Disease phenotypes in adult patients with suspected undifferentiated autoinflammatory diseases and PFAPA syndrome: Clinical and therapeutic implications.

BACKGROUND: Undifferentiated autoinflammatory diseases are characterized by recurrent or persistent fever, usually combined with other inflammatory manifestations, and negative or inconclusive genetic studies for monogenic autoinflammatory disorders. AIMS: To define and characterize disease phenotypes in adult patients diagnosed in an adult reference center with undifferentiated autoinflammatory diseases, and to analyze the efficacy of the drugs used in order to provide practical diagnostic and therapeutic recommendations. METHODS: Retrospective study (2015-2022) of patients with undifferentiated autoinflammatory diseases among all patients visited in our reference center. Demographic, clinical, laboratory features and detailed therapeutic information was collected. RESULTS: Of the 334 patients with a suspected autoinflammatory disease, 134 (40%) patients (61% women) were initially diagnosed with undifferentiated autoinflammatory diseases. Mean age at disease onset and at diagnosis was 28.7 and 37.7 years, respectively. In 90 (67.2%) patients, symptoms started during adulthood. Forty-four (32.8%) patients met diagnostic/classification criteria for adult PFAPA syndrome. In the remaining patients, four additional phenotypes were differentiated according to the predominant manifestations: a) Predominantly fever phenotype (n = 18; 13.4%); b) Predominantly abdominal/pleuritic pain phenotype (n = 9; 6.7%); c) Predominantly pericarditis phenotype (n = 18; 13.4%), and d) Complex syndrome phenotype (n = 45; 33.6%). Prednisone (mainly on demand), colchicine and anakinra were the drugs commonly used. Overall, complete responses were achieved with prednisone in 41.3%, colchicine in 40.2%, and anakinra in 58.3% of patients in whom they were used. By phenotypes, prednisone on demand was more effective in adult PFAPA syndrome and colchicine in patients with the abdominal/pleuritic pain pattern and PFAPA syndrome. Patients with complex syndrome achieved complete responses with prednisone (21.9%), colchicine (25.7%) and anakinra (44.4%), and were the group more often requiring additional immunosuppressive drugs. CONCLUSIONS: The analysis of the largest single-center series of adult patients with undifferentiated autoinflammatory diseases identified and characterized different disease phenotypes and their therapeutic approaches. This study is expected to contribute to increase the awareness of physicians for an early identification of these conditions, and to provide the best known therapeutic options.

Ocular Manifestations in Juvenile Behçet's Disease: A Registry-Based Analysis from the AIDA Network.

INTRODUCTION: This study aims to characterize ocular manifestations of juvenile Behçet's disease (jBD). METHODS: This was a registry-based observational prospective study. All subjects with jBD from the Autoinflammatory Diseases Alliance (AIDA) Network BD Registry showing ocular manifestations before 18 years were enrolled. RESULTS: We included 27 of 1000 subjects enrolled in the registry (66.7% male patients, 45 affected eyes). The median (interquartile range [IQR]) age at ocular involvement was 14.2 (4.7) years. Uveitis affected 91.1% of eyes (anterior 11.1%, posterior 40.0%, panuveitis 40.0%), retinal vasculitis 37.8% and other manifestations 19.8%. Later onset (p = 0.01) and male predominance (p = 0.04) characterized posterior involvement. Ocular complications occurred in 51.1% of eyes. Patients with complications had earlier onset (p < 0.01), more relapses (p = 0.02) and more prolonged steroidal treatment (p = 0.02). The mean (standard deviation [SD]) central macular thickness (CMT) at the enrolment and last visit was 302.2 (58.4) and 293.3 (78.2) µm, respectively. Fluorescein angiography was pathological in 63.2% of procedures, with a mean (SD) Angiography Scoring for Uveitis Working Group (ASUWOG) of 17.9 (15.5). At the last visit, ocular damage according to the BD Overall Damage Index (BODI) was documented in 73.3% of eyes. The final mean (SD) best corrected visual acuity (BCVA) logMAR was 0.17 (0.47) and blindness (BCVA logMAR < 1.00 or central visual field ≤ 10°) occurred in 15.6% of eyes. At multivariate regression analysis, human leukocyte antigen (HLA)-B51 + independently predicted a + 0.35 change in the final BCVA logMAR (p = 0.01), while a higher BCVA logMAR at the first assessment (odds ratio [OR] 5.80; p = 0.02) independently predicted blindness. CONCLUSIONS: The results of this study may be leveraged to guide clinical practice and future research on this rare sight-threatening condition.

Factors associated with early hydroxychloroquine-induced retinal toxicity in patients with systemic lupus erythematosus.

PURPOSE: Hydroxychloroquine is currently recommended for the treatment of systemic lupus erythematosus (SLE), but it can cause irreversible retinal toxicity. This study aimed to identify factors associated with early hydroxychloroquine-induced retinal toxicity in patients with SLE from a single centre for 20 years. METHODS: SLE patients diagnosed between 1998 and 2017 and followed up for at least 1 year were included. Demographic, clinical, laboratory and therapeutic data were collected from the electronic medical records and retrospectively analysed. Early hydroxychloroquine-induced retinal toxicity was defined as the development of macular toxicity within the first 5 years of hydroxychloroquine treatment. RESULTS: A total of 345 patients followed for a median of 15 years were analysed; 337 (97.7%) patients received hydroxychloroquine, 38 (11.3%) of them presented with retinal toxicity, and 10 (3%) developed early retinal toxicity. These patients had a mean treatment duration of 3.3 years with a mean cumulative dose of 241 g. Patients were diagnosed by visual field (VF) and fundoscopy, and two were also assessed using spectral domain optical coherence tomography (SD-OCT). The median (IQR) age of patients with early toxicity was 56 (51-66) years, and 80% were female. Factors independently associated with early hydroxychloroquine-induced retinal toxicity were lupus anticoagulant positivity (OR 4.2; 95% CI 1.2-15.5) and hypercholesterolaemia (OR 5.6; 95% CI 1.5-21.5). CONCLUSION: Our results suggest that lupus anticoagulant positivity and hypercholesterolaemia among SLE patients may be risk factors for early hydroxychloroquine-induced retinal toxicity, regardless of the dose or duration of treatment.

Building an Equity-Centered Ecosystem: University of Utah Health as a Microcosm.

Academic medicine, and medicine in general, are less diverse than the general patient population. Family Medicine, while still lagging behind the general population, has the most diversity in leadership and in the specialty in general, and continues to lead in this effort, with 16.7% of chairs identifying as underrepresented in medicine. Historical and current systematic marginalization of Black or African American, Latina/e/o/x, Hispanic or of Spanish Origin (LHS), American Indian/Alaska Native, Native Hawaiian/Pacific Islander, and Southeast Asian individuals has created severe underrepresentation within health sciences professions. Over the last 30 years, the percentage of faculty from these groups has increased from 7 to 9% in allopathic academic medicine, with similar increases in Osteopathic Medicine, Dentistry, and Pharmacy, but all lag behind age-adjusted population means. Traditionally, diversity efforts have focused on increasing pathway programs to address this widening disparity. While pathway programs are a good start, they are only a portion of what is needed to create lasting change in the diversity of the medical profession as well as the career trajectory and success of underrepresented in medicine (URiM) health professionals toward self-actualization and positions of leadership. This article elucidates all parts of an ecosystem necessary to ensure that equity, diversity, and inclusion outcomes can improve.

miR-218-5p, miR-124-3p and miR-23b-3p act synergistically to modulate the expression of NACC1, proliferation, and apoptosis in C-33A and CaSki cells.

Background: In cervical cancer (CC), miR-218-5p, -124-3p, and -23b-3p act as tumor suppressors. These miRNAs have specific and common target genes that modulate apoptosis, proliferation, invasion, and migration; biological processes involved in cancer. Methods: miR-218-5p, -124-3p, and -23b-3p mimics were transfected into C-33A and CaSki cells, and RT-qPCR was used to quantify the level of each miRNA and NACC1. Proliferation was assessed by BrdU and apoptosis by Annexin V/PI. In the TCGA and The Human Protein Atlas databases, the level of NACC1 mRNA and protein (putative target of the three miRNAs) was analyzed in CC and normal tissue. The relationship of NACC1 with the overall survival in CC was analyzed in GEPIA2. NACC1 mRNA and protein levels were higher in CC tissues compared with cervical tissue without injury. Results: An increased expression of NACC1 was associated with lower overall survival in CC patients. The levels of miR-218-5p, -124-3p, and -23b-3p were lower, and NACC1 was higher in C-33A and CaSki cells compared to HaCaT cells. The increase of miR-218-5p, -124-3p, and -23b-3p induced a significant decrease in NACC1 mRNA. The transfection of the three miRNAs together caused more drastic changes in the level of NACC1, in the proliferation, and in the apoptosis with respect to the individual transfections of each miRNA. Conclusion: The results indicate that miR-218-5p, -124-3p, and -23b-3p act synergistically to decrease NACC1 expression and proliferation while promoting apoptosis in C-33A and CaSki cells. The levels of NACC1, miR-218-5p, -124-3p, and -23b-3p may be a potential prognostic indicator in CC.

Immunoglobulin G4-related disease and B-cell malignancy due to an IKZF1 gain-of-function variant.

BACKGROUND: Monoallelic loss-of-function IKZF1 (IKAROS) variants cause B-cell deficiency or combined immunodeficiency, whereas monoallelic gain-of-function IKZF1 variants have recently been reported to cause hypergammaglobulinemia, abnormal plasma cell differentiation, autoimmune and allergic manifestations, and infections. METHODS: We studied seven relatives with autoimmune/inflammatory diseases and lymphoproliferative diseases. We analysed biopsy results and performed whole-exome sequencing and immunological studies. RESULTS: Disease onset occurred at a mean age of 25.2 years (range: 10-64, years). Six patients suffered from autoimmune/inflammatory diseases, four had confirmed immunoglobulin G4-related disease (IgG4-RD), and five developed B-cell malignancies: lymphoma in four and multiple myeloma in the remaining patient. Patients without immunosuppression were not particularly prone to infectious diseases. Three patients suffered from life-threatening COVID-19 pneumonia, one of whom had autoantibodies neutralizing interferon (IFN)-α. The recently described IKZF1 gain-of-function p.R183H variant was found in the five affected relatives tested and in a six-year-old asymptomatic girl. Immunological analysis revealed hypergammaglobulinemia and high frequencies of certain lymphocyte subsets (exhausted B cells, effector memory CD4 T cells, TEMRA and CD28-CD57+ CD4+ and CD8+ T cells, Th2 and Tfh2 cells) attesting to immune dysregulation. Partial clinical responses to rituximab and corticosteroids were observed, and treatment with lenalidomide, which promotes IKAROS degradation, was initiated in three patients. CONCLUSION: Heterozygosity for gain-of-function IKZF1 variants underlies autoimmunity/inflammatory diseases, IgG4-RD and B-cell malignancies, the onset of which may occur in adulthood. Clinical and immunological data are similar to those for patients with unexplained IgG4-RD. Patients may therefore benefit from treatments inhibiting pathways displaying IKAROS-mediated overactivity.

Departmental Metrics to Guide Equity, Diversity, and Inclusion for Academic Family Medicine Departments.

PROBLEM: Equity, diversity, and inclusion (EDI) efforts have accelerated over the past several years, without a traditional guidebook that other missions often have. To evaluate progress over time, departments of family medicine are seeking ways to measure their current EDI state. Across the specialty, unity regarding which EDI metrics are meaningful is absent, and discordance even exists about what should be measured. APPROACH: This paper provides a general metrics framework, including a wide array of possibilities to consider measuring, for assessing individual departmental progress in this broad space. These measures are designed to be general enough to provide common language and can be customized to align with strategic priorities of individual family medicine departments. OUTCOMES: The Diversity, Equity, and Inclusion Committee of the Association of Departments of Family Medicine has produced a common framework to facilitate measurement of EDI outcomes in the following areas: care delivery and health, workforce recruitment and retention, learner recruitment and training, and research participation. This framework allows departments to monitor progress across these domains that impact the tripartite mission, providing opportunities to capitalize on measured gains in EDI. NEXT STEPS: Departments can review this framework and consider which metrics are applicable or develop their own metrics to align with their strategic priorities. In the future, collective departments could compare notes and measure aggregate progress together. Evaluating progress is a step in the journey toward the goal of ensuring that departments are operating from inclusive and just academic systems.

Inhibition and working memory capacity modulate the mental space-time association.

This research aimed to investigate whether the mental space-time association of temporal concepts could be modulated by the availability of cognitive resources (in terms of working memory and inhibitory control capacities) and to explore whether access to this association could be an automatic process. To achieve this, two experiments were carried out. In Experiment 1, participants had to classify words with future and past meanings. The working memory load (high vs. low) was manipulated and the participants were grouped into quartiles according to their visuospatial working memory capacity (WMC). Temporal concepts were displayed subliminally (immediate masking) and supraliminally (delayed masking). The ANOVA showed a performance pattern consistent with the left-past right-future conceptual scheme, regardless of both the type of masking and the working memory load, except in high WMC participants, in which, interestingly, the space-time association effect was absent. In Experiment 2, participants were asked to respond to the colour of the font of the temporal words, and their attentional control capacity was assessed. The results indicated a timeline effect that was irrespective of the WM load and the type of perceptual processing, but not of the WM capacity or the inhibitory abilities. These findings partially endorse the automatic and implicit access to the mental space-time association and suggest the involvement of the availability of cognitive resources. Individual WMC differences appear to modulate the automatic nature of the effect rather than the processing conditions themselves.

Unambiguous identification of asymmetric and symmetric synapses using volume electron microscopy.

The brain contains thousands of millions of synapses, exhibiting diverse structural, molecular, and functional characteristics. However, synapses can be classified into two primary morphological types: Gray's type I and type II, corresponding to Colonnier's asymmetric (AS) and symmetric (SS) synapses, respectively. AS and SS have a thick and thin postsynaptic density, respectively. In the cerebral cortex, since most AS are excitatory (glutamatergic), and SS are inhibitory (GABAergic), determining the distribution, size, density, and proportion of the two major cortical types of synapses is critical, not only to better understand synaptic organization in terms of connectivity, but also from a functional perspective. However, several technical challenges complicate the study of synapses. Potassium ferrocyanide has been utilized in recent volume electron microscope studies to enhance electron density in cellular membranes. However, identifying synaptic junctions, especially SS, becomes more challenging as the postsynaptic densities become thinner with increasing concentrations of potassium ferrocyanide. Here we describe a protocol employing Focused Ion Beam Milling and Scanning Electron Microscopy for studying brain tissue. The focus is on the unequivocal identification of AS and SS types. To validate SS observed using this protocol as GABAergic, experiments with immunocytochemistry for the vesicular GABA transporter were conducted on fixed mouse brain tissue sections. This material was processed with different concentrations of potassium ferrocyanide, aiming to determine its optimal concentration. We demonstrate that using a low concentration of potassium ferrocyanide (0.1%) improves membrane visualization while allowing unequivocal identification of synapses as AS or SS.

Clinical Outcomes of Isolated Polyethylene Exchange versus Full Component Revision for the Management of Instability Following Total Knee Arthroplasty.

BACKGROUND: Instability following total knee arthroplasty (TKA) is a common cause for revision. Isolated polyethylene exchange (IPE) can be performed to increase knee joint stability, but results have been mixed. The purpose of this study was to compare the survivorship and patient-reported outcomes of patients undergoing revision TKA for instability with IPE versus full component revision. METHODS: We reviewed 280 primary TKAs undergoing revision TKA for instability. There were 181 knees that underwent revision with IPE, compared to 99 knees treated with full component revision. The mean follow-up was 32.8 months (range, 24.8 to 82.5). Patient demographics, radiographic parameters, prosthesis constraints, reoperations for instability, and patient-reported outcomes were compared. RESULTS: The survivorship for instability was significantly higher at 2 years (99 versus 92%, P = 0.024) and 5 years (94 versus 84%, P = 0.024) for patients undergoing full component revision. Although there was no difference in Knee Injury and Osteoarthritis Outcome Score for Joint Replacements (KOOS Jr) and Veterans RAND 12 (VR-12) physical component scores between the 2 groups at 6 weeks, 1 year, and 2 years after surgery, full revision patients reported greater pain relief (P = 0.006) and greater improvements in VR-12 physical component scores (P = 0.027) at 1 year and KOOS JR scores at 2 years (P = 0.017) compared to IPE patients. Men were associated with an increased risk for recurrent instability following IPE (HR [hazard ratio] 3.3, 95% confidence interval (CI): [1.0 to 10.6]). CONCLUSIONS: Isolated polyethylene exchange was not as reliable or durable compared to full component revision for the management of postoperative instability. These procedures should only be reserved in cases with competent collaterals and when component position, offset, and rotation are optimized.

The impact of cultural stress on family functioning among Puerto Rican displaced families and the effect on mental health.

Hurricane María caused significant devastation on the island of Puerto Rico, impacting thousands of lives. Puerto Rican crisis migrant families faced stress related to displacement and relocation (cultural stress), often exhibited mental health symptoms, and experienced distress at the family level. Although cultural stress has been examined as an individual experience, little work has focused on the experience as a family. To address this gap, we conducted a mixed-methods study designed to examine the predictive effects of cultural stress on family conflict and its mental health implications among Puerto Rican Hurricane María parent and child dyads living on the U.S. mainland. In the quantitative phase of the study, 110 parent-child dyads completed an online survey assessing cultural stress, family dynamics, and mental health. As part of our primary analysis, we estimated a structural equation path model. Findings from the quantitative phase showed a significant positive relationship between family cultural stress and family conflict, as well as individual parent and child mental health symptoms. In the qualitative phase of the study, 35 parent-child dyads participated in individual interviews. Findings from the interviews revealed variations in difficulties related to language, discrimination, and financial burdens, with some participants adapting more quickly and experiencing fewer stressors. Findings also highlight the impact on mental health for both parents and youth, emphasizing the family-level nature of cultural stress, while noting a potential discrepancy between qualitative and quantitative findings in the discussion of family conflict.

Ten steps to transform ideas into product innovations: An interdisciplinary collaboration between nursing and engineering.

AIMS: To describe the development process of a device from the conception of the idea to the first contact with the commercial environment, and to demonstrate its practical application through an interdisciplinary collaboration between nursing and engineering for the design of a protective device for peripheral venous catheters. BACKGROUND: Nurses are key agents for identifying unresolved needs or problems related to nursing care. To address these needs, creative ideation processes are often triggered among nurses to seek technological answers to these challenges. RESULTS: The ten steps to develop a device are presented: (1) detecting an unsatisfied clinical need; (2) searching for preexisting marketed products; (3) searching for patents; (4) maintaining confidentiality throughout the process; (5) obtaining institutional support; (6) forming a multidisciplinary team; (7) developing the idea; (8) applying for a patent; (9) building the prototype; (10) marketing the device. This methodology was applied to design a protective device for peripheral venous catheters in hospitalized patients. CONCLUSIONS: Nurses can play a key role in the promotion of healthcare innovation in their field to improve procedures, thanks to their direct contact with patients, and by providing their insight on devices that can enhance patient care. The successful interdisciplinary collaboration between nurses and engineers can provide a response to relevant clinical problems such as the manipulation or removal of peripheral venous catheters. IMPLICATIONS FOR NURSING AND/OR HEALTH POLICY: A hospital policy is required to encourage the participation of nurses in innovative actions. Furthermore, it is important to support nurse leaders who can play a pivotal role in incorporating creativity into work environments and empowering other nurses to innovatively address clinical issues. NO PATIENT OR PUBLIC CONTRIBUTION: This article describes the process for developing a health device.

Psychological distress among unemployed migrants settling in southwestern Spain: A cross-sectional study.

Migrants living in the informal settlements of Southern Spain tend to have precarious employment and poor living conditions, making then vulnerable to mental health issues. This study aimed to assess psychological distress in a sample of unemployed migrants residing in informal settlements in the province of Huelva (southern Spain), during the fourth wave of the COVID-19 pandemic. A descriptive cross-sectional study was conducted during the months of April to June 2021, through a heteroadministered questionnaire, in informal settlements. The measurement instrument was the General Health Questionnaire (GHQ-12), used to analyze psychological distress, and other sociodemographic and health-related variables. Univariate and bivariate descriptive data analysis were performed, using the nonparametric statistics Mann-Whitney U test, Kruskal-Wallis H test, and Tau ß correlation. A categorical regression analysis was performed to study the relationship between psychological distress and the rest of the variables. The sample consisted of 317 subjects, 83.9% of whom were males, and the mean age was 33.4 years (SD = 10.7 years). The mean score obtained in the GHQ-12 questionnaire was 13.69 points (SD = 3.86). Significant differences were found between levels of psychological distress and substance abuse (H = 14.085; P = .049), people who wished to stay in Spain (t = 6987; P = .049), people who experienced isolation due to COVID-19 contact (t = 1379.5; P = .001), people who needed medical assistance due to COVID-19 (t = 7.990; P = .018), and those who reported having chronic illnesses (t = 2686.5, P = .02). The mean score of psychological distress indicates general high levels of psychological distress. Participants who had experienced isolation due to COVID-19 contact, who consumed substances, and who had chronic illnesses reported the highest levels of psychological distress.

Reduced mitochondrial pyruvate carrier expression in hearts with heart failure and reduced ejection fraction patients: ischemic vs. non-ischemic origin.

Introduction and objectives: Mitochondrial pyruvate carrier (MPC) mediates the entry of pyruvate into mitochondria, determining whether pyruvate is incorporated into the Krebs cycle or metabolized in the cytosol. In heart failure (HF), a large amount of pyruvate is metabolized to lactate in the cytosol rather than being oxidized inside the mitochondria. Thus, MPC activity or expression might play a key role in the fate of pyruvate during HF. The purpose of this work was to study the levels of the two subunits of this carrier, named MPC1 and MPC2, in human hearts with HF of different etiologies. Methods: Protein and mRNA expression analyses were conducted in cardiac tissues from three donor groups: patients with HF with reduced ejection fraction (HFrEF) with ischemic cardiomyopathy (ICM) or idiopathic dilated cardiomyopathy (IDC), and donors without cardiac pathology (Control). MPC2 plasma levels were determined by ELISA. Results: Significant reductions in the levels of MPC1, MPC2, and Sirtuin 3 (SIRT3) were observed in ICM patients compared with the levels in the Control group. However, no statistically significant differences were revealed in the analysis of MPC1 and MPC2 gene expression among the groups. Interestingly, Pyruvate dehydrogenase complex (PDH) subunits expression were increased in the ICM patients. In the case of IDC patients, a significant decrease in MPC1 was observed only when compared with the Control group. Notably, plasma MPC2 levels were found to be elevated in both disease groups compared with that in the Control group. Conclusion: Decreases in MPC1 and/or MPC2 levels were detected in the cardiac tissues of HFrEF patients, with ischemic or idiopatic origen, indicating a potential reduction in mitochondrial pyruvate uptake in the heart, which could be linked to unfavorable clinical features.

The systemic score may identify life-threatening evolution in Still's disease: data from the GIRRCS AOSD-study group and the AIDA Network Still's Disease Registry.

OBJECTIVES: To evaluate the clinical usefulness of the systemic score in the prediction of life-threatening evolution in Still's disease. To assess the clinical relevance of each component of the systemic score in predicting life-threatening evolution and to derive patient subsets accordingly. METHODS: A multicenter, observational, prospective study was designed including patients included in the GIRRCS (Gruppo Italiano Di Ricerca in Reumatologia Clinica e Sperimentale) AOSD-study group and AIDA (AutoInflammatory Disease Alliance) Network Still's Disease Registry. Patients were assessed if variables to derive the systemic score were available. The life-threatening evolution was defined as mortality, whichever the clinical course, and/or macrophage activation syndrome (MAS), a secondary hemophagocytic lymphohistiocytosis associated with a poor prognosis. RESULTS: Totally 597 patients with Still's disease were assessed (age 36.6±17.3 years; male 44.4%). The systemic score, assessed as continuous variable, significantly predicted the life-threatening evolution (OR: 1.24, 95%CI:1.07-1.42; p=0.004). A systemic score ≥7 also significantly predicted the likelihood of a patient experiencing life-threatening evolution (OR: 3.36, 95%CI:1.81-6.25; p<0.001). Assessing the clinical relevance of each component of the systemic score, liver involvement (OR: 1.68, 95%CI:1.48-2.67; p=0.031) and lung disease (OR: 2.12, 95%CI:1.14-4.49; p=0.042) both significantly predicted life-threatening evolution. The clinical characteristics of patients with liver involvement and lung disease were derived, highlighting their relevance in multiorgan disease manifestations. CONCLUSION: The clinical utility of the systemic score was shown in identifying Still's disease at higher risk of life-threatening evolution in a large cohort. Furthermore, the clinical relevance of liver involvement and lung disease was highlighted.

Reactance inversion in moderate to severe persistent asthma: low birth weight, prematurity effect, and bronchodilator response.

INTRODUCTION: Reactance inversion (RI) has been associated with impaired peripheral airway function in persistent asthma. However, there is little to no data about the difference between asthmatic children with and without RI. This study aimed to detect clinical and lung function differences in moderate-severe asthmatic children with and without RI. METHODS: This study was conducted between 2021 and 2022 in asthmatic school-age children. Impulse oscillometry (IOS) and spirometry were performed according to ATS/ERS standards. RESULTS: A total of 62 patients, with a mean age of 8.4 years, 54.8% were males and were divided into three groups: group 1 (32.3%) with no RI, group 2 (27.4%) with RI but disappearing after bronchodilator test and group 3 (40.3%) with persistent RI after bronchodilator test. Children in groups 2 and 3 had significantly lower birth weights than in group 1. Group 2 had lower gestational age compared to group 1. FEV1 and FEF25-75 of forced vital capacity were significantly lower in groups 2 and 3. In group 3, R5, AX, R5-20, and R5-R20/R5 ratios were significantly higher. Bronchodilator responses (BDR) in X5c, AX, and R5-R20 were significantly different between groups and lower in group 3. CONCLUSION: RI is frequently found in children with moderate-severe persistent asthma, particularly in those with a history of prematurity or low birth weight. In some patients, RI disappears after the bronchodilator test; however, it, persists in those with the worst pulmonary function. RI could be a small airway dysfunction marker.

Orbital/ocular inflammatory involvement in VEXAS syndrome: Data from the international AIDA network VEXAS registry.

VEXAS syndrome is a recently described monogenic autoinflammatory disease capable of manifesting itself with a wide array of organs and tissues involvement. Orbital/ocular inflammatory manifestations are frequently described in VEXAS patients. The objective of this study is to further describe orbital/ocular conditions in VEXAS syndrome while investigating potential associations with other disease manifestations. In the present study, twenty-seven out of 59 (45.8 %) VEXAS patients showed an inflammatory orbital/ocular involvement during their clinical history. The most frequent orbital/ocular affections were represented by periorbital edema in 8 (13.6 %) cases, episcleritis in 5 (8.5 %) patients, scleritis in 5 (8.5 %) cases, uveitis in 4 (6.8 %) cases, conjunctivitis in 4 (6.8 %) cases, blepharitis in 3 (5.1 %) cases, orbital myositis in 2 (3.4 %) cases. A diagnosis of systemic immune-mediated disease was observed in 15 (55.6 %) cases, with relapsing polychondritis diagnosed in 12 patients. A significant association was observed between relapsing polychondritis and orbital/ocular involvement in VEXAS syndrome (Relative Risk: 2.37, 95 % C.I. 1.03-5.46, p = 0.048). Six deaths were observed in the whole cohort of patients after a median disease duration of 1.2 (IQR=5.35) years, 5 (83.3 %) of which showed orbital/ocular inflammatory involvement. In conclusion, this study confirms that orbital/ocular inflammatory involvement is a common finding in VEXAS patients, especially when relapsing polychondritis is diagnosed. This makes ophthalmologists a key figure in the diagnostic process of VEXAS syndrome. The high frequency of deaths observed in this study seems to suggest that patients with orbital/ocular involvement may require increased attention and more careful follow-up.

The structural line between prion and "prion-like": Insights from prion protein and tau.

The concept of 'prion-like' behavior has emerged in the study of diseases involving protein misfolding where fibrillar structures, called amyloids, self-propagate and induce disease in a fashion similar to prions. From a biological standpoint, in order to be considered 'prion-like,' a protein must traverse cells and tissues and further propagate via a templated conformational change. Since 2017, cryo-electron microscopy structures from patient-derived 'prion-like' amyloids, in particular tau, have been presented and revealed structural similarities shared across amyloids. Since 2021, cryo-EM structures from prions of known infectivity have been added to the ex vivo amyloid structure family. In this review, we discuss current proposals for the 'prion-like' mechanisms of spread for tau and prion protein as well as discuss different influencers on structures of aggregates from tauopathies and prion diseases. Lastly, we discuss some of the current hypotheses for what may distinguish structures that are 'prion-like' from transmissible prion structures.