PAAN/MIF nuclease inhibition prevents neurodegeneration in Parkinson's disease.

Parthanatos-associated apoptosis-inducing factor (AIF) nuclease (PAAN), also known as macrophage migration inhibitor factor (MIF), is a member of the PD-D/E(X)K nucleases that acts as a final executioner in parthanatos. PAAN's role in Parkinson's disease (PD) and whether it is amenable to chemical inhibition is not known. Here, we show that neurodegeneration induced by pathologic α-synuclein (α-syn) occurs via PAAN/MIF nuclease activity. Genetic depletion of PAAN/MIF and a mutant lacking nuclease activity prevent the loss of dopaminergic neurons and behavioral deficits in the α-syn preformed fibril (PFF) mouse model of sporadic PD. Compound screening led to the identification of PAANIB-1, a brain-penetrant PAAN/MIF nuclease inhibitor that prevents neurodegeneration induced by α-syn PFF, AAV-α-syn overexpression, or MPTP intoxication in vivo. Our findings could have broad relevance in human pathologies where parthanatos plays a role in the development of cell death inhibitors targeting the druggable PAAN/MIF nuclease.

Wetting transition and fluid trapping in a microfluidic fracture.

Immiscible fluid-fluid displacement in confined geometries is a fundamental process occurring in many natural phenomena and technological applications, from geological CO2 sequestration to microfluidics. Due to the interactions between the fluids and the solid walls, fluid invasion undergoes a wetting transition from complete displacement at low displacement rates to leaving a film of the defending fluid on the confining surfaces at high displacement rates. While most real surfaces are rough, fundamental questions remain about the type of fluid-fluid displacement that can emerge in a confined, rough geometry. Here, we study immiscible displacement in a microfluidic device with a precisely controlled structured surface as an analogue for a rough fracture. We analyze the influence of the degree of surface roughness on the wetting transition and the formation of thin films of the defending liquid. We show experimentally, and rationalize theoretically, that roughness affects both the stability and dewetting dynamics of thin films, leading to distinct late-time morphologies of the undisplaced (trapped) fluid. Finally, we discuss the implications of our observations for geologic and technological applications.

Evaporation of alcohol droplets on surfaces in moist air.

Droplets of alcohol-based formulations are common in applications from sanitizing sprays to printing inks. However, our understanding of the drying dynamics of these droplets on surfaces and the influence of ambient humidity is still very limited. Here, we report the drying dynamics of picoliter droplets of isopropyl alcohol deposited on a surface under controlled humidity. Condensation of water vapor in the ambient environment onto alcohol droplets leads to unexpectedly complex drying behavior. As relative humidity (RH) increases, we observed a variety of phenomena including enhanced spreading, nonmonotonic changes in the drying time, the formation of pancake-like shapes that suppress the coffee-ring effect, and the formation of water-rich films around an alcohol-rich drop. We developed a lubrication model that accounts for the coupling between the flow field within the drop, the shape of the drop, and the vapor concentration field. The model reproduces many of the experimentally observed morphological and dynamic features, revealing the presence of unusually large spatial compositional gradients within the evaporating droplet and surface-tension-gradient-driven flows arising from water condensation/evaporation at the surface of the droplet. One unexpected feature from the simulation is that water can evaporate and condense concurrently in different parts of the drop, providing fundamental insights that simpler models based on average fluxes lack. We further observed rim instabilities at higher RH that are well-described by a model based on the Rayleigh-Plateau instability. Our findings have implications for the testing and use of alcohol-based disinfectant sprays and printing inks.

Oil-on-water droplets faceted and stabilized by vortex halos in the subphase.

For almost 200 y, the dominant approach to understand oil-on-water droplet shape and stability has been the thermodynamic expectation of minimized energy, yet parallel literature shows the prominence of Marangoni flow, an adaptive gradient of interfacial tension that produces convection rolls in the water. Our experiments, scaling arguments, and linear stability analysis show that the resulting Marangoni-driven high-Reynolds-number flow in shallow water overcomes radial symmetry of droplet shape otherwise enforced by the Laplace pressure. As a consequence, oil-on-water droplets are sheared to become polygons with distinct edges and corners. Moreover, subphase flows beneath individual droplets can inhibit the coalescence of adjacent droplets, leading to rich many-body dynamics that makes them look alive. The phenomenon of a "vortex halo" in the liquid subphase emerges as a hidden variable.

Unconventional localization of electrons inside of a nematic electronic phase.

The magnetotransport behavior inside the nematic phase of bulk FeSe reveals unusual multiband effects that cannot be reconciled with a simple two-band approximation proposed by surface-sensitive spectroscopic probes. In order to understand the role played by the multiband electronic structure and the degree of two-dimensionality, we have investigated the electronic properties of exfoliated flakes of FeSe by reducing their thickness. Based on magnetotransport and Hall resistivity measurements, we assess the mobility spectrum that suggests an unusual asymmetry between the mobilities of the electrons and holes, with the electron carriers becoming localized inside the nematic phase. Quantum oscillations in magnetic fields up to 38 T indicate the presence of a hole-like quasiparticle with a lighter effective mass and a quantum scattering time three times shorter, as compared with bulk FeSe. The observed localization of negative charge carriers by reducing dimensionality can be driven by orbitally dependent correlation effects, enhanced interband spin fluctuations, or a Lifshitz-like transition, which affect mainly the electron bands. The electronic localization leads to a fragile two-dimensional superconductivity in thin flakes of FeSe, in contrast to the two-dimensional high-[Formula: see text] induced with electron doping via dosing or using a suitable interface.

Effect of Ziltivekimab on Determinants of Hemoglobin in Patients with CKD Stage 3-5: An Analysis of a Randomized Trial (RESCUE).

SIGNIFICANCE STATEMENT: Systemic inflammation in CKD can lead to anemia. Ziltivekimab, a fully human monoclonal antibody targeting the IL-6 ligand, has been shown to reduce systemic inflammation in patients with CKD. It has also been shown to increase serum albumin in patients on hemodialysis with inflammation and hyporesponsiveness to treatment with erythropoiesis-stimulating agents. This exploratory analysis of the RESCUE clinical trial found that among patients with CKD stage 3-5 and systemic inflammation, ziltivekimab treatment significantly increased hemoglobin (Hb) levels after 12 weeks compared with placebo. Ziltivekimab was also associated with significant increases in serum iron levels, total iron-binding capacity, and transferrin saturation. No major safety concerns were reported. Further clinical trials are warranted to study ziltivekimab's potential for anemia management in patients with CKD. BACKGROUND: In the phase 2 RESCUE clinical trial, ziltivekimab, a fully human monoclonal antibody against the IL-6 ligand, significantly reduced the biomarkers of inflammation compared with placebo, in patients with CKD and systemic inflammation (high-sensitivity C-reactive protein ≥2 mg/L). The aim of this subanalysis of RESCUE trial data was to assess the effect of ziltivekimab on Hb and iron homeostasis in this patient population. METHODS: This was an analysis of exploratory end points from the RESCUE trial ( NCT03926117 ), which included 264 adults with CKD stage 3-5 and high-sensitivity C-reactive protein ≥2 mg/L. Participants received placebo or subcutaneous ziltivekimab (7.5, 15, or 30 mg) (1:1:1:1) once every 4 weeks, up to 24 weeks. End points for this analysis were changes in Hb and biomarkers of iron homeostasis from baseline to week 12. RESULTS: The trial was terminated early due to the coronavirus disease 2019 pandemic, and thus, data up to week 12 are presented. Hb levels significantly increased from baseline to week 12 with ziltivekimab 7.5, 15, and 30 mg (treatment differences versus placebo: +0.57 g/dl [95% confidence interval, 0.27 to 0.86], +1.05 g/dl [0.76 to 1.33], and +0.99 g/dl [0.70 to 1.28], respectively, all P < 0.001). Ziltivekimab was associated with significant increases in serum iron levels, total iron-binding capacity, and transferrin saturation from baseline to week 12 ( P < 0.05 versus placebo for all doses and comparisons). Cases of sustained thrombocytopenia, sustained neutropenia, anemia, and iron deficiency anemia were infrequent and similar across all groups. CONCLUSIONS: Anti-inflammatory therapy with ziltivekimab improved the markers of anemia and iron homeostasis in people with stage 3-5 CKD and systemic inflammation, suggesting a possible role in anemia management.

SARS-CoV-2 vaccination in the first year after hematopoietic cell transplant or chimeric antigen receptor T cell therapy: A prospective, multicenter, observational study.

BACKGROUND: The optimal timing of vaccination with SARS-CoV-2 vaccines after cellular therapy is incompletely understood. The objectives of this study are to determine whether humoral and cellular responses after SARS-CoV-2 vaccination differ if initiated <4 months versus 4-12 months after cellular therapy. METHODS: We conducted a multicenter prospective observational study at 30 cancer centers in the United States. SARS-CoV-2 vaccination was administered as part of routine care. We obtained blood prior to and after vaccinations at up to five time points and tested for SARS-CoV-2 spike (anti-S) IgG in all participants and neutralizing antibodies for Wuhan D614G, Delta B.1.617.2, and Omicron B.1.1.529 strains, as well as SARS-CoV-2-specific T cell receptors (TCRs), in a subgroup. RESULTS: We enrolled 466 allogeneic hematopoietic cell transplant (HCT; n=231), autologous HCT (n=170), and chimeric antigen receptor T cell (CAR-T cell) therapy (n=65) recipients between April 2021 and June 2022. Humoral and cellular responses did not significantly differ among participants initiating vaccinations <4 months vs 4-12 months after cellular therapy. Anti-S IgG ≥2,500 U/mL was correlated with high neutralizing antibody titers and attained by the last time point in 70%, 69%, and 34% of allogeneic HCT, autologous HCT, and CAR-T cell recipients, respectively. SARS-CoV-2-specific T cell responses were attained in 57%, 83%, and 58%, respectively. Pre-cellular therapy SARS-CoV-2 infection or vaccination were key predictors of post-cellular therapy immunity. CONCLUSIONS: These data support mRNA SARS-CoV-2 vaccination prior to, and reinitiation three to four months after, cellular therapies with allogeneic HCT, autologous HCT, and CAR-T cell therapy.

Phase 1/2 trial of avelumab combined with utomilumab (4-1BB agonist), PF-04518600 (OX40 agonist), or radiotherapy in patients with advanced gynecologic malignancies.

BACKGROUND: Immune checkpoint blockade has shown mixed results in advanced/recurrent gynecologic malignancies. Efficacy may be improved through costimulation with OX40 and 4-1BB agonists. The authors sought to evaluate the safety and efficacy of avelumab combined with utomilumab (a 4-1BB agonist), PF-04518600 (an OX40 agonist), and radiotherapy in patients with recurrent gynecologic malignancies. METHODS: The primary end point in this six-arm, phase 1/2 trial was safety of the combination regimens. Secondary end points included the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors and immune-related Response Evaluation Criteria in Solid Tumors, the disease control rate (DCR), the duration of response, progression-free survival, and overall survival. RESULTS: Forty patients were included (35% with cervical cancer, 30% with endometrial cancer, and 35% with ovarian cancer). Most patients (n = 33; 83%) were enrolled in arms A-C (no radiation). Among 35 patients who were evaluable for efficacy, the ORR was 2.9%, and the DCR was 37.1%, with a median duration of stable disease of 5.4 months (interquartile range, 4.1-7.3 months). Patients with cervical cancer in arm A (avelumab and utomilumab; n = 9 evaluable patients) achieved an ORR of 11% and a DCR of 78%. The median progression-free survival was 2.1 months (95% CI, 1.8-3.5 months), and overall survival was 9.4 months (95% CI, 5.6-11.9 months). No dose-limiting toxicities or grade 3-5 immune-related adverse events were observed. CONCLUSIONS: The findings from this trial highlight that, in heavily pretreated patients with gynecologic cancer, even multidrug regimens targeting multiple immunologic pathways, although safe, did not produce significant responses. A DCR of 78% in patients with cervical cancer who received avelumab and utomilumab indicates that further research on this combination in select patients may be warranted.

Randomized phase 2 trial of tremelimumab and durvalumab in combination versus sequentially in recurrent platinum-resistant ovarian cancer.

BACKGROUND: Single-agent immune checkpoint inhibitors (ICIs) have demonstrated limited responses in recurrent ovarian cancer; however, 30%-40% of patients achieve stable disease. The primary objective was to estimate progression-free survival (PFS) after sequential versus combination cytotoxic T-lymphocyte antigen 4 and programmed death ligand 1 ICIs in patients with platinum-resistant high-grade serous ovarian cancer (HGSOC). METHODS: Patients were randomized to a sequential arm (tremelimumab followed by durvalumab on progression) or a combination arm (tremelimumab plus durvalumab, followed by durvalumab) via a Bayesian adaptive design that made it more likely for patients to be randomized to the more effective arm. The primary end point was immune-related PFS (irPFS). RESULTS: Sixty-one subjects were randomized to sequential (n = 38) or combination therapy (n = 23). Thirteen patients (34.2%) in the sequential arm received durvalumab. There was no difference in PFS in the sequential arm (1.84 months; 95% CI, 1.77-2.17 months) compared with the combination arm (1.87 months; 95% CI, 1.77-2.43 months) (p = .402). In the sequential arm, no responses were observed, although 12 patients (31.6%) demonstrated stable disease. In the combination arm, two patients (8.7%) had partial response, whereas one patient (4.4%) had stable disease. Adverse events were consistent with those previously reported for ICIs. Patient-reported outcomes were similar in both arms. CONCLUSIONS: There was no difference in irPFS for combination tremelimumab plus durvalumab compared to tremelimumab alone (administered as part of a sequential treatment strategy) in a heavily pretreated population of patients with platinum-resistant HGSOC. Response rates were comparable to prior reports, although the combination regimen did not add significant benefit, as has been previously described.

Liver transplantation for refractory hepatic hydrothorax is associated with a greater survival benefit compared to other complications of cirrhosis.

Hepatic hydrothorax (HH) is a significant complication of cirrhosis associated with increased mortality. Liver transplantation (LT) remains the best treatment modality. We aim to assess predictors of mortality and the survival benefit of LT in patients with HH. A prospectively maintained cohort of adult patients with cirrhosis, being evaluated for LT at our institution, was retrospectively reviewed from 2015 to 2020. The primary outcome was death or LT. Cox proportional hazard regression identified associations between covariates and death. We calculated the years saved due to LT by comparing patients who were on the waiting list with patients who received an LT. This was done by calculating the area under the Kaplan-Meier curve. Censoring occurred at the time of the last follow-up or death. Patients with refractory HH had the lowest median survival of only 0.26 years. Within the HH group, having a refractory HH group was significantly associated with an increased risk of mortality (HR 1.73; 95% CI 1.06-2.81; p -value 0.03). Refractory HH was also significantly associated with mortality when evaluated in the entire cohort and after adjusting for other covariates (HR 1.48, 95% CI 1.03-2.11; p -value 0.03). Patients with refractory HH had the highest 1-year survival benefit with LT (0.48 y), followed by patients with non-refractory HH (0.28 y), then patients with other complications of cirrhosis (0.19 y). In this large study evaluating the prognostic impact of HH on patients with cirrhosis, refractory HH was an independent predictor of mortality. LT provides an additional survival benefit to patients with HH compared with those without HH.

Priming chondrocytes during expansion alters cell behavior and improves matrix production in 3D culture.

OBJECTIVE: Cartilage tissue engineering strategies that use autologous chondrocytes require in vitro expansion of cells to obtain enough cells to produce functional engineered tissue. However, chondrocytes dedifferentiate during expansion culture, limiting their ability to produce chondrogenic tissue and their utility for cell-based cartilage repair strategies. The current study identified conditions that favor cartilage production and the mechanobiological mechanisms responsible for these benefits. DESIGN: Chondrocytes were isolated from juvenile bovine knee joints and cultured with (primed) or without (unprimed) a growth factor cocktail. Gene expression, cell morphology, cell adhesion, cytoskeletal protein distribution, and cell mechanics were assessed. Following passage 5, cells were embedded into agarose hydrogels to evaluate functional properties of engineered cartilage. RESULTS: Priming cells during expansion culture altered cell phenotype and chondrogenic tissue production. Unbiased ribonucleic acid-sequencing analysis suggested, and experimental studies confirmed, that growth factor priming delays dedifferentiation associated changes in cell adhesion and cytoskeletal organization. Priming also overrode mechanobiological pathways to prevent chondrocytes from remodeling their cytoskeleton to accommodate the stiff, monolayer microenvironment. Passage 1 primed cells deformed less and had lower yes associated protein 1 activity than unprimed cells. Differences in cell adhesion, morphology, and cell mechanics between primed and unprimed cells were mitigated by passage 5. CONCLUSIONS: Priming suppresses mechanobiologic cytoskeletal remodeling to prevent chondrocyte dedifferentiation, resulting in more cartilage-like tissue-engineered constructs.

Including socioeconomic status reduces readmission penalties to safety-net hospitals.

OBJECTIVE: Medicare's Hospital Readmissions Reduction Program (HRRP) financially penalizes "excessive" postoperative readmissions. Concerned with creating a double standard for institutions treating a high percentage of economically vulnerable patients, Medicare elected to exclude socioeconomic status (SES) from its risk-adjustment model. However, recent evidence suggests that safety-net hospitals (SNHs) caring for many low-SES patients are disproportionately penalized under the HRRP. We sought to simulate the impact of including SES-sensitive models on HRRP penalties for hospitals performing lower extremity revascularization (LER). METHODS: This is a retrospective, cross-sectional analysis of national data on Medicare patients undergoing open or endovascular LER procedures between 2007 and 2009. We used hierarchical logistic regression to generate hospital risk-standardized 30-day readmission rates under Medicare's current model (adjusting for age, sex, comorbidities, and procedure type) compared with models that also adjust for SES. We estimated the likelihood of a penalty and penalty size for SNHs compared with non-SNHs under the current Medicare model and these SES-sensitive models. RESULTS: Our study population comprised 1708 hospitals performing 284,724 LER operations with an overall unadjusted readmission rate of 14.4% (standard deviation: 5.3%). Compared with the Centers for Medicare and Medicaid Services model, adjusting for SES would not change the proportion of SNHs penalized for excess readmissions (55.1% vs 53.4%, P = .101) but would reduce penalty amounts for 38% of SNHs compared with only 17% of non-SNHs, P < .001. CONCLUSIONS: For LER, changing national Medicare policy to including SES in readmission risk-adjustment models would reduce penalty amounts to SNHs, especially for those that are also teaching institutions. Making further strides toward reducing the national disparity between SNHs and non-SHNs on readmissions, performance measures require strategies beyond simply altering the risk-adjustment model to include SES.

Stability Transition in Gap Expansion-Driven Interfacial Flow.

We investigate interfacial instability in a lifting Hele-Shaw cell by experiments and theory. We characterize the unexplored transition from stable to unstable patterns under a wide range of controlling parameters. Surprisingly, we find that the perturbation growth rate-based criterion for the onset of instability from linear stability theory is too strict by over 3 orders of magnitude. To reconcile this striking discrepancy, we propose a new criterion based on perturbation amplitude, which is in excellent agreement with the experimental results. We further show that the fingering pattern evolves to produce a hierarchical fluid structure and derive a theoretical equation to predict the fingering evolution.

"Air That Once Was Breath" Part 1: Wildfire-Smoke-Induced Mechanisms of Airway Inflammation - "Climate Change, Allergy and Immunology" Special IAAI Article Collection: Collegium Internationale Allergologicum Update 2023.

BACKGROUND: Wildfires are a global concern due to their wide-ranging environmental, economic, and public health impacts. Climate change contributes to an increase in the frequency and intensity of wildfires making smoke exposure a more significant and recurring health concern for individuals with airway diseases. Some of the most prominent effects of wildfire smoke exposure are asthma exacerbations and allergic airway sensitization. Likely due to the delayed recognition of its health impacts in comparison with cigarette smoke and industrial or traffic-related air pollution, research on the composition, the mechanisms of toxicity, and the cellular/molecular pathways involved is poor or non-existent. SUMMARY: This review discusses potential underlying pathological mechanisms of wildfire-smoke-related allergic airway disease and asthma. We focused on major gaps in understanding the role of wildfire smoke composition in the development of airway disease and the known and potential mechanisms involving cellular and molecular players of oxidative injury at the epithelial barrier in airway inflammation. We examine how PM2.5, VOCs, O3, endotoxin, microbes, and toxic gases may affect oxidative stress and inflammation in the respiratory mucosal barrier. We discuss the role of AhR in mediating smoke's effects in alarmin release and IL-17A production and how glucocorticoid responsiveness may be impaired by IL-17A-induced signaling and epigenetic changes leading to steroid-resistant severe airway inflammation. KEY MESSAGE: Effective mitigation of wildfire-smoke-related respiratory health effects would require comprehensive research efforts aimed at a better understanding of the immune regulatory effects of wildfire smoke in respiratory health and disease.

"Air That Once Was Breath" Part 2: Wildfire Smoke and Airway Disease - "Climate Change, Allergy and Immunology" Special IAAI Article Collection: Collegium Internationale Allergologicum Update 2023.

BACKGROUND: Population growth and climate change have led to more frequent and larger wildfires, increasing the exposure of individuals to wildfire smoke. Notably, asthma exacerbations and allergic airway sensitization are prominent outcomes of such exposure. SUMMARY: Key research questions relate to determining the precise impact on individuals with asthma, including the severity, duration, and long-term consequences of exacerbations. Identifying specific risk factors contributing to vulnerability, such as age, genetics, comorbidities, or environmental factors, is crucial. Additionally, reliable biomarkers for predicting severe exacerbations need exploration. Understanding the long-term health effects of repeated wildfire smoke exposures in individuals with asthma and addressing healthcare disparities are important research areas. KEY MESSAGES: This review discusses the need for comprehensive research efforts to better grasp wildfire smoke-induced respiratory health, particularly in vulnerable populations such as farmworkers, firefighters, pregnant women, children, the elderly, and marginalized communities. Effective mitigation would require addressing the current limitations we face by supporting research aimed at a better understanding of wildfire smoke-induced airway disease.

A colostomy for large bowel obstruction at the end of life: What do patients gain from palliative surgery?

OBJECTIVES: Malignant large bowel obstruction (LBO) is a frequent complication affecting women with gynecologic cancers and is an indication for emergent surgery. However, the life expectancy and subsequent medical care utilization are unknown. We sought to estimate overall survival (OS) following colostomy and describe subsequent healthcare utilization among patients with advanced gynecologic malignancies. METHODS: We conducted a retrospective analysis of patients with advanced gynecologic cancers who underwent colostomy with palliative intent due to LBO at our institution between March 2014 and January 2023. Summary statistics were used to describe the clinical and demographic characteristics of the study population. OS was estimated using the Kaplan-Meier method, and we defined healthcare utilization at the end-of-life using criteria published by the National Quality Forum. RESULTS: A total of 78 patients were included. The median age at the time of surgery was 61 (range: 34-83), and most patients had recurrent ovarian, fallopian tube, or primary peritoneal cancer (n = 51, 65.4%), followed by cervical cancer (n = 16, 20.5%), and uterine cancer (n = 10, 12.8%). The median Charlson comorbidity index was 3 and median postoperative length of stay was five days (range: 1-26). The median follow-up for all patients was 4.5 months (range: 0.07-46.2), and the median OS was 4.5 months (95% CI: 2.9-6.0), including 12 patients (15.4%) with <30-day OS and 21 (26.9%) with <60-day OS. In the last 30 days of life, 62.7% of patients were re-admitted to the hospital, 53.0% were seen in the emergency department, and 18.5% were admitted to an intensive care unit. CONCLUSIONS: A significant proportion of patients died within 60 days of surgery, and many had high healthcare utilization at the end of life.

Electrically mediated self-assembly and manipulation of drops at an interface.

The fluid-fluid interface is a complex environment for a floating object where the statics and dynamics may be governed by capillarity, gravity, inertia, and other external body forces. Yet, the alignment of these forces in intricate ways may result in beautiful pattern formation and self-assembly of these objects, as in the case of crystalline order observed with bubble rafts or colloidal particles. While interfacial self-assembly has been explored widely, controlled manipulation of floating objects, e.g. drops, at the fluid-fluid interface still remains a challenge largely unexplored. In this work, we reveal the self-assembly and manipulation of water drops floating at an oil-air interface. We show that the assembly occurs due to electrostatic interactions between the drops and their environment. We highlight the role of the boundary surrounding the system by showing that even drops with a net zero electric charge can self-assemble under certain conditions. Using experiments and theory, we show that the depth of the oil bath plays an important role in setting the distance between the self-assembled drops. Furthermore, we demonstrate ways to manipulate the drops actively and passively at the interface.

Barriers to Participation in a Structured Quality Improvement Initiative to Reduce Avoidable Emergency Department Visits-A Qualitative Study.

INTRODUCTION: Barriers to quality improvement (QI) initiatives in multi-institutional hospital settings are understudied. Here we describe a qualitative investigation of factors negatively affecting a QI initiative focused on reducing avoidable emergency department (ED) visits after bariatric surgery across 17 hospitals. Our goal was to explore participant perspectives and identify themes describing why the program was not effectively implemented or why the program may have been ineffective when correctly implemented. METHODS: We performed semistructured group interviews with 17 sites (42 interviews) participating in a statewide bariatric QI program. We used descriptive content analysis to identify challenges, facilitators, and barriers to implementation of the QI program. All analyses were conducted using MAXQDA software. RESULTS: Results revealed barriers across hospitals related to four themes: buy-in, provider accessibility, resources at participating hospitals, and patient barriers to care. In particular, the initiative faced difficulty if it was not well-matched to the factors driving increasing ED visits at a particular site, such as lack of patient access to outpatient or primary care. Additional challenges occurred if the initiative was not adapted and customized to the working systems in place at each site, involving employees, surgeons, support staff, and leadership. CONCLUSIONS: Overall, findings can direct future focused efforts aimed at site-specific interventions to reduce unnecessary postoperative ED visits. Results demonstrated a need for a nuanced approach that can be adapted based on facility needs and resources.

From Alpha to Omicron and Beyond: Associations Between SARS-CoV-2 Variants and Surgical Outcomes.

INTRODUCTION: The COVID-19 pandemic has significantly influenced surgical practices, with SARS-CoV-2 variants presenting unique pathologic profiles and potential impacts on perioperative outcomes. This study explores associations between Alpha, Delta, and Omicron variants of SARS-CoV-2 and surgical outcomes. METHODS: We conducted a retrospective analysis using the National COVID Cohort Collaborative database, which included patients who underwent selected major inpatient surgeries within eight weeks post-SARS-CoV-2 infection from January 2020 to April 2023. The viral variant was determined by the predominant strain at the time of the patient's infection. Multivariable logistic regression models explored the association between viral variants, COVID-19 severity, and 30-d major morbidity or mortality. RESULTS: The study included 10,617 surgical patients with preoperative COVID-19, infected by the Alpha (4456), Delta (1539), and Omicron (4622) variants. Patients infected with Omicron had the highest vaccination rates, most mild disease, and lowest 30-d morbidity and mortality rates. Multivariable logistic regression demonstrated that Omicron was linked to a reduced likelihood of adverse outcomes compared to Alpha, while Delta showed odds comparable to Alpha. Inclusion of COVID-19 severity in the model rendered the odds of major morbidity or mortality equal across all three variants. CONCLUSIONS: Our study examines the associations between the clinical and pathological characteristics of SARS-CoV-2 variants and surgical outcomes. As novel SARS-CoV-2 variants emerge, this research supports COVID-19-related surgical policy that assesses the severity of disease to estimate surgical outcomes.

Sex differences in sociodemographic, clinical, and laboratory variables in childhood asthma: A birth cohort study.

BACKGROUND: There are marked sex differences in the prevalence and severity of asthma, both during childhood and adulthood. There is a relative lack of comprehensive studies exploring sexdifferences in pediatric asthma cohorts. OBJECTIVE: To identify the most relevant sex differences in sociodemographic, clinical, and laboratory variables in a well-characterized large pediatric asthma cohort. METHODS: We performed a cross-sectional analysis of the Mayo Clinic Olmsted County Birth Cohort. In the full birth cohort, we used a natural language-processing algorithm based on the Predetermined Asthma Criteria for asthma ascertainment. In a stratified random sample of 300 children, we obtained additional pulmonary function tests and laboratory data. We identified the significant sex differences among available sociodemographic, clinical, and laboratory variables. RESULTS: Boys were more frequently diagnosed with having asthma than girls and were younger at the time of asthma diagnosis. There were no sex differences in relation to socioeconomic status. We identified a male predominance in the presence of a tympanostomy tube and a female predominance in the history of pneumonia. A higher percentage of boys had a forced expiratory volume in 1 second/forced vital capacity ratio less than 0.85. Blood eosinophilia and atopic sensitization were also more common in boys. Finally, boys had higher levels of serum periostin than girls. CONCLUSION: This study described significant sex differences in a large pediatric asthma cohort. Overall, boys had earlier and more severe asthma than girls. Differences in blood eosinophilia and serum periostin provide insights into possible mechanisms of the sex bias in childhood asthma.