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Previous work has shown the chemosensory dysfunction item of the 22-item Sinonasal Outcome Test (SNOT-22) that assesses problems with "taste/smell" has poor psychometric performance compared with other items on the SNOT-22, which we have hypothesized is due to the simultaneous assessment of two different senses. Our aim was to determine whether distinct smell and taste items in the SNOT-22 would improve psychometric performance.One hundred and eighty-one CRS patients were recruited and completed the SNOT-22. Additional items querying problems with the senses of "smell" and "taste," using the same response scale and recall period were given to study participants. Item response theory (IRT) was used to determine IRT parameters, including item discrimination, difficulty, and information provided by each SNOT-22 item.Confirming previous studies, the chemosensory item of the SNOT-22 (reflecting "taste/smell") had poor psychometric performance. Use of a distinct smell or taste item instead of the combined "taste/smell" item did not improve psychometric performance. However, a dedicated smell question resulted in a left shift of threshold parameters, showing that the dedicated smell item better captures moderate CRS disease burden than the original taste/smell item of the SNOT-22, which by virtue of near-identical IRT parameters appears to more greatly reflect problems with taste.A dedicated smell- or taste-specific item, rather than the combined "taste/smell" item currently in the SNOT-22 does not provide significantly greater psychometric performance. However, a dedicated smell item may better capture moderate CRS disease burden compared with the current chemosensory item on the SNOT-22. Laryngoscope, 132:1644-1651, 2022.

Background and purpose: The retrograde femoral approach is an established technique for implantation of nails for leg lengthening and correction and in cases of distal femoral fractures. The purpose of this study was to determine the 10-year outcome of this technique by analyzing the clinical long-term effects and radiological status of the knee after leg lengthening via a retrograde femoral approach.Patients and methods: This retrospective single-center study included 13 patients (median age at surgery 17 [range 15–20] years) who underwent unilateral, retrograde, femoral lengthening with a motorized nail. Outcome measurements were graded variables of the SF-36, ISKD score, and Lysholm score. MRI of both knees was performed in all patients. MRI was evaluated for the presence of degenerative changes and compared with the healthy contralateral knee. Cartilage condition was graded according to the International Cartilage Repair Society (ICRS) scoring system.Results: All patients were pain-free and had a full range of motion 10 (range 10.0–12.2) years after surgery. All postoperative knees showed fibrosis of Hoffa’s fat pad and moderate to severe cartilage defects (ICRS Grade 2–4) of the trochlear groove (nail entry site). 6 out of 13 operated knees exhibited retropatellar cartilage defects.Conclusion: Our study showed that patients were pain-free, but cartilage defects at the entry point and arthrofibrosis at Hoffa’s fat pad were observed without causing clinical impairment.

The burden of chronic rhinosinusitis (CRS) symptomatology is frequently measured with the 22-item Sinonasal Outcome Test (SNOT-22). In some situations, such as when there is need for frequent sampling, a full SNOT-22 may be impractical, and an abbreviated measure may be useful. Herein, we study 4 questions reflecting the 4 SNOT-22 subdomains as accurate reflections of SNOT-22 content. In total, 250 patients with CRS completed a SNOT-22 and answered 4 questions about their total nasal symptoms, poor sleep quality, ear/facial pain, and mood (reflecting SNOT-22 subdomains) using visual analog scales (VASs). The 4 SNOT-22 subdomain VAS scores each correlated strongly with the corresponding SNOT-22 subdomain scores. The sum of the 4 subdomain question VAS scores was highly correlated with the total SNOT-22 score (

The U.S. Food and Drug Administration–approved proteasomal inhibitor bortezomib (BTZ) has attracted interest for its potential antifibrotic actions. However, neither its in vivo efficacy in lung fibrosis nor its dependence on proteasome inhibition has been conclusively defined. In this study, we assessed the therapeutic efficacy of BTZ in a mouse model of pulmonary fibrosis, developed an in vitro protocol to define its actions on diverse fibroblast activation parameters, determined its reliance on proteasome inhibition for these actions in vivo and in vitro, and explored alternative mechanisms of action. The therapeutic administration of BTZ diminished the severity of pulmonary fibrosis without reducing proteasome activity in the lung. In experiments designed to mimic this lack of proteasome inhibition in vitro, BTZ reduced fibroblast proliferation, differentiation into myofibroblasts, and collagen synthesis. It promoted dedifferentiation of myofibroblasts and overcame their characteristic resistance to apoptosis. Mechanistically, BTZ inhibited kinases important for fibroblast activation while inducing the expression of DUSP1 (dual-specificity protein phosphatase 1), and knockdown of DUSP1 abolished its antifibrotic actions in fibroblasts. Collectively, these findings suggest that BTZ exhibits a multidimensional profile of robust inhibitory actions on lung fibroblasts as well as antifibrotic actions in vivo. Unexpectedly, these actions appear to be independent of proteasome inhibition, instead attributable to the induction of DUSP1.

The SNOT-22 (22-item Sinonasal Outcome Test) is a high-quality outcome measure that assesses chronic rhinosinusitis-specific quality of life. The aim of this study was to gain greater insight into the information provided by the SNOT-22 by determining its item-based psychometric properties.Retrospective cohort study.Tertiary care academic centers.This study used a previously described data set of the SNOT-22 completed by 800 patients with chronic rhinosinusitis. Item response theory graded response models were used to determine parameters reflecting item discrimination, difficulty, and information provided by each item toward the SNOT-22 subdomain to which it belonged.The unconstrained graded response model fitted the SNOT-22 data best. Item discrimination parameters and total information provided showed the greatest variability within the nasal subdomain, and the item related to sense of smell/taste demonstrated the lowest discrimination and provided the least amount of information overall. The dizziness item provided disparately lower total information and discrimination in the otologic/facial pain subdomain. Items in the sleep and emotional subdomains generally provided high discrimination. While items in the nasal, sleep, and otologic/facial pain subdomains spanned all levels of difficulty, emotional subdomain items covered higher levels of difficulty, indicating greater information provided at higher levels of disease severity.The item-specific psychometric properties of the SNOT-22 support it as a high-quality instrument. Our results suggest the need and possibility for revision of the smell/taste dysfunction item, for example its wording, to improve its ability to discriminate among the different levels of disease burden.

ObjectiveCurrent epidemiologic predictions of COVID-19 suggest that SARS-CoV-2 mitigation strategies must be implemented long-term. In-office aerosol-generating procedures pose a risk to staff and ...

Hip reconstruction is an established procedure in pediatric patients with neurogenic hip dislocation. An open triradiate cartilage provides the advantage of a high plasticity of the bone which prevents an intraarticular fracture and postoperative adaptation of shape. Some patients with dislocated hips, however, arrive late. A hip reconstruction is still feasible as shown earlier but the long-term risk for osteoarthritis, and recurrence of dislocation, and functional outcome is unknown. It is the aim of our investigation to evaluate long-term clinical and radiological outcomes of hip reconstruction by Dega type pelvic osteotomy performed after fusion of the triradiate epiphyseal cartilage in patients suffering from cerebral palsy. We retrospectively analyzed 43 hips in 37 patients with a hip reconstruction for correction of hip dislocation or subluxation. In all patients, the triradiate cartilage was fused before surgery. Age at surgery was 15 years and 2 months on average and follow-up time was mean 13 years 5 months. Mean Kellgren Lawrence score at final follow-up was significantly higher than at preoperative investigation (P

Objective Patient reported outcome measures (PROMs) for assessment of chronic rhinosinusitis (CRS) employ a variety of recall periods and response scales for reporting CRS symptom burden. CRS patient perspective is unknown with respect to recall periods and response scales in PROMs. Design Cross-sectional study. Setting Tertiary rhinology clinic. Participants 63 adults with CRS. Main outcome measures Participants were asked to choose which CRS symptom recall period - one day, two weeks, one month, or greater than one month - was most reflective of their current disease state and best to base treatment recommendations (including surgery) upon. Participants were also asked to report on which of six response scales (one visual analogue scale [VAS] and five Likert scales ranging from four to eight items) was easiest to use and understand, and most preferred. Results A majority of participants felt the current state of their CRS symptoms was best reflected by a recall period of two weeks to one month; however, patients preferred that recommendations about treatments, including endoscopic sinus surgery, be determined by symptoms experienced over at least a one-month period. Participants generally found the VAS and seven-item Likert scale to be the easiest to use and understand, and their most preferred scales. No patient characteristics associated with preferences for recall periods or response scales. Conclusion Future PROMs for CRS symptoms should consider assessment of symptoms over a one-month time frame and use either a VAS or seven-item Likert response scale to optimally balance reflection of current disease state, need for intervention and patient preference.

Acute exacerbations of chronic rhinosinusitis (AECRS) are currently defined as a transient worsening of symptoms that return to baseline. This definition is narrow and can only be made retrospectively. The literature has studied this phenomenon from the physician perspective, yet a key stakeholder's-the patient's perspective is not well elucidated in the literature. To understand AECRS from the patient's perspective, we performed this study to further clarify this phenomenon.Basic qualitative study via patient interviews using constant comparative methodology was conducted.Tertiary care academic center.Two of the authors served as coders, and via group discussion, a common codebook was created and used to identify recurrent themes. The themes were analyzed for meaning and conclusions were summarized.Ten interviews were conducted with chronic rhinosinusitis (CRS) patients. Recurring themes included the following: (1) patients identify with the termBeyond worsening of sinonasal symptoms, the concept of AECRS reflects a more complex construct to patients with associated extranasal symptoms and systemic manifestations. In addition, AECRS have a large impact on patients, and therefore, understanding this component of CRS is pivotal in improving disease control and QOL in this patient population.

There is a paucity of information about potential molecular brakes on the activation of fibroblasts that drive tissue fibrosis. The transcription factor Krüppel-like factor 4 (KLF4) is best known as a determinant of cell stemness and a tumor suppressor. We found that its expression was diminished in fibroblasts from fibrotic lung. Gain- and loss-of-function studies showed that KLF4 inhibited fibroblast proliferation, collagen synthesis, and differentiation to myofibroblasts, while restoring their sensitivity to apoptosis. Conditional deletion of KLF4 from fibroblasts potentiated the peak degree of pulmonary fibrosis and abrogated the subsequent spontaneous resolution in a model of transient fibrosis. A small molecule inducer of KLF4 was able to restore its expression in fibrotic fibroblasts and elicit resolution in an experimental model characterized by more clinically relevant persistent pulmonary fibrosis. These data identify KLF4 as a pivotal brake on fibroblast activation whose induction represents a therapeutic approach in fibrosis of the lung and perhaps other organs.

ObjectiveWe sought to determine if chronic rhinosinusitis (CRS) patients with nasal polyps (CRSwNP) differentially perceived CRS symptom burden compared to patients without nasal polyps (CRSsNP) and to what extent CRS symptom severity was associated with quality of life (QOL) and patient-reported symptom control in the 2 groups.MethodsA total of 600 patients (266 CRSwNP and 334 CRSsNP) presenting with CRS were recruited. CRS symptom burden was assessed with the 22-item Sinonasal Outcome Test (SNOT-22). SNOT-22 nasal, sleep, ear/facial discomfort, and emotional subdomain scores were calculated. General health-related QOL was assessed with the visual analog scale of the 5-dimensional EuroQol questionnaire (EQ-5D VAS). Patients rated their CRS symptom control on a 5-point scale.ResultsSNOT-22 scores did not differ between CRSwNP (mean: 35.6) and CRSsNP (mean: 36.3). There were no differences in nasal, sleep, and emotional subdomains of the SNOT-22. CRSsNP had higher ( P = .003) ear/facial subdomain scores than CRSwNP, while CRSwNP reported greater hyposmia ( P ConclusionCRSwNP and CRSsNP have differences in symptom profile, effect on health-related QOL, and patient-perceived symptom control. CRSsNP experience significantly greater burden of ear/facial discomfort, while CRSwNP report greater hyposmia. Although CRSsNP reports lower general health-related QOL overall, CRSwNP patients had lower levels of CRS symptom control for every incremental increase in symptom burden suggesting greater sensitivity/intolerance to CRS symptoms.

Coronavirus disease 2019 (COVID-19) is a global pandemic affecting millions of individuals, killing hundreds of thousands. Although typically described with characteristic symptoms of fever, cough, and shortness of breath, greater understanding of COVID-19 has revealed myriad clinical manifestations. Olfactory dysfunction (OD)-hyposmia and anosmia-has recently been recognized as an important symptom of COVID-19 and increasingly gained traction as a public health tool for identifying COVID-19 patients, in particular otherwise asymptomatic carriers who, unawares, may be major drivers of disease spread. The objective of this study is to review the scientific evidence about anosmia in COVID-19.PubMed, Google Scholar, and Web of Science.Comprehensive literature search of primary studies pertinent to the objectives of this review using the chosen data sources.Current evidence shows that OD is highly prevalent in COVID-19, with up to 80% of patients reporting subjective OD and objective olfactory testing potentially showing even higher prevalence. OD is frequently accompanied by taste dysfunction. Up to 25% of COVID-19 patients may experience sudden-onset OD as the first symptom. A large proportion of COVID-19 OD cases may resolve over the period of a few weeks.Sudden anosmia should be considered a symptom of COVID-19. Assessing for sudden-onset anosmia may increase sensitivity of COVID-19 screening strategies, in particular for identifying patients at the earliest stages of disease. Since many cases of OD due to COVID-19 may resolve in the short term, conservative management, including observation, is reasonable, while advanced imaging is unnecessary.

Background Spastic cerebral palsy is the most common cause of motor disability in children. It often leads to foot drop or equinus, interfering with walking. Ankle-foot orthoses (AFOs) are commonly used in these cases. However, AFOs can be too restrictive for mildly impaired patients. Functional electrical stimulation (FES) of the ankle-dorsiflexors is an alternative treatment as it could function as a dynamic functional orthosis. Despite previous research, high level evidence on the effects of FES on activities and participation in daily life is missing. The primary aim of this study is to evaluate whether FES improves the activity and participation level in daily life according to patients, and the secondary aim is to provide evidence of the effect of FES at the level of body functions and activities. Furthermore, we aim to collect relevant information for decisions on its clinical implementation. Methods A randomized crossover trial will be performed on 25 children with unilateral spastic cerebral palsy. Patients aged between 4 and 18 years, with Gross Motor Functioning Classification System level I or II and unilateral foot drop of central origin, currently treated with AFO or adapted shoes, will be included. All participants will undergo twelve weeks of conventional treatment (AFO/adapted shoes) and 12 weeks of FES treatment, separated by a six-week washout-phase. FES treatment consists of wearing the WalkAide® device, with surface electrodes stimulating the peroneal nerve during swing phase of gait. For the primary objective, the Goal Attainment Scale is used to test whether FES improves activities and participation in daily life. The secondary objective is to prove whether FES is effective at the level of body functions and structures, and activities, including ankle kinematics and kinetics measured during 3D-gait analysis and questionnaire-based frequency of falling. The tertiary objective is to collect relevant information for clinical implementation, including acceptability using the device log file and side effect registration, cost-effectiveness based on quality adjusted life years (QALYs) and clinical characteristics for patient selection. Discussion We anticipate that the results of this study will allow evidence-based use of FES during walking in children with unilateral spastic cerebral palsy. Trial registration ClinicalTrials.gov: NCT03440632.

Resident alveolar macrophages (AMs) suppress allergic inflammation in murine asthma models. Previously we reported that resident AMs can blunt inflammatory signaling in alveolar epithelial cells (ECs) by transcellular delivery of suppressor of cytokine signaling 3 (SOCS3) within extracellular vesicles (EVs). Here we examined the role of vesicular SOCS3 secretion as a mechanism by which AMs restrain allergic inflammatory responses in airway ECs. Bronchoalveolar lavage fluid (BALF) levels of SOCS3 were reduced in asthmatics and in allergen-challenged mice. Ex vivo SOCS3 secretion was reduced in AMs from challenged mice and this defect was mimicked by exposing normal AMs to cytokines associated with allergic inflammation. Both AM-derived EVs and synthetic SOCS3 liposomes inhibited the activation of STAT3 and STAT6 as well as cytokine gene expression in ECs challenged with IL-4/IL-13 and house dust mite (HDM) extract. This suppressive effect of EVs was lost when they were obtained from AMs exposed to allergic inflammation-associated cytokines. Finally, inflammatory cell recruitment and cytokine generation in the lungs of OVA-challenged mice were attenuated by intrapulmonary pretreatment with SOCS3 liposomes. Overall, AM secretion of SOCS3 within EVs serves as a brake on airway EC responses during allergic inflammation, but is impaired in asthma. Synthetic liposomes encapsulating SOCS3 can rescue this defect and may serve as a framework for novel therapeutic approaches targeting airway inflammation.

BACKGROUND Even with a high-quality instrument, such as the 22-item Sino-Nasal Outcome Test (SNOT-22), patients can be overwhelmed by repeated completion of questionnaires, leading to nonadherence and reduced data quality. The aim of this study was to evaluate whether the SNOT-22 could be made more concise without losing the valuable information that it provides. METHODS A modern psychometric approach, item response theory (IRT), was used on a sample of 800 patients with chronic rhinosinusitis (CRS). The SNOT-22 was refined based on: (1) the item information criteria, retaining only items with above-average information; and (2) the total test information, retaining only the most discriminating items to cover at least 30% of the information within each subdomain. The preliminary validity and reliability of these refined scales were assessed using Cronbach's alpha and Pearson's correlation. RESULTS Using an IRT approach, we find that it may be possible to shorten the SNOT-22 to an 11-item and six-item version based on psychometric properties. Item information functions of the shortened 11-item and six-item scales demonstrate that both versions accurately covered the CRS symptom-severity continuum. Preliminary reliability and validity analysis showed that both refined scales had good to excellent reliability (Cronbach's alpha ≥ 0.80) and were highly associated with the original full-length scale (r ≥ 0.90). CONCLUSION IRT provides data-driven opportunities for the continuous development and refinement of the SNOT-22. While patient and provider input must be accounted for too, our results show that future revisions of the SNOT-22 could include significantly fewer items.

Supramalleolar osteotomy (SMO) in pediatric patients can be fixed in various ways. We analyzed the records of 77 pediatric patients (124 SMOs) aged &le, 16 years. In 56 patients (96 SMOs), K-wires were used to stabilize SMOs (WF group), while 21 patients (28 SMOs) were treated with locking compression plates (LCPs, PF group). We recorded time to radiographic consolidation, rate of complications, length of hospital stay (LOS), and time to implant removal. Mean time to radiographic consolidation of SMOs was 7.2 weeks in the WF group and 11.1 weeks in the PF group. Complication rate in the WF group was 10.7%. LOS was similar in the two groups (7.0 days in the WF group vs. 7.3 days in the PF group). K-wire stabilization resulted in a shortened interval until consolidation of osteotomies, but children were required to use a cast. Stabilization of SMOs with LCPs facilitated early mobilization and functional rehabilitation with no need to apply a cast. In conclusion, both methods provided safe fixation of SMOs with a low rate of complications. K-wire stabilization combined with a cast achieves fast consolidation of SMOs. We recommend SMO stabilization with angular stable LCPs in patients with muscular weakness or spasticity in whom early mobilization and physiotherapy are necessary to prevent loss of muscle power, muscle function, and bone mass.

BackgroundIn contrast with the setting of acute myocardial infarction, there are limited data regarding the impact of diabetes mellitus on clinical outcomes in contemporary cohorts of patients with chronic coronary syndromes. We aimed to investigate the prevalence and prognostic impact of diabetes according to geographical regions and ethnicity.Methods and resultsCLARIFY is an observational registry of patients with chronic coronary syndromes, enrolled across 45 countries in Europe, Asia, America, Middle East, Australia, and Africa in 2009–2010, and followed up yearly for 5 years. Chronic coronary syndromes were defined by ≥1 of the following criteria: prior myocardial infarction, evidence of coronary stenosis >50%, proven symptomatic myocardial ischaemia, or prior revascularization procedure.Among 32 694 patients, 9502 (29%) had diabetes, with a regional prevalence ranging from below 20% in Northern Europe to ∼60% in the Gulf countries. In a multivariable-adjusted Cox proportional hazards model, diabetes was associated with increased risks for the primary outcome (cardiovascular death, myocardial infarction, or stroke) with an adjusted hazard ratio of 1.28 (95% confidence interval 1.18, 1.39) and for all secondary outcomes (all-cause and cardiovascular mortality, myocardial infarction, stroke, heart failure, and coronary revascularization). Differences on outcomes according to geography and ethnicity were modest.ConclusionIn patients with chronic coronary syndromes, diabetes is independently associated with mortality and cardiovascular events, including heart failure, which is not accounted by demographics, prior medical history, left ventricular ejection fraction, or use of secondary prevention medication. This is observed across multiple geographic regions and ethnicities, despite marked disparities in the prevalence of diabetes.ClinicalTrials identifierISRCTN43070564

OBJECTIVES/HYPOTHESIS As a cardinal symptom of chronic rhinosinusitis (CRS), hyposmia has been recommended to be assessed as a component of CRS disease control. Herein we determine the significance of hyposmia in CRS in the context of nasal obstruction and drainage symptoms. STUDY DESIGN Prospective, cross-sectional METHODS: Cross-sectional study of 308 CRS patients (102 CRSwNP, 206 CRSsNP) without prior endoscopic sinus surgery. The burden of nasal obstruction and hyposmia were assessed using the corresponding item scores on the 22-item Sinonasal Outcome Test (SNOT-22). Burden of nasal discharge was assessed using the mean of "thick nasal discharge" and "thick post-nasal discharge" SNOT-22 item scores. Patients were all asked to rate their CRS symptom control as "not at all," "a little," "somewhat," "very," or "completely." RESULTS In CRSwNP, only 4.9% had a hyposmia score > 1 with nasal obstruction and drainage scores less than or equal to 1. In CRSsNP, only 1.9% had a hyposmia score > 1 with nasal obstruction and drainage scores less than or equal to 1. On univariate association, CRS symptom control was significantly associated with nasal obstruction, hyposmia, and drainage in both CRSwNP and CRSsNP (P

To evaluate associations between self-perceived chemosensory functions of smell, taste, and flavor perception with olfactory-specific quality of life (QoL) in patients with olfactory dysfunction (OD) and whether these associations would be influenced by other factors, such as duration or etiology of smell loss.Retrospective cohort study.Tertiary care, academic center.Olfactory-specific QoL was measured with the Questionnaire of Olfactory Disorders (QOD). The QOD measures the impact of OD on QoL (QOD-negative statements) and the ability of patients to cope with smell loss (QOD-positive statements). Orthonasal olfactory function, patients' demographics, self-perceived chemosensory perception, and duration and etiology of OD were retrospectively collected in a cohort of patients with quantitative OD. Correlations and multivariable linear regression models were computed to determine possible associations with the outcome measure of QOD-negative and QOD-positive statement scores.A total of 133 patients with OD were included. Analysis revealed a positive correlation between self-perceived taste and flavor perception with QOD-negative statement scores, while self-perceived smell showed no significant correlation. Similarly, longer duration of smell loss and higher age were also correlated with higher QOD-positive statement scores. Multivariable regression models confirmed that self-perceived taste was independently associated with the QOD-negative statement score, while age and duration of OD were independently associated with the QOD-positive statement score.These findings suggest that the impact of diminished flavor perception during eating and drinking has a stronger impact on the QoL of patients with OD as compared with decreased orthonasal olfaction.

Background The personal importance of a lost neurologic - motor or sensory - function in several conditions has been shown to decrease as the afflicted patient becomes accustomed to not having that function. It is unknown how the importance of olfaction changes with duration of olfactory dysfunction (OD). The aim of this study was to evaluate the association between duration of smell loss and individual significance of olfaction, and whether this relationship would be modulated by other factors, such as etiology of smell loss. Methods This is a retrospective study including a total 163 subjects with different degrees of olfactory function. Individual significance of olfaction was measured using the Importance of Olfaction Questionnaire (IOQ). Demographics, olfactory function, duration and etiology of OD were evaluated. Group comparisons, bivariate correlations, analyses of variance and multivariate linear regression were applied to detect differences and associations with the outcome measure of IOQ. Results A significant negative correlation was found between duration of OD and the IOQ. Other important findings include a significantly higher IOQ in patients with posttraumatic- compared to idiopathic OD and in patients with higher aggravation scores compared to the lower aggravation group. Multivariate regression analysis further confirmed that duration of smell loss was independently associated with IOQ. Conclusions The duration of smell loss is negatively correlated with the individual importance of olfaction, suggesting that patients develop coping mechanisms for adjusting to OD.

Dysregulation of self-renewal contributes to alterations in alveolar macrophages (AMs). In this study, Penke et al identify PGE2 as a suppressor of AM proliferation, whose divergent bioavailability in aged and cigarette smoke-exposed mice could explain opposite effects on AM numbers., Alveolar macrophages (AMs) are resident immune cells of the lung that are critical for host defense. AMs are capable of proliferative renewal, yet their numbers are known to decrease with aging and increase with cigarette smoking. The mechanism by which AM proliferation is physiologically restrained, and whether dysregulation of this brake contributes to altered AM numbers in pathologic circumstances, however, remains unknown. Mice of advanced age exhibited diminished basal AM numbers and contained elevated PGE2 levels in their bronchoalveolar lavage fluid (BALF) as compared with young mice. Exogenous PGE2 inhibited AM proliferation in an E prostanoid receptor 2 (EP2)-cyclic AMP-dependent manner. Furthermore, EP2 knockout (EP2 KO) mice exhibited elevated basal AM numbers, and their AMs resisted the ability of PGE2 and aged BALF to inhibit proliferation. In contrast, increased numbers of AMs in mice exposed to cigarette smoking were associated with reduced PGE2 levels in BALF and were further exaggerated in EP2 KO mice. Collectively, our findings demonstrate that PGE2 functions as a tunable brake on AM numbers under physiologic and pathophysiological conditions.

Alveolar macrophages (AMs) and epithelial cells (ECs) are the lone resident lung cells positioned to respond to pathogens at early stages of infection. Extracellular vesicles (EVs) are important vectors of paracrine signaling implicated in a range of (patho)physiologic contexts. Here we demonstrate that AMs, but not ECs, constitutively secrete paracrine activity localized to EVs which inhibits influenza infection of ECs in vitro and in vivo. AMs exposed to cigarette smoke extract lost the inhibitory activity of their secreted EVs. Influenza strains varied in their susceptibility to inhibition by AM‐EVs. Only those exhibiting early endosomal escape and high pH of fusion were inhibited via a reduction in endosomal pH. By contrast, strains exhibiting later endosomal escape and lower fusion pH proved resistant to inhibition. These results extend our understanding of how resident AMs participate in host defense and have broader implications in the defense and treatment of pathogens internalized within endosomes.

OBJECTIVE The objective of this study was to determine the burden of depressed mood and anxiety in COVID-19, and associated disease characteristics. MATERIALS AND METHODS This is a prospective, cross-sectional study of 114 COVID-19 positive patients diagnosed using RT-PCR-based testing over a 6-week period. The two-item Patient Health Questionnaire (PHQ-2) and the two-item Generalized Anxiety Disorder questionnaire (GAD-2) were used to measure depressed mood and anxiety level, respectively, at enrollment and for participants' baseline, pre-COVID-19 state. Severity of smell loss, loss of taste, nasal obstruction, rhinorrhea/mucus production, fever, cough, and shortness of breath (SOB) during COVID-19 were assessed. RESULTS PHQ-2 and GAD-2 significantly (P

Chronic rhinosinusitis (CRS) disease burden is associated with pulmonary status in asthmatic CRS patients. Asthma-related emergency department (ED) usage is a predictor of asthma-related mortality. We sought to determine whether measures of CRS disease burden are associated with asthma-related ED usage. We prospectively recruited 263 asthmatic CRS patients for this cross-sectional study. CRS burden was measured using the 22-item Sinonasal Outcome Test (SNOT-22), and patient-reported CRS-related antibiotic usage and CRS-related oral corticosteroids usage over the preceding year. Asthma-related ED visits over the prior year were also assessed. Of all participants, 18.6% had at least 1 asthma-related ED visit (mean 0.3 ED visits for the whole cohort). Asthma-related ED usage was associated with SNOT-22 score [adjusted rate ratio (RR) = 1.02, 95% CI 1.01–1.03, p = 0.040] and CRS-related oral corticosteroids usage in the past year (RR = 1.52, 95% CI 1.26–1.83, p

By now, the 2019 novel coronavirus disease (COVID-19), caused by the SARS-CoV-2 virus, is widely recognized around the world as a pandemic that has infected millions and claimed the lives of hundreds of thousands (1). Despite months of mitigation strategies, COVID-19 continues to spread and ascertainment of new knowledge about the disease process continues to be a priority of the medical community. Originally described by characteristic symptoms of fever, cough and/or shortness of breath that can rapidly progress to acute respiratory distress syndrome, it has become clear that COVID-19 has manifold clinical presentations (2-4). Notably, olfactory dysfunction (OD) "decreased sense of smell" has been reported to occur in up to 85.6% of COVID-19 patients (2,5).

Objective Olfactory dysfunction (OD)—hyposmia or anosmia—is a symptom of coronavirus disease 2019 (COVID-19), caused by the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We sought to better determine prevalence, severity, and timing of OD in COVID-19 relative to other sinonasal and pulmonary symptoms. Study Design Prospective, cross-sectional. Setting Regional/cantonal hospital. Subjects In total, 103 patients diagnosed with COVID-19 with reverse transcription polymerase chain reaction (RT-PCR)–based testing. Methods All patients testing positive for COVID-19 at Kantonsspital Aarau over a 6-week period were approached. Timing and severity (at its worst, on scale of 0 [none], 1 [mild], 2 [moderate], and 3 [severe]) of OD, loss of taste, nasal obstruction, rhinorrhea/mucus production, fever, cough and shortness of breath (SOB) were assessed for each patient. Results Prevalence of OD was 61.2%, and severity of OD was strongly correlated with severity of loss of taste experienced (ρ = 0.87, P < .001). OD was experienced on the first day of COVID-19 by 8.7% and overall occurred at median infection day 3 (mean, 3.4; range, 0-12). Most experiencing OD reported anosmia, and mean severity of all with OD was moderate to severe (mean [SD], 2.7 [0.6]). Nasal obstruction (49.5%) and rhinorrhea (35.0%) were frequently reported but not correlated with OD. SOB was more severe in patients with OD. OD was associated negatively with older age (OR, 0.96; 95% CI, 0.93-0.99; P = .007) and positively with female sex (OR, 2.46; 95% CI, 0.98-6.19; P = .056). Conclusions OD is highly prevalent during COVID-19, occurring early and severely, often in conjunction with loss of taste. OD is associated negatively with older age and positively with female sex. Patients with OD may also experience more severe SOB.

Objective The ongoing pandemic of coronavirus disease (2019 coronavirus disease [COVID‐19]), caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV‐2) virus, is highly contagious with high morbidity and mortality. The role of the nasal and paranasal sinus cavities is increasingly recognized for COVID‐19 symptomatology and transmission. We therefore conducted a systematic review, synthesizing existing scientific evidence about sinonasal pathophysiology in COVID‐19. Study Design Systematic review. Methods Systematic searches were performed of all indexed studies in PubMed/Medline and Cochrane databases through 28 March 2020 and studies searchable on http://preprints.com (including ArXiv and Scilit repositories) through 30 March 2020. Data extraction focused on sinonasal pathophysiology in COVID‐19. Results A total of 19 studies were identified. The sinonasal cavity may be a major site of infection by SARS‐CoV‐2, where susceptibility genes required for infection are expressed at high levels and may be modulated by environmental and host factors. Viral shedding appears to be highest from the nose, therefore reflecting a major source for transmission. This has been highlighted by multiple reports of health care‐associated infection (HAI) during rhinologic procedures, which are now consequently considered to be high risk for SARS‐CoV‐2 transmission to health care workers. While sinonasal symptomatology, such as rhinorrhea or congestion, appears to be a rarer symptom of COVID‐19, anosmia without nasal obstruction is reported as highly specific predictor of COVID‐19+ patients. Conclusion Sinonasal pathophysiology is increasingly important in our understanding of COVID‐19. The sinonasal tract may be an important site of infection while sinonasal viral shedding may be an important transmission mechanism—including HAI. Anosmia without nasal obstruction may be a highly specific indicator of COVID‐19. Level of Evidence 2a.

Previous work has shown that the symptoms of chronic rhinosinusitis (CRS) differentially associate with decreased general health-related quality of life (QOL).We sought to determine whether longitudinal changes in different types of CRS symptomatology lead to correspondingly different magnitude changes in general health-related QOL.Prospective observational study of 145 patients undergoing medical management for CRS. Chronic rhinosinusitis symptom severity was measured using the 22-item Sinonasal Outcome Test (SNOT-22) and associated nasal, sleep, ear/facial discomfort, and emotional subdomains of the SNOT-22. General health-related QOL was measured using the 5-dimensional EuroQoL questionnaire's visual analog scale (EQ-5D VAS). These data were collected at 2 time points: at enrollment and at a subsequent follow-up visit within the next 2 to 6 months. Associations were sought between the changes in SNOT-22 and EQ-5D VAS.The change in SNOT-22 was associated with change in EQ-5D VAS (adjusted linear regression coefficient [β] = -0.37, 95%CI: -0.51 to -0.24, P .001). The change in EQ-5D VAS was only associated with changes in the sleep (adjusted β = -0.42, 95% confidence interval [95%CI]: -0.81 to -0.04, P = .034) and ear/facial discomfort (adjusted β = -1.00, 95%CI: -1.89 to -0.10, P = .031) subdomains but not nasal (adjusted β = -0.12, 95%CI: -0.52 to 0.28, P = .564) or emotional (adjusted β = -0.17, 95%CI: -1.83 to 1.49, P = .840) subdomains.Changes in the severity of sleep and ear/facial discomfort symptoms associate most greatly with the change in general health-related QOL that CRS patients experience during routine medical management. Reduction of these extranasal symptoms of CRS may therefore lead to the greatest improvement in general health-related QOL.

Recalcitrance of allergic rhinitis (AR) to medical management may be reflective of patient-specific impact of AR symptoms. To understand the relationship between AR symptoms and general health-related quality of life (QOL) or AR control, based on treatment status. Cross-sectional cohort study of 130 adult participants—65 using no allergy medications and 65 consistently using intranasal corticosteroid sprays (ICS) in the last 3 months—presenting with persistent AR. General health-related QOL was measured using the EuroQol 5-dimensional visual analog scale (EQ-5D VAS). Severity and control of AR symptoms were measured using the 22-item Sinonasal Outcome Test (SNOT-22) and the Rhinitis Control Assessment Test (RCAT), respectively. We compared associations between AR symptoms and general health-related QOL and AR control in patients presenting with persistent AR with and without ICS use. Severity of AR symptoms was similar between cohorts. In participants using no allergy medications, extranasal AR symptom severities were most dominantly associated with decreased EQ-5D VAS and RCAT score. In participants using ICS, only nasal symptom severities were associated with decreased EQ-5D VAS and RCAT scores. Consistently, only in participants on ICS was a deviated septum associated with decreased EQ-5D VAS (β = − 12.1, 95% CI − 21.1 to − 3.1, p = 0.011) and poorly controlled AR (OR = 4.27, 96% CI 1.27 to 14.33; p = 0.019). In persistent AR despite consistent ICS use, nasal symptoms may be the dominant drivers of AR-associated decreased general health-related QOL in contrast to persistent AR on no medication, when extranasal symptoms of AR are most significant. Longitudinal study is needed to investigate whether these results are predictive of responsiveness to ICS.

Endothelial cells (ECs) are components of the hematopoietic microenvironment and regulate hematopoietic stem and progenitor cell (HSPC) homeostasis. Cytokine treatments that cause HSPC trafficking to peripheral blood are associated with an increase in dipeptidylpeptidase 4/CD26 (DPP4/CD26), an enzyme that truncates the neurotransmitter neuropeptide Y (NPY). Here, we show that enzymatically altered NPY signaling in ECs caused reduced VE-cadherin and CD31 expression along EC junctions, resulting in increased vascular permeability and HSPC egress. Moreover, selective NPY2 and NPY5 receptor antagonists restored vascular integrity and limited HSPC mobilization, demonstrating that the enzymatically controlled vascular gateway specifically opens by cleavage of NPY by CD26 signaling via NPY2 and NPY5 receptors. Mice lacking CD26 or NPY exhibited impaired HSPC trafficking that was restored by treatment with truncated NPY. Thus, our results point to ECs as gatekeepers of HSPC trafficking and identify a CD26-mediated NPY axis that has potential as a pharmacologic target to regulate hematopoietic trafficking in homeostatic and stress conditions.

Using Tibialis Anterior Shortening (TATS) in combination with Achilles Tendon Lengthening (TAL) to treat spastic equinus in children with cerebral palsy (CP) was described in 2011. Short-term results have indicated a good outcome, especially an improvement of the drop foot in swing phase and the correction of equinus in stance phase. The aim of this study was to analyse the results of the long-term follow-up and to determine the relapse rate of TATS and TAL. The kinematics of the sagittal, frontal and transversal planes were measured by using instrumented 3D gait analysis at three defined time points and then described using the Gait Profile Score (GPS) and Movement Analysis Profile (MAP). The data was exported into Gaitabase and then the preoperative (T0), short- term (T1) and long-term (T2) follow-up data was statistically compared. 23 patients (mean age at index-surgery=14.9years) were included, there was a mean follow-up time of 5.8 years. 3 children (13%) have shown a relapse. The data of 12 children with spastic hemiplegia (12 legs), as well as 8 children with spastic diplegia (10 legs) has been analysed. There has been a significant (p

Background The impact of specific allergic rhinitis symptoms on patient quality of life (QOL) is currently unknown. Objective In this study, we sought to determine the association between nasal and extranasal symptoms of allergic rhinitis with general health–related QOL. Methods A total of 150 participants with ages > 18 years and persistent allergic rhinitis were prospectively recruited for this cross-sectional study. General health–related QOL was measured by using the visual analog scale (VAS) from the five-dimension EuroQol QOL survey (EQ-5D). The severity of nasal and extranasal symptoms was measured by using the 22-item Sino-Nasal Outcome Test (SNOT-22). The severity of nasal obstruction was measured by using the Nasal Obstruction Severity Evaluation (NOSE) scale. Each participant also completed a Rhinitis Control Assessment Test (RCAT). Results The total SNOT-22 score was significantly correlated with RCAT (r = -0.68 [95% confidence interval {CI}, -0.75 to -0.58]; p < 0.001) and EQ-5D VAS (r = -0.44 [95% CI, -0.56 to -0.30]; p < 0.001). Of the 22 symptoms assessed on the SNOT-22, sleep-related symptoms, and otologic symptoms were associated with the greatest decrease in general health–related QOL. Nasal symptoms were least associated with general health–related QOL. The symptom of nasal obstruction was not at all associated with general health–related QOL (p = 0.267). We confirmed this finding by showing no significant correlation between the NOSE score and EQ-5D VAS (r = -0.05 [95% CI, -0.21 to 0.12]; p = 0.582). Conclusion Sleep and otologic symptoms were associated with the greatest negative impact on QOL in adults with persistent allergic rhinitis and should be routinely assessed in their clinical evaluation.

PURPOSE: To investigate the effects of Hybrid-Constrained Induced Movement Therapy (H-CIMT), defined as CIMT combined with Bimanual Intensive Movement Therapy (BIMT), on grip and pinch strength and fatigability we measured grip and pinch strength and fatigability during clinical H-CIMT.METHODS: The children participated in a H-CIMT model organized in a therapeutic summer-camp. Children received 90 hours of intensive treatment. Grip and pinch strength and fatigability was measured and fatigue was calculated according to a Static Fatigue Index (SFI).RESULTS: Pinch strength significantly increased, grip strength did not increase significantly. A non-significant decrease was seen in SFI in pinch and grip.CONCLUSIONS: H-CIMT showed to be effective in increasing muscle pinch strength in the AH. Effectiveness in decreasing muscle fatigue during grip and pinch tests is not yet shown although there was a tendency towards a decrease in muscle fatigue. However, the long-term effects on these aspects are also important in future research.

Interleukin (IL)−13 is a type 2 cytokine with important roles in allergic diseases, asthma, and tissue fibrosis. Its receptor (R) α1 is primarily responsible for the biological actions of this cytokine, while Rα2 possesses a decoy function which can block IL-13 signaling. Although the expression of Rα2 is known to be subject to modulation, information about its transcriptional regulation is limited. In this study, we sought to expand the understanding of transcriptional control of Rα2 in lung fibroblasts. We confirmed previous reports that IL-13 elicited modest induction of Rα2 in normal adult human lung fibroblasts, but found that prostaglandin E2 (PGE2) and fibroblast growth factor 2 (FGF-2) –mediators known to influence fibroblast activation in tissue fibrosis but not previously investigated in this regard – led to a much greater magnitude of Rα2 induction. Although both PGE2 (via protein kinase A) and FGF-2 (via protein kinase B, also known as AKT) depended on activation of cAMP-responsive element-binding protein (CREB) for induction of Rα2 expression, they nevertheless demonstrated synergy in doing so, likely attributable to their differential utilization of distinct transcriptional start sites on the Rα2 promoter. Our data identify CREB activation via PGE2 and FGF-2 as a previously unrecognized molecular controller of Rα2 gene induction and provide potential new insights into strategies for therapeutic manipulation of this endogenous brake on IL-13 signaling.

Background The frequencies of systemic antibiotics and oral corticosteroids taken for chronic rhinosinusitis (CRS) indicate poor CRS disease control. We sought to determine the validity and responsiveness of these metrics as reflections of CRS disease burden. Methodology One hundred and eighty-seven patients undergoing medical management for CRS were recruited. Participants were assessed at two time points: enrollment and a follow-up appointment three to nine months later. At each time point, CRS related antibiotic and oral corticosteroid usage in the previous three months was measured, while general and disease-specific quality of life (QOL) was measured using the visual analog scale of the 5-dimension EuroQol questionnaire (EQ-5D VAS) and the 22-item Sinonasal Outcome Test (SNOT-22), respectively. Results The frequency of CRS-related antibiotics and oral corticosteroids use was cross-sectionally correlated with EQ-5D VAS and SNOT-22 at the corresponding time points. For participants reporting usage of these medications at enrollment, there was a decrease of 1 course per 3 months for both CRS-related antibiotics and oral corticosteroids. Change in CRS-related antibiotics from enrollment to follow-up was correlated with change in both EQ-5D and SNOT-22 over the same timeframe. The change in CRSrelated oral corticosteroids was correlated with change in both EQ-5D VAS and SNOT-22). These correlations were stronger in the subset of patients who had a change in these metrics over the study period. Conclusions The frequencies of CRS-related antibiotic use and oral corticosteroid use are valid and responsive measures of CRS disease burden.

OBJECTIVES Chronic rhinosinusitis (CRS), like other sinonasal diseases, may be associated with avoidance of daily activities. Our goal was to identify characteristics associated with avoidance of activities due to CRS. MATERIALS AND METHODS A total of 194 CRS patients were recruited. CRS symptom burden was assessed with the 22-item Sinonasal Outcome Test (SNOT-22). SNOT-22 nasal, sleep, ear/facial discomfort and emotional/psychological subdomain scores were calculated. Depressed mood was assessed using the two-item Patient Health Questionnaire (PHQ-2). Personality traits including conscientiousness, neuroticism, agreeableness, openness, and extraversion were assessed using the Big Five Inventory-10 (BFI-10) questionnaire. As the primary outcome, participants rated how often in the prior week that they had avoided any activities in day-to-day life due to their nasal or sinus symptoms on a scale of "never," "rarely," "sometimes," "often," or "extremely often." Ordinal regression models, with bootstrap validation, were used to identify associations between activity avoidance and participants' characteristics. RESULTS On multivariable analysis, SNOT-22 score (odds ratio [OR] = 1.03, 95% CI, 1.01-1.04, P = .026), and conscientiousness personality trait (OR = 1.38, 95% CI, 1.05-1.81, P = .019) were positively associated with activity avoidance while age (OR = 0.98, 95% CI, 0.96-0.99, P = .049) was negatively associated with activity avoidance. Of CRS symptom burden/SNOT-22 subdomains, only the emotional/psychological subdomain score (OR = 1.28, 95% CI, 1.12-1.46, P

OBJECTIVES/HYPOTHESIS Antibiotics and oral corticosteroids are used in the treatment of acute exacerbations of chronic rhinosinusitis (AECRS) and reflect poor disease control. We sought to characterize utilization of these systemic medications after appropriate medical management of chronic rhinosinusitis (CRS). STUDY DESIGN Prospective observational study. METHODS One hundred fifty patients undergoing medical management for CRS were studied. Data were collected at enrollment and follow-up 3 to 12 months later. All patients were asked to report the number of CRS-related antibiotics and oral corticosteroids used in the last 3 months. CRS symptom burden was measured using the 22-item Sino-Nasal Outcome Test (SNOT-22). Associations were sought between CRS-related antibiotics and oral corticosteroids use at follow-up compared to enrollment. RESULTS From enrollment to follow-up, the mean number of CRS-related antibiotics courses used decreased by 0.2 courses (95% confidence interval [CI]: 0.1-0.4, P = .012), and the mean number of CRS-related oral corticosteroid courses used also decreased by 0.2 courses (95% CI: 0.1-0.3, P = .029). The number of CRS-related antibiotics used at follow-up was associated with CRS-related antibiotic use at enrollment (adjusted rate ratio [RR] = 1.58, 95% CI: 1.17-2.13, P = .003). The number of CRS-related oral corticosteroids used at follow-up was associated with reported CRS-related oral corticosteroid use at enrollment (adjusted RR = 3.20, 95% CI: 1.69-6.07, P

Lung cancer remains the leading cause of cancer-related death in the United States. Although the alveolar macrophage (AM) comprises the major resident immune cell in the lung, few studies have investigated its role in lung cancer development. We recently discovered a potentially novel mechanism wherein AMs regulate STAT-induced inflammatory responses in neighboring epithelial cells (ECs) via secretion and delivery of suppressors of cytokine signaling 3 (SOCS3) within extracellular vesicles (EVs). Here, we explored the impact of SOCS3 transfer on EC tumorigenesis and the integrity of AM SOCS3 secretion during development of lung cancer. AM-derived EVs containing SOCS3 inhibited STAT3 activation as well as proliferation and survival of lung adenocarcinoma cells. Levels of secreted SOCS3 were diminished in lungs of patients with non–small cell lung cancer and in a mouse model of lung cancer, and the impaired ability of murine AMs to secrete SOCS3 within EVs preceded the development of lung tumors. Loss of this homeostatic brake on tumorigenesis prompted our effort to “rescue” it. Provision of recombinant SOCS3 loaded within synthetic liposomes inhibited proliferation and survival of lung adenocarcinoma cells in vitro as well as malignant transformation of normal ECs. Intratumoral injection of SOCS3 liposomes attenuated tumor growth in a lung cancer xenograft model. This work identifies AM-derived vesicular SOCS3 as an endogenous antitumor mechanism that is disrupted within the tumor microenvironment and whose rescue by synthetic liposomes can be leveraged as a potential therapeutic strategy for lung cancer.

The effects of nasal obstruction in patients with chronic rhinosinusitis (CRS) are associated with depressed mood. We sought to validate this finding by determining whether improvement in nasal obstruction would translate to improvement in depressed mood. This was a prospective observational study of 150 patients undergoing medical management for CRS. Data were collected at two timepoints: enrollment and a subsequent follow-up visit 3–12 months later. Impact of nasal obstruction was measured using the Nasal Obstruction Symptom Evaluation (NOSE) instrument and depressed mood was measured using the 2-item Patient Health Questionnaire (PHQ-2). Sinonasal symptoms associated with CRS were also measured using the 22-item Sinonasal Outcome Test (SNOT-22). Clinical and demographic characteristics were collected. The relationship between changes in PHQ-2 and NOSE scores was determined with correlation and linear regression. Change in PHQ-2 score was significantly correlated with change in NOSE score (ρ = 0.30, p