Lipid regulation of NLRP3 inflammasome activity through organelle stress.

Inflammation driven by the NLRP3 inflammasome in macrophages is an important contributor to chronic metabolic diseases that affect growing numbers of individuals. Many of these diseases involve the pathologic accumulation of endogenous lipids or their oxidation products, which can activate NLRP3. Other endogenous lipids, however, can inhibit the activation of NLRP3. The intracellular mechanisms by which these lipids modulate NLRP3 activity are now being identified. This review discusses emerging evidence suggesting that organelle stress, particularly involving mitochondria, lysosomes, and the endoplasmic reticulum, may be key in lipid-induced modification of NLRP3 inflammasome activity.

Subunit Reconstruction With Local and Regional Flaps of a Total Cervicofacial Defect From Necrotizing Fasciitis.

A 60-year-old woman with a ∼450 cm 2 right cervicofacial defect following successful treatment of necrotizing fasciitis was consulted for reconstruction. She had complete orbital, malar, buccal, labial, submental, and anterolateral neck skin and soft tissue defects and near complete defects of the forehead and nasal sidewall. She underwent reconstruction with a large 24 cm×11 cm supraclavicular, deltopectoral, forehead rotational, and labial advancement flaps with skin grafting of the orbit. Follow-up at 2 months demonstrated complete take of all flaps. The patient was satisfied with her appearance and considered her outcome favorable. She exhibited comparably premorbid speech and oral competence. Large defects of the head and neck require thorough surgical planning and consideration of a subunit reconstruction technique. While free tissue transfer provides a large area of healthy tissue from a suitable donor site, subunit reconstruction with local and regional flaps can provide a superior outcome in the correct patient.

Type I IFNs facilitate innate immune control of the opportunistic bacteria Burkholderia cenocepacia in the macrophage cytosol.

The mammalian immune system is constantly challenged by signals from both pathogenic and non-pathogenic microbes. Many of these non-pathogenic microbes have pathogenic potential if the immune system is compromised. The importance of type I interferons (IFNs) in orchestrating innate immune responses to pathogenic microbes has become clear in recent years. However, the control of opportunistic pathogens-and especially intracellular bacteria-by type I IFNs remains less appreciated. In this study, we use the opportunistic, Gram-negative bacterial pathogen Burkholderia cenocepacia (Bc) to show that type I IFNs are capable of limiting bacterial replication in macrophages, preventing illness in immunocompetent mice. Sustained type I IFN signaling through cytosolic receptors allows for increased expression of autophagy and linear ubiquitination mediators, which slows bacterial replication. Transcriptomic analyses and in vivo studies also show that LPS stimulation does not replicate the conditions of intracellular Gram-negative bacterial infection as it pertains to type I IFN stimulation or signaling. This study highlights the importance of type I IFNs in protection against opportunistic pathogens through innate immunity, without the need for damaging inflammatory responses.

Correction: Type I IFNs facilitate innate immune control of the opportunistic bacteria Burkholderia cenocepacia in the macrophage cytosol.

[This corrects the article DOI: 10.1371/journal.ppat.1009395.].

A systematic scoping review of communication skills training in medical schools between 2000 and 2020.

BACKGROUND: Communication skills training (CST) remains poorly represented and prioritised in medical schools despite its importance. A systematic scoping review (SSR) of CST is proposed to better appreciate current variability in their structure, content, and assessment. This is to guide their future design in medical school curricula. METHODS: The Systematic Evidence-Based Approach (SEBA) was used to guide concurrent SSRs of teaching and assessment in CST. After independent database searches, concurrent thematic and content analysis of included articles were conducted separately. Resultant themes/categories were combined via the jigsaw perspective to provide a more holistic view of the data. These were then compared to tabulated summaries of the included articles to create funnelled domains. RESULTS: 52,300 papers were identified, 150 full-text articles included, and four funnelled domains were identified: Indications, Design, Assessment, and Barriers and Enablers of CST. CSTs confer numerous benefits to physicians and patients. It saw increased confidence, improved diagnostic capabilities and better clinical management, as well as greater patient satisfaction and treatment compliance. Skills may be divided into core, prerequisite competencies, and advanced skills pertinent to more challenging and nuanced scenarios - such as population or setting-specific situations. CST teaching and assessment modalities were found to align with Miller's Pyramid, with didactic teaching gradually infused with experiential approaches to enhance their understanding and integration. A plethora of CST frameworks, teaching and assessment methods were identified and are presented together. CONCLUSION: While variable in approach, content and assessment, CST in medical schools often employ stage-based curricula to instil competency-based topics of increasing complexity throughout medical school education. This process builds on the application of prior knowledge and skills, influencing practice and, potentially, the students' professional identity formation. In addition, the institution plays a critical role in overseeing training, ensuring longitudinal guidance and holistic assessments of the students' progress.

The efficacy of surgery for upper airway resistance syndrome: A systematic review, meta-analysis and case series.

PURPOSE: Upper airway resistance syndrome (UARS) is a sleep related breathing disorder that was first described in 1993. This goal of this study is to determine the efficacy of surgical intervention for UARS. MATERIALS AND METHODS: Systematic review of the literature and a case series of UARS patients at a large integrated healthcare system. Meta-analysis was performed. RESULTS: For the systematic review, 971 abstracts were reviewed and 3 articles were included, yielding 49 subjects. All of the included studies were of level 3 or 4 evidence. Significant improvement in Epworth Sleepiness Scale (ESS) score was noted after surgery in two level 4 studies. No significant change in ESS was noted in one level 3 study. Our retrospective chart review of eleven UARS patients compared preoperative and postoperative ESS scores, as well as sleep study data. Patients underwent a variety of surgical procedures. Our findings show a significant improvement in mean ESS scores after surgery, from 11.0 (±3.5) to 7.0 (±4.8) with p = 0.01, though no difference in apnea hypopnea index (AHI) and respiratory disturbance index (RDI) were identified. Meta-analysis was performed on 2 studies from the systematic review and our cases series data. UARS surgery showed a mean change in ESS of -5.89 (95% CI, -8.29 to -3.50). CONCLUSIONS: This systematic review, meta-analysis and retrospective case series indicate that surgery may improve ESS scores in patients with UARS. AHI and RDI are unlikely to be impacted by surgery.

Discrete roles of STAT4 and STAT6 transcription factors in tuning epigenetic modifications and transcription during T helper cell differentiation.

Signal transducer and activator of transcription 4 (STAT4) and STAT6 are key factors in the specification of helper T cells; however, their direct roles in driving differentiation are not well understood. Using chromatin immunoprecipitation and massive parallel sequencing, we quantitated the full complement of STAT-bound genes, concurrently assessing global STAT-dependent epigenetic modifications and gene transcription by using cells from cognate STAT-deficient mice. STAT4 and STAT6 each bound over 4000 genes with distinct binding motifs. Both played critical roles in maintaining chromatin configuration and transcription of a core subset of genes through the combination of different epigenetic patterns. Globally, STAT4 had a more dominant role in promoting active epigenetic marks, whereas STAT6 had a more prominent role in antagonizing repressive marks. Clusters of genes negatively regulated by STATs were also identified, highlighting previously unappreciated repressive roles of STATs. Therefore, STAT4 and STAT6 play wide regulatory roles in T helper cell specification.

Endoscopic versus external dacryocystorhinostomy: temporal and regional trends in the United States Medicare population.

Purpose: Endoscopic surgeries, such as dacryocystorhinostomy (DCR), are increasingly performed for orbital and lacrimal conditions. This study describes and compares recent trends in endoscopic DCR with open, or external, DCR in the United States (US). Methods: Medicare-Part-B National Summary data files were analyzed from 2000 to 2015 for temporal and geographic trends in endoscopic and external DCR. Medicare Physician and Other Supplier public use files detailing provider information were collected and analyzed from 2012 to 2015. Results: Between 2000 and 2015, the number of external DCRs remained relatively unchanged (8008 to 7086, -0.7% average annual growth), while the number of endoscopic DCRs steadily increased (881 to 1674, 4.6% average annual growth). The greatest number of endoscopic DCRs were performed in the South Atlantic region, whereas the Mountain region had the greatest number per capita. From 2000 to 2015, the average payment per procedure for external DCR was $526.63, compared with $512.45 for endoscopic DCR. Of endoscopic DCRs performed from 2012 to 2015, 831 (79%) were performed by Ophthalmology, 184 (18%) were performed by Otolaryngology, and the remainder by other subspecialties. Conclusions: The number of endoscopic DCR surgeries increased over the last 15 years while the number of external DCR surgeries remained stable and continued to surpass endoscopic procedures. While ophthalmologists perform the overwhelming majority of endoscopic DCR, otolaryngologists are performing a growing number.

Exploring Sociodemographic Factors in Allergic Fungal Rhinosinusitis in a Northern California Patient Population.

BACKGROUND: Allergic fungal rhinosinusitis (AFRS) is a subtype of chronic rhinosinusitis (CRS) that has previously been associated with younger age and Black patients. However, the role of demographic and socioeconomic factors in AFRS severity remains to be fully elucidated. OBJECTIVE: The objective of this study was to determine whether demographic and socioeconomic factors are associated with incidence of AFRS, as well as with disease severity in Northern California. METHODS: A retrospective cohort study was conducted of adult patients with AFRS and CRS from 2010 to 2019. AFRS was determined by the Bent and Kuhn criteria, and severity was assessed by radiographic evidence of cranioorbital invasion and other clinical parameters. Chi-square and t-test were used to assess demographic and socioeconomic differences between AFRS and CRS cohorts, and multivariable logistic regression was used to assess risk factors for severe AFRS. RESULTS: Black patients represented 26.2% (55/210 patients) of the AFRS group and 4.9% (842/17,300 patients) of the CRS group, with pairwise comparison of race/ethnicity categories showing that the AFRS group had significantly higher proportions of Black race/ethnicity compared with other race/ethnicities (p < 0.01). AFRS and CRS groups differed significantly by age, with mean ages of 48.7 and 51.0 years, respectively (p = 0.04). There were no significant differences in gender, Medicaid status, comorbidities, and socioeconomic status measures. Multivariate logistic regression showed that Black patients had higher odds of having severe AFRS (adjusted odds ratio = 2.29; 95% confidence interval: 1.18-4.45). CONCLUSION: AFRS has a unique predilection for Black patients, and severe disease is also more likely in this population.

Arachidonic acid inhibition of the NLRP3 inflammasome is a mechanism to explain the anti-inflammatory effects of fasting.

Elevated interleukin (IL)-1ß levels, NLRP3 inflammasome activity, and systemic inflammation are hallmarks of chronic metabolic inflammatory syndromes, but the mechanistic basis for this is unclear. Here, we show that levels of plasma IL-1ß are lower in fasting compared to fed subjects, while the lipid arachidonic acid (AA) is elevated. Lipid profiling of NLRP3-stimulated mouse macrophages shows enhanced AA production and an NLRP3-dependent eicosanoid signature. Inhibition of cyclooxygenase by nonsteroidal anti-inflammatory drugs decreases eicosanoid, but not AA, production. It also reduces both IL-1ß and IL-18 production in response to NLRP3 activation. AA inhibits NLRP3 inflammasome activity in human and mouse macrophages. Mechanistically, AA inhibits phospholipase C activity to reduce JNK1 stimulation and hence NLRP3 activity. These data show that AA is an important physiological regulator of the NLRP3 inflammasome and explains why fasting reduces systemic inflammation and also suggests a mechanism to explain how nonsteroidal anti-inflammatory drugs work.

The impact of online education during the Covid-19 pandemic on the professional identity formation of medical students: A systematic scoping review.

Evolving individual, contextual, organizational, interactional and sociocultural factors have complicated efforts to shape the professional identity formation (PIF) of medical students or how they feel, act and think as professionals. However, an almost exclusive reliance on online learning during the COVID-19 pandemic offers a unique opportunity to study the elemental structures that shape PIF and the environmental factors nurturing it. We propose two independent Systematic Evidence-Based Approach guided systematic scoping reviews (SSR in SEBA)s to map accounts of online learning environment and netiquette that structure online programs. The data accrued was analysed using the clinically evidenced Krishna-Pisupati Model of Professional Identity Formation (KPM) to study the evolving concepts of professional identity. The results of each SSR in SEBA were evaluated separately with the themes and categories identified in the Split Approach combined to create richer and deeper 'themes/categories' using the Jigsaw Perspective. The 'themes/categories' from each review were combined using the Funnelling Process to create domains that guide the discussion. The 'themes/categories' identified from the 141 included full-text articles in the SSR in SEBA of online programs were the content and effects of online programs. The themes/categories identified from the 26 included articles in the SSR in SEBA of netiquette were guidelines, contributing factors, and implications. The Funnelling Process identified online programs (encapsulating the content, approach, structures and the support mechanisms); their effects; and PIF development that framed the domains guiding the discussion. This SSR in SEBA identifies the fundamental elements behind developing PIF including a structured program within a nurturing environment confined with netiquette-guided boundaries akin to a Community of Practice and the elemental aspect of a socialisation process within online programs. These findings ought to be applicable beyond online training and guide the design, support and assessment of efforts to nurture PIF.

Serial tissue Doppler imaging in the evaluation of bronchopulmonary dysplasia-associated pulmonary hypertension among extremely preterm infants: a prospective observational study.

Objectives: To evaluate serial tissue Doppler cardiac imaging (TDI) in the evolution of bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH) among extremely preterm infants. Design: Prospective observational study. Setting: Single-center, tertiary-level neonatal intensive care unit. Patients: Infant born <28 weeks gestation. Main outcome measures: Utility of TDI in the early diagnosis and prediction of BPD-PH and optimal timing for screening of BPD-PH. Results: A total of 79 infants were included. Of them, 17 (23%) had BPD-PH. The mean gestational age was 25.9 ± 1.1 weeks, and mean birth weight was 830 ± 174 g. The BPD-PH group had a high incidence of hemodynamically significant patent ductus arteriosus (83% vs. 56%, p < 0.018), longer oxygen days (96.16 ± 68.09 vs. 59.35 ± 52.1, p < 0.008), and prolonged hospital stay (133.8 ± 45.9 vs. 106.5 ± 37.9 days, p < 0.005). The left ventricular eccentricity index (0.99 ± 0.1 vs. 1.1 ± 0.7, p < 0.01) and the ratio of acceleration time to right ventricular ejection time showed a statistically significant trend from 33 weeks (0.24 ± 0.05 vs. 0.28 ± 0.05, p < 0.05). At 33 weeks, the BPD-PH group showed prolonged isovolumetric contraction time (27.84 ± 5.5 vs. 22.77 ± 4, p < 0.001), prolonged isovolumetric relaxation time (40.3 ± 7.1 vs. 34.9 ± 5.3, p < 0.003), and abnormal myocardial performance index (0.39 ± 0.05 vs. 0.32 ± 0.03, p < 0.001). These differences persisted at 36 weeks after conceptional gestational age. Conclusions: TDI parameters are sensitive in the early evolution of BPD-PH. Diagnostic accuracy can be increased by combining the TDI parameters with conventional echocardiographic parameters. BPD-PH can be recognizable as early as 33-34 weeks of gestation.

Drug-induced olfactory and gustatory dysfunction: Analysis of FDA adverse events reporting system.

OBJECTIVES: With the COVID-19 pandemic, there is growing interest and research in olfactory and gustatory dysfunction (OGD). Drug-induced dysfunction is an often overlooked etiology. While several medications include smell or taste disturbance as a side effect, there are no publications describing which medications are most frequently implicated. We aim to describe the patterns of these adverse drug reactions (ADRs) using the FDA Adverse Events Reporting System (FAERS). METHODS: The FAERS database was queried from 2011 to 2021 for terms describing ADRs related to OGD. Terms included anosmia, hyposmia, olfactory test abnormal, olfactory nerve disorder, hallucination olfactory, parosmia, ageusia, hypogeusia, dysgeusia, and taste disorder. We identified the top reported medications associated with general smell dysfunction, general taste dysfunction, reduced smell, and altered smell. RESULTS: From 2011 to 2021, 16,091 ADRs were reported with OGD, of which13,641 (84.8%) and 2,450 (15.2%) were associated with gustatory and olfactory reactions, respectively. Zinc products (370 reports) and fluticasone propionate (214) were most commonly associated with olfactory dysfunction, specifically reduced olfaction. Varenicline (24) and fluticasone propionate (23) were most commonly associated with altered smell. Lenalidomide (490) and sunitinib (468) were most commonly associated with gustatory dysfunction. Antineoplastic and immunomodulating medications accounted for 21.6% and 36.3% of olfactory and gustatory ADRs, respectively. Among this category, immunoglobulin drugs were the most commonly associated with OGD ADRs. CONCLUSION: Gustatory dysfunction is more commonly reported ADR compared with olfactory dysfunction. Immunologic/rheumatologic medications are the leading culprit of reported OGD. With increasing numbers of patients presenting to otolaryngologists for OGD, it is important to consider drug-induced etiology. LEVEL OF EVIDENCE: III.

Providing Evidence for Dogma: Risk of Epistaxis After COVID-19 Nasal-Screening Swab.

OBJECTIVE: There is anecdotal evidence SARS-CoV-2 (COVID) RT-PCR screening nasal swabs confer an elevated epistaxis risk. We aimed to assess the association between epistaxis and exposure to a COVID nasal swab. STUDY DESIGN: A matched pairs design was used. SETTING: The study was performed in a single, integrated health care system. METHODS: All patients who received a single COVID nasal swab at our institution between April 2020 and March 2021 were included. McNemar's test was used to compare rates of epistaxis between the 7 days following the index COVID swab (hazard period), and the 7 days preceding the index COVID swab (control period). Conditional logistic regression was used to evaluate sociodemographic and clinical risk factors for epistaxis. RESULTS: A total of 827,987 participants were included, with 1047 epistaxis encounters. The prevalence of epistaxis during the hazard and control periods were 0.08% and 0.04%, respectively. Swab exposure was associated with 1.92-fold odds of epistaxis during the hazard period (95% confidence interval [1.73, 2.12]). Older age, Asian/Pacific Islander (PI) (compared to white), male sex, hypertension, prior facial trauma, and warfarin or direct-acting oral anticoagulant use were also associated with significantly increased odds of epistaxis (p ≦ 0.01). CONCLUSION: COVID nasal swabs are associated with increased odds of epistaxis. Physicians should counsel patients, particularly those at the highest risk, including a history of prior facial trauma, anticoagulants/antiplatelets, or hypertension.

Multi-Institutional Journal Club as a Component of Diversity, Equity, and Inclusion Curricula in Residency Programs.

Topics of diversity, equity, and inclusion (DEI) are an integral component of post-graduate medical education. However, it is currently unclear the extent to which physical medicine and rehabilitation residency programs have incorporated a DEI curriculum into their training programs. Here, a novel, multi-institutional DEI journal club is described. This journal club format can be an important component of the DEI curriculum as it provides non-local perspectives and insights into specific issues and allows for a simple way to introduce DEI training in programs currently without such training. The virtual format also provides further opportunities for discussion and networking.

Ocular Surface Adverse Events are not Associated with Dupilumab use in Nasal Polyp Treatment.

OBJECTIVES: Ocular surface reactions (OSR) have been associated with dupilumab for atopic dermatitis (AD) treatment. However, the association of dupilumab-associated OSR (DA-OSR) for nasal polyps (CRSwNP) treatment has not been studied. We evaluated DA-OSR for CRSwNP treatment using the FDA Adverse Event Reporting System (FAERS). METHODS: FAERS was queried for any general ocular reactions (DA-GOR) from 2019Q1 to 2022Q4. DA-OSR were subcategorized from DA-GOR and compared between treatment groups (CRSwNP, asthma, AD). Logistic regression was used to predict DA-OSR. Disproportionality analysis (DPA) of DA-OSR was performed using OpenVigil. RESULTS: There were 60,198 total observations, of which 5344 were treated for CRSwNP. The prevalence of DA-GOR and DA-OSR was greatest for AD (15.3%, 7.8%), followed by CRSwNP (12.2%, 6.7%) and asthma (9.2%, 3.5%). The most commonly reported OSRs were dry eyes (35.9%), conjunctivitis (15.7%), and increased lacrimation (11.0%). The reported odds ratio (ROR) of CRSwNP-treated DA-OSR was 0.84 (0.73-0.97; p = 0.015), compared to 1.29 (1.20-1.40; p < 0.001) for AD and 0.66 (0.59-0.73; p < 0.001) for asthma. For CRSwNP treatment, the DA-OSR ROR was 0.97 (0.90-1.03; p = 0.3) for men and 0.78 (0.73-0.83, p < 0.001) for older adults (age > 50). ROR in the DPA for DA-OSR was 12.5 (12.2-12.8; p < 0.001) for any indication and 0.58 (0.53-0.64; p < 0.001) for CRSwNP treatment only. CONCLUSIONS: While there are limitations to FAERS, this study confirms the association between dupilumab and OSR for AD treatment, and does not support an association between dupilumab and OSR for CRSwNP treatment. Younger adults experience more DA-OSR in CRSwNP treatment without a specific predilection for sex. LEVEL OF EVIDENCE: IV Laryngoscope, 2023.

Image-Guided Surgical Device Failures in Functional Endoscopic Sinus Surgery: A MAUDE Analysis.

OBJECTIVE: Image-guided surgery (IGS) devices have become widely used for anatomic localization during functional endoscopic sinus surgery (FESS). However, there are no studies that analyze the post-market complications associated with IGS device use during FESS. The objective of this study was to better characterize post-market complications associated with the use of IGS devices during sinus surgery. METHODS: The US Food and Drug Administration's Manufacturer and User Facility Device Experience database was queried for event reports associated with neurological stereotaxic devices utilized in IGS between the dates of January 1, 2016 and December 31, 2020. Medical device reports that were analyzed for this study pertained strictly to FESS. RESULTS: There were 1873 reports involving IGS devices for FESS included in this study. Fifty-five reports involved adverse events to patients (2.9%) and 1818 (97.1%) involved device malfunctions. Of the adverse events to patients, the most common included cerebrospinal fluid leakage (45.6%), tissue damage (12.7%), and nervous system injury (3.6%). The most commonly reported device malfunction was imprecision (21.1%). CONCLUSION: IGS devices are widely utilized in FESS. Of the medical device reports between 2016 and 2020, less than 3% resulted in adverse events. Further studies of the infrequent post-market complications of IGS devices used in FESS can help guide surgeons on the risks of their clinical use. LEVEL OF EVIDENCE: 4-Retrospective database survey without controls Laryngoscope, 133:1310-1314, 2023.

Efficacy of Cryoablation on Chronic Rhinitis Management: A Systematic Review and Meta-Analysis.

BACKGROUND: ClariFix for posterior nasal nerve ablation has been approved for use since 2017, and this is the first study attempting to synthesize and assess the efficacy of this new device on the management of chronic rhinitis. OBJECTIVE: The primary objective of this meta-analysis is to assess the efficacy of ClariFix in the symptomatic management of patients with chronic rhinitis. The main outcome measure is the mean difference in the reflective total nasal symptom score (rTNSS). METHODS: A systematic search of Pubmed/Medline, Web of Science, and EBSCOhost was conducted from inception to May 2022. Peer-reviewed clinical trials reporting postcryotherapy rTNSS at both 1- and 3-month intervals for patients with chronic rhinitis were included. A random-effects model was utilized for meta-analysis. Study heterogeneity, bias, and overall quality were all assessed. The authors followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. The primary outcome measures included mean differences in rTNSS from baseline to both 1- and 3-month postoperative time points. Secondary measures included other questionnaires including the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ). RESULTS: There were 5 studies that met the criteria (247 individuals). The pooled rTNSS mean difference from baseline to 1 and 3 months postoperatively was found to be -3.48 points (95% CI: -3.73 to -3.23, I2 = 0.13). and -3.50 (95% CI: -3.71 to -3.29, I2 = 0.00), respectively. The mean difference from baseline to 3 months postoperatively regarding the RQLQ was found to be -1.53 (95% CI: -1.74 to -1.31, I2 = 0.00). The most common adverse effects included facial or surgical site pain (40.4%), followed by headache (18.2%), oral numbness (11.1%), and sinusitis (4.0%). CONCLUSIONS: The findings of this systematic review suggest that cryoablation with Clarifix is an effective treatment modality for chronic rhinitis. However, higher-quality randomized controlled trials will need to be performed to affirm the findings of this study.

High but Inequitable COVID-19 Vaccine Uptake Among Rehabilitation Patients.

INTRODUCTION: There is a paucity of studies evaluating vaccine uptake in adults with neurological and musculoskeletal medical conditions. We sought to evaluate the rates of COVID-19 vaccine uptake in patients seen in an outpatient rehabilitation clinic. METHODS: We conducted a retrospective, single center study of adults seen at an outpatient rehabilitation clinic from December 1, 2020, through June 30, 2021, with an active Wisconsin Immunization Registry record. The primary outcome was completion of a COVID-19 primary vaccine series. RESULTS: Of 1362 patients, 83.3% completed a COVID-19 vaccination series. Younger patients had increased odds of not completing a COVID-19 vaccination series (mean [SD] 46.7 [14.7] vs 54.3 [15.8]; OR 1.03; 95% CI, 1.02-1.04; P < 0.001). Those who identified as non-White (1.88; 95% CI, 1.16-3.04; P = 0.010) or current smoker (1.85, 95% CI, 1.85-2.79; P = 0.004) had increased odds of not completing a COVID-19 vaccination series. Those who resided in rural ZIP codes (1.81; 95% CI, 1.35-2.43; P < 0.001), had not received a 2019-2020 influenza vaccine (5.13; 95% CI, 3.79-6.96; P < 0.001), or had lower comorbidity scores (2.95; 95% CI, 1.98-4.41; P < 0.001) had higher odds of not completing a COVID-19 vaccination series. CONCLUSIONS: There was a high rate of COVID-19 vaccine uptake among patients seen in a rehabilitation clinic, though racial, ethnic, and geographic differences did exist. Further studies are needed to determine why these disparities exist and investigate interventions to increase vaccine uptake in these populations.

Biphasic JNK signaling reveals distinct MAP3K complexes licensing inflammasome formation and pyroptosis.

Kinase signaling in the tiered activation of inflammasomes and associated pyroptosis is a prime therapeutic target for inflammatory diseases. While MAPKs subsume pivotal roles during inflammasome priming, specifically the MAP3K7/JNK1/NLRP3 licensing axis, their involvement in successive steps of inflammasome activation is poorly defined. Using live-cell MAPK biosensors to focus on the inflammasome triggering event allowed us to identify a subsequent process of biphasic JNK activation. We find that this biphasic post-trigger JNK signaling initially facilitates the mitochondrial reactive oxygen species generation needed to support core inflammasome formation, then supports the gasdermin-mediated cell permeation required for release of active IL-1ß from human macrophages. We further identify and characterize a xanthine oxidase-ROS activated MAP3K5/JNK2 substrate licensing complex as a novel regulator of the GSDMD mobilization which precedes pyroptosis. We show that inhibitors targeting this MAP3K5 cascade alleviate morbidity in mouse models of colitis and dampen both augmented IL-1ß release and cell permeation in monocytes derived from patients with gain-of-function inflammasomopathies.