma control is often overestimated in routine practice, and despite advances in the understanding of immunopathology and the availability of new precision therapies, the burden of disease remains unacceptably high., Objective: To compare the performance of the Asthma Impairment and Risk Questionnaire (AIRQ) with patient and physician assessments and the Asthma Control Test (ACT) in identifying asthma control., Methods: Baseline data from a longitudinal study of the AIRQ were analyzed. Patients with asthma in the United States aged 12 years and older followed in 24 specialty practices and 1 specialty-affiliated primary care clinic were enrolled between May and November 2019. At entry, participants completed AIRQ and ACT, and participants and physicians completed 5-point Likert scale assessments of control., Results: A total of 1112 participants were enrolled (mean [SD] age = 43.9 [19.3] years, 70% of the female sex, 78% White). Overall, 62% of participants rated themselves as well- or completely controlled, and 54% were rated comparably by physicians. The ACT classified 49% of participants as well-controlled, with 35% similarly categorized by AIRQ. Previous-year exacerbations were experienced by 32% of participants who self-rated as well- or completely controlled, 30% who were rated as well- or completely controlled by physicians, and 29% assessed as well-controlled by ACT, but only 15% of those classified as well-controlled by AIRQ., Conclusion: The burden of asthma is substantial in patients cared for by asthma specialists, and asthma control is overestimated by patients, physicians, and the symptom-based ACT. The AIRQ assesses risk in addition to symptom control and may serve to improve asthma control determination by assessing previous exacerbations., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Pseudomonas aeruginosa frequently becomes resistant to aminoglycosides by the acquisition of aminoglycoside modifying enzyme (AME) genes and the occurrence of mutations in the mexZ, fusA1, parRS, and armZ genes. We examined resistance to aminoglycosides in a collection of 227 P. aeruginosa bloodstream isolates collected over 2 decades from a single United States academic medical institution. Resistance rates of tobramycin and amikacin were relatively stable over this time, while the resistance rates of gentamicin were somewhat more variable. For comparison, we examined resistance rates to piperacillin-tazobactam, cefepime, meropenem, ciprofloxacin, and colistin. Resistance rates to the first four antibiotics were also stable, although uniformly higher for ciprofloxacin. Colistin resistance rates were initially quite low, rose substantially, and then began to decrease at the end of the study. Clinically relevant AME genes were identified in 14% of isolates, and mutations predicted to cause resistance were relatively common in the mexZ and armZ genes. In a regression analysis, resistance to gentamicin was associated with the presence of at least one gentamicin-active AME gene and significant mutations in mexZ, parS, and fusA1 . Resistance to tobramycin was associated with the presence of at least one tobramycin-active AME gene. An extensively drug-resistant strain, PS1871, was examined further and found to contain five AME genes, most of which were within clusters of antibiotic resistance genes embedded in transposable elements. These findings demonstrate the relative contributions of aminoglycoside resistance determinants to P. aeruginosa susceptibilities at a United States medical center. IMPORTANCE Pseudomonas aeruginosa is frequently resistant to multiple antibiotics, including aminoglycosides. The rates of resistance to aminoglycosides in bloodstream isolates collected over 2 decades at a United States hospital remained constant, suggesting that antibiotic stewardship programs may be effective in countering an increase in resistance. Mutations in the mexZ, fusA1, parR, pasS, and armZ genes were more common than acquisition of genes encoding aminoglycoside modifying enzymes. The whole-genome sequence of an extensively drug resistant isolate indicates that resistance mechanisms can accumulate in a single strain. Together, these results suggest that aminoglycoside resistance in P. aeruginosa remains problematic and confirm known resistance mechanisms that can be targeted for the development of novel therapeutics., Competing Interests: The authors declare no conflict of interest.

Progressive tissue remodeling after myocardial infarction (MI) promotes cardiac arrhythmias. This process is well studied in young animals, but little is known about pro-arrhythmic changes in aged animals. Senescent cells accumulate with age and accelerate age-associated diseases. Senescent cells interfere with cardiac function and outcome post-MI with age, but studies have not been performed in larger animals, and the mechanisms are unknown. Specifically, age-associated changes in timecourse of senescence and related changes in inflammation and fibrosis are not well understood. Additionally, the cellular and systemic role of senescence and its inflammatory milieu in influencing arrhythmogenesis with age is not clear, particularly in large animal models with cardiac electrophysiology more similar to humans than previously studied animal models. Here, we investigated the role of senescence in regulating inflammation, fibrosis, and arrhythmogenesis in young and aged infarcted rabbits. Aged rabbits exhibited increased peri-procedural mortality and arrhythmogenic electrophysiological remodeling at the infarct border zone (IBZ) compared to young rabbits. Studies of the aged infarct zone revealed persistent myofibroblast senescence and increased inflammatory signaling over a 12-week timecourse. Senescent IBZ myofibroblasts in aged rabbits appear to be coupled to myocytes, and our computational modeling showed that senescent myofibroblast-cardiomyocyte coupling prolongs action potential duration (APD) and facilitates conduction block permissive of arrhythmias. Aged infarcted human ventricles show levels of senescence consistent with aged rabbits, and senescent myofibroblasts also couple to IBZ myocytes. Our findings suggest that therapeutic interventions targeting senescent cells may mitigate arrhythmias post-MI with age., Competing Interests: BB, KM, ES, EM, YC, NT, YL, LS, TK, AK, PB, ZQ, PC, PD, DT, Fd, BC, JS, GK No competing interests declared, (© 2023, Baggett, Murphy, Sengun et al.)

Omalizumab, a recombinant anti-immunoglobulin E (IgE) monoclonal antibody, is indicated for moderate to severe allergic asthma, chronic spontaneous urticaria, and nasal polyps, and is approved for self-administration. However, specific guidance on identifying candidates with characteristics suitable for this type of administration is lacking. To help address this issue, this article provides practical considerations for the health care provider treating patients with omalizumab. We encourage health care providers to consider self-administration of omalizumab as an option for all appropriate, but not all, patients, and we recommend an individualized approach when considering self-administration of omalizumab., (© 2022. The Author(s).)

Background: The Asthma Impairment and Risk Questionnaire (AIRQ) is a 10-item, equally weighted, yes/no control tool validated in patients with asthma aged 12 years and older., Objective: To evaluate AIRQ's ability to predict patient-reported exacerbations over 12 months., Methods: Patients completed a baseline AIRQ during an in-person enrollment visit and reported exacerbations (ie, asthma-related courses of oral corticosteroids, emergency department/urgent care visits, and hospitalizations) via monthly online surveys. Logistic regressions were performed using AIRQ control level (well-controlled [WC], not well-controlled [NWC], very poorly controlled [VPC]), age, sex, race, and body mass index as covariates and 1 or more and 2 or more exacerbations as the dependent variables (adjusted odds ratios [OR] and 95% Wald CIs). Kaplan-Meier analyses of time to first exacerbation by AIRQ control level were performed., Results: A total of 1,112 patients were enrolled; 1,070 completed 1 or more surveys over 12 months (mean ± SD 10.5 ± 2.8 months); 70.5% female; age 43.9 ± 19.3 years; 20.4% non-White; body mass index 30.6 ± 8.7 kg/m 2 ; AIRQ: WC 35.2%, NWC 38.1%, VPC 26.6%. A total of 45.7% of patients reported 1 or more exacerbations and 26.7% 2 or more exacerbations (WC 28.4% ≥ 1, 11.1% ≥ 2; NWC 46.3% ≥ 1, 27.9% ≥ 2; VPC 67.7% ≥ 1, 45.6% ≥ 2). The ORs for 1 or more exacerbations NWC versus WC were 2.1 (CI 1.6-2.9), and VPC versus WC were 4.6 (CI 3.3-6.5). The ORs for 2 or more exacerbations NWC versus WC were 3.1 (CI 2.1-4.6), and VPC versus WC were 6.1 (CI 4.0-9.1). Kaplan-Meier curves demonstrated clear differentiation of time to first exacerbation by AIRQ control level (P < .001)., Conclusions: The AIRQ control level predicts exacerbation risk over 12 months and probability of time to first exacerbation., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Focused ultrasound (FUS) is a powerful tool for noninvasive modulation of deep brain activity with promising therapeutic potential for refractory epilepsy; however, tools for examining FUS effects on specific cell types within the deep brain do not yet exist. Consequently, how cell types within heterogeneous networks can be modulated and whether parameters can be identified to bias these networks in the context of complex behaviors remains unknown. To address this, we developed a fiber Photometry Coupled focused Ultrasound System (PhoCUS) for simultaneously monitoring FUS effects on neural activity of subcortical genetically targeted cell types in freely behaving animals. We identified a parameter set that selectively increases activity of parvalbumin interneurons while suppressing excitatory neurons in the hippocampus. A net inhibitory effect localized to the hippocampus was further confirmed through whole brain metabolic imaging. Finally, these inhibitory selective parameters achieved significant spike suppression in the kainate model of chronic temporal lobe epilepsy, opening the door for future noninvasive therapies.

Despite our growing understanding of the global carbon cycle, scientific consensus on the drivers and mechanisms that control dissolved organic carbon (DOC) turnover in aquatic systems is lacking, hampered by the mismatch between research that approaches DOC reactivity from either intrinsic (inherent chemical properties) or extrinsic (environmental context) perspectives. Here we propose a conceptual view of DOC reactivity in which the combination of intrinsic and extrinsic factors controls turnover rates and determines which reactions will occur. We review three major types of reactions (biological, photochemical, and flocculation) from an intrinsic chemical perspective and further define the environmental features that modulate the expression of chemically inherent reactivity potential. Finally, we propose hypotheses of how extrinsic and intrinsic factors together shape patterns in DOC turnover across the land-to-ocean continuum, underscoring that there is no intrinsic DOC reactivity without environmental context. By acknowledging the intrinsic-extrinsic control duality, our framework intends to foster improved modeling of DOC reactivity and its impact on ecosystem services., (© 2022 The Authors. Ecology published by Wiley Periodicals LLC on behalf of The Ecological Society of America.)

DNA barcoding is critical to conservation and biodiversity research, yet public reference databases are incomplete. Existing barcode databases are biased toward cytochrome oxidase subunit I (COI) and frequently lack associated voucher specimens or geospatial metadata, which can hinder reliable species assignments. The emergence of metabarcoding approaches such as environmental DNA (eDNA) has necessitated multiple marker techniques combined with barcode reference databases backed by voucher specimens. Reference barcodes have traditionally been generated by Sanger sequencing, however sequencing multiple markers is costly for large numbers of specimens, requires multiple separate PCR reactions, and limits resulting sequences to targeted regions. High-throughput sequencing techniques such as genome skimming enable assembly of complete mitogenomes, which contain the most commonly used barcoding loci ( e.g., COI, 12S, 16S), as well as nuclear ribosomal repeat regions ( e.g., ITS1&2, 18S). We evaluated the feasibility of genome skimming to generate barcode references databases for marine fishes by assembling complete mitogenomes and nuclear ribosomal repeats. We tested genome skimming across a taxonomically diverse selection of 12 marine fish species from the collections of the National Museum of Natural History, Smithsonian Institution. We generated two sequencing libraries per species to test the impact of shearing method (enzymatic or mechanical), extraction method (kit-based or automated), and input DNA concentration. We produced complete mitogenomes for all non-chondrichthyans (11/12 species) and assembled nuclear ribosomal repeats (18S-ITS1-5.8S-ITS2-28S) for all taxa. The quality and completeness of mitogenome assemblies was not impacted by shearing method, extraction method or input DNA concentration. Our results reaffirm that genome skimming is an efficient and (at scale) cost-effective method to generate all mitochondrial and common nuclear DNA barcoding loci for multiple species simultaneously, which has great potential to scale for future projects and facilitate completing barcode reference databases for marine fishes., Competing Interests: The authors declare there are no competing interests., (©2022 Hoban et al.)

Background: Spinal cord stimulation (SCS) effectively reduces opioid usage in some patients, but preoperatively, there is no objective measure to predict who will most benefit., Objective: To predict successful reduction or stabilization of opioid usage after SCS using machine learning models we developed and to assess if deep learning provides a significant benefit over logistic regression (LR)., Methods: We used the IBM MarketScan national databases to identify patients undergoing SCS from 2010 to 2015. Our models predict surgical success as defined by opioid dose stability or reduction 1 year after SCS. We incorporated 30 predictors, primarily regarding medication patterns and comorbidities. Two machine learning algorithms were applied: LR with recursive feature elimination and deep neural networks (DNNs). To compare model performances, we used nested 5-fold cross-validation to calculate area under the receiver operating characteristic curve (AUROC)., Results: The final cohort included 7022 patients, of whom 66.9% had successful surgery. Our 5-variable LR performed comparably with the full 30-variable version (AUROC difference <0.01). The DNN and 5-variable LR models demonstrated similar AUROCs of 0.740 (95% CI, 0.727-0.753) and 0.737 (95% CI, 0.728-0.746) ( P = .25), respectively. The simplified model can be accessed at SurgicalML.com ., Conclusion: We present the first machine learning-based models for predicting reduction or stabilization of opioid usage after SCS. The DNN and 5-variable LR models demonstrated comparable performances, with the latter revealing significant associations with patients' pre-SCS pharmacologic patterns. This simplified, interpretable LR model may augment patient and surgeon decision making regarding SCS., (Copyright © Congress of Neurological Surgeons 2022. All rights reserved.)

Samples from fifty-five surface water resources and twenty-five drinking water treatment plants in Europe, Africa, Asia, and USA were used to analyse the fluorescence composition of global surface waters and predict aromaticity and treatability from fluorescence excitation emission matrices. Nine underlying fluorescence components were identified in the dataset using parallel factor analysis (PARAFAC) and differences in aromaticity and treatability could be predicted from ratios between components H ii (λ ex /λ em = 395/521), H iii (λ ex /λ em = 330/404), P i , (λ ex /λ em =290/365) and P ii (λ ex /λ em = 275/302). Component H ii tracked humic acids of primarily plant origin, H iii tracked weathered/oxidised humics and the "building block" fraction measured by LC-OCD, while P i and P ii tracked amino acids in the "low molecular weight neutrals" LC-OCD fraction. Ratios between PARAFAC components predicted DOC removal at lab scale for French rivers in standardized tests involving coagulation, powdered activated carbon (PAC), chlorination, ion exchange (IEX), and ozonation, alone and in combination. The ratio H ii /H iii , for convenience named "PARIX" standing for "PARAFAC index", predicted SUVA according to a simple relationship: SUVA = 4.0 x PARIX (RMSEp=0.55) Lmg -1 m -1 . These results expand the utility of fluorescence spectroscopy in water treatment applications, by demonstrating the existence of previously unknown relationships between fluorescence composition, aromaticity and treatability that appear to hold across diverse surface waters at various stages of drinking water treatment., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Cannabis is the most widely used recreational drug in the world. Cannabis sativa and Cannabis indica have been selectively bred to develop their psychoactive properties. The increasing use in many countries has been accelerated by the COVID-19 pandemic. Cannabis can provoke both type 1 and type 4 allergic reactions. Officially recognized allergens include a pathogenesis-related class 10 allergen, profilin, and a nonspecific lipid transfer protein. Other allergens may also be relevant, and recognition of allergens may vary between countries and continents. Cannabis also has the potential to provoke allergic cross-reactions to plant foods. Since cannabis is an illegal substance in many countries, research has been hampered, leading to challenges in diagnosis since no commercial extracts are available for testing. Even in countries such as Canada, where cannabis is legalized, diagnosis may rely solely on the purchase of cannabis for prick-to-prick skin tests. Management consists of avoidance, with legal issues hindering the development of other treatments such as immunotherapy. Education of healthcare professionals is similarly lacking. This review aimed to summarize the current status of cannabis allergy and proposes recommendations for the future management of this global issue., (© 2022 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Patients undergoing sacroiliac (SI) fusion can oftentimes experience significant improvements in pain and quality of life., Objective: To describe a novel application of robotic navigation to assist with minimally invasive SI joint fusion., Methods: Patients undergoing stand-alone SI joint fusion with ExcelsiusGPS robotic navigation from July 2020 through June 2021 were retrospectively enrolled. Baseline demographic and perioperative variables including radiation exposure, postoperative pain scores, and narcotic requirements in the postanesthesia care unit (PACU) were recorded. Length of stay and any postoperative complications were also noted., Results: A total of 10 patients (64.4 ± 8.2 years, body mass index 28.7 ± 4.8 kg/m2) met inclusion criteria. Seven patients (70.0%) were female, and there was a 6:4 split between left-sided and right-sided SI joint fusion. The total operative time was 54 ± 9 minutes, and the estimated blood loss was 21.0 ± 16.7 mL. The intraoperative radiation exposure was 13.7 ± 6.2 mGy, and there were no complications. The average pain score in PACU was 5.2 ± 1.0, and the average opioid administration in PACU was 27.6 ± 10.3 morphine equivalents. Length of stay was 0.4 ± 0.7 days, with 7 of 10 patients discharged on the same day as surgery. There were no readmissions. The average length of follow-up was 4.3 ± 2.5 months. At the last follow-up, patients reported an average of 73.1% ± 30.1% improvement in their preoperative pain., Conclusion: Robot-navigated SI joint fusion is a feasible and reproducible method for addressing refractory SI joint disease. Further investigation on clinical outcomes and long-term fusion rates is needed, as are studies comparing robot-navigated SI joint fusion with more traditional techniques., (Copyright © Congress of Neurological Surgeons 2022. All rights reserved.)

Interest in robotic-assisted spine surgery has grown as surgeon comfort and technology has evolved to maximize benefits of time saving and precision. However, the Food and Drug Administration (FDA) has currently only approved robotics to assist in determining the ideal trajectory for pedicle screw placement after extensive research supporting its efficacy and efficiency. To be considered a durable and effective option, robotics need to expand beyond the indication of just placing pedicle screws. This article aims to illustrate a multi-surgeon, single-institution experience with unique applications of robotic technologies in spine surgery. We will explore accessing Kambin's Triangle in percutaneous transforaminal interbody fusion (percLIF), iliac fixation in metastatic cancer, and sacroiliac (SI) fusions. Each of these topics will be covered in depth with associated background information and subsequent discussion. We show that with proper understanding of its limitations, robots can help surgeons perform difficult surgeries in a safe manner., Competing Interests: Khoi Than is a consultant for Bioventus, DePuy Synthes, and Integrity Implants. Than is also an honoraria of Globus and LifeNet Health. Timothy Wang has received grant funding from AlphaTec. Rory Goodwin has received grants from the Robert Wood Johnson Harold Amos Medical Faculty Development Program, the Federal Food and Drug Administration, and the NIH/NINDS K12 NRCDP Physician Scientist Award. Goodwin is also a consultant for Johnson & Johnson and Medtronic. Phillip Horne has consultancy with Globus for navigation applications., (Copyright © 2022 Tabarestani, Sykes, Murphy, Wang, Shaffrey, Goodwin, Horne, Than and Abd-El-Barr.)

Background: Recurrent assessment of asthma control is essential to evaluating disease stability and intervention impacts. An assessment that can be administered between annual clinic visits is needed. The Asthma Impairment and Risk Questionnaire (AIRQ) is a cross-sectionally validated, 10-item, yes or no, composite control tool evaluating previous 2-week symptoms and previous 12-month exacerbations., Objective: To evaluate the construct validity of the AIRQ using a 3-month recall period for exacerbation-based risk questions and retaining the 2-week recall for symptom-based impairment items., Methods: At baseline, patients completed the AIRQ with 12-month recall exacerbation items, Asthma Control Test (ACT), St. George's Respiratory Questionnaire (SGRQ), and global self-assessments of asthma risk, control, and symptom severity. Patient-reported exacerbations were captured monthly. The AIRQ with 3-month recall exacerbation items, ACT, and global self-assessments was administered at months 3, 6, and 9, and SGRQ at month 6., Results: A total of 1112 patients aged 12 years or older were enrolled (mean [SD] age, 43.9 [19.5] years). The AIRQ and each administration of the AIRQ with 3-month recall exacerbation items classified asthma control similarly to an ACT plus exacerbation validation standard. For both AIRQ versions, SGRQ scores were higher with worsening asthma control (P < .001). At months 3, 6, and 9, worse AIRQ control levels were associated with higher proportions of patients with 1 or more and 2 or more exacerbations in the previous 3 months and patient global self-assessments indicating greater asthma morbidity (all P < .001)., Conclusion: The AIRQ using exacerbation risk items with a 3-month recall period exhibits construct validity for classifying current asthma control and can be administered between annual AIRQ assessments., (Copyright © 2022 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Improved therapeutics for malignant brain tumors are urgently needed. High-frequency irreversible electroporation (H-FIRE) is a minimally invasive, nonthermal tissue ablation technique, which utilizes high-frequency, bipolar electric pulses to precisely kill tumor cells. The mechanisms of H-FIRE-induced tumor cell death and potential for cellular recovery are incompletely characterized. We hypothesized that tumor cells treated with specific H-FIRE electric field doses can survive and retain proliferative capacity. F98 glioma and LL/2 Lewis lung carcinoma cell suspensions were treated with H-FIRE to model primary and metastatic brain cancer, respectively. Cell membrane permeability, apoptosis, metabolic viability, and proliferative capacity were temporally measured using exclusion dyes, condensed chromatin staining, WST-8 fluorescence, and clonogenic assays, respectively. Both tumor cell lines exhibited dose-dependent permeabilization, with 1,500 V/cm permitting and 3,000 V/cm inhibiting membrane recovery 24 h post-treatment. Cells treated with 1,500 V/cm demonstrated significant and progressive recovery of apoptosis and metabolic activity, in contrast to cells treated with higher H-FIRE doses. Cancer cells treated with recovery-permitting doses of H-FIRE maintained while those treated with recovery-inhibiting doses lost proliferative capacity. Taken together, our data suggest that H-FIRE induces reversible and irreversible cellular damage in a dose-dependent manner, and the presence of dose-dependent recovery mechanisms permits tumor cell proliferation., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Davalos, Aycock, Dervisis, and Rossmeisl have pending and issued patents related to electroporation., (Copyright © 2021 Elsevier B.V. All rights reserved.)